Diet and Cancer

Livia SA Augustin, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, National Cancer Institute, Naples, Italy; Clinical Nutrition and Risk
Factor Modification Centre, St Michael’s Hospital, Toronto, On, Canada
Concetta Montagnese, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, National Cancer Institute, Naples, Italy
Ilaria Calabrese, “Federico II” University, Naples, Italy
Giuseppe Porciello, Elvira Palumbo, and Sara Vitale, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, National Cancer Institute,
Naples, Italy
Stephanie Nishi, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, National Cancer Institute, Naples, Italy; University of Toronto,
Toronto, On, Canada
© 2018 Elsevier Inc. All rights reserved.

Introduction

Dietary Carbohydrates and Glycemic Index 1

Potential Mechanisms 2
Insulin-like growth factor—1 (IGF-1) 2
Oxidative stress 2
Conclusions and Future Directions 2
References 3
Further Reading 5

Diet plays a key role in the prevention of chronic diseases including cancer. Cancer is one of the leading cause of death accounting
for 8.2 million deaths globally (International Agency for Research on Cancer, 2014). Cancer rates vary across geographical regions
and population migration studies observed a 20-fold variation in rates (Rastogi et al., 2008; Ziegler et al., 1993; King et al., 1985)
suggesting that environmental factors including diet play may be important contributors. Historically there is evidence supporting a
role of diet in carcinogenesis from observations by Peyton Rous who, in Rous (1914) found that food restriction in mice reduced
tumor metastasis (Rous, 1914), while in the 1920s obesity was found to be associated with greater cancer mortality and in the 1930s
high plant food consumption was suggested to be protective in cancer development (Stocks et al., 2009). Doll and Peto (1981)
estimated that approximately 35% of cancer deaths could be avoided by dietary modifications (Doll and Peto, 1981) and this seems
to be confirmed by more recent epidemiological studies (McCullough and Giovannucci, 2004; Willett, 1995). Generally, high
calorie diets as well as high consumption of red and processed meat are linked to increased cancer risk whereas high vegetable and
fruit intake, particularly citrus fruit and vegetables from the brassica family, are consistently found to be protective against cancer
development (Kushi et al., 2012; Pan et al., 2012; Santarelli et al., 2008; Willett, 1995; Bosetti et al., 2012; Turati et al., 2015b). There
is a paucity of data from clinical trials of diet in cancer patients owing to the challenges and high costs of such trials. Below sections
targeting nutrients, selected food groups and dietary patterns are discussed.

Dietary Carbohydrates and Glycemic Index

Amongst dietary compounds, carbohydrates have been implicated in the etiology of cancer at various sites (Franceschi et al., 1997;
Giovannucci, 1995; Augustin et al., 2002) while sources of carbohydrates such as whole grains have been found to reduce cancer
mortality in many studies and have been included in the guidelines for breast cancer recurrence of the American Cancer Society
(Runowicz et al., 2016). In a recent meta-analysis published in 2016 of ten large international epidemiological studies showed that
higher consumption of whole grains compared to low or no consumption reduced cancer mortality by 12% (Zong et al., 2016). This
suggest that not all dietary carbohydrates are the same and some may give protection while others increase risk. Specifically it has
been proposed that the extent of the blood glucose rise produced by carbohydrates and captured by the glycemic index (GI), may
play a differential role in cancer development (Augustin et al., 2002). The GI is a ranking of carbohydrate foods based on the ability
to raise blood glucose concentration by the food ingested (Jenkins et al., 1981). In equicarbohydrate amounts, low GI foods
increase blood glucose levels mildly while high GI foods result in larger rises in blood glucose and insulin (Jenkins et al., 1981).
Hyperglycemia and hyperinsulinemia have been suggested to increase cancer risk. McKeown-Eyssen (1994) and Giovannucci
(1995) independently suggested that blood glucose and insulin may be important factors promoting malignant transformation
and tumor growth. Indeed hyperglycemia, both fasting and postprandial, and even at concentrations below the diabetes threshold
have been associated with a higher risk of cancer incidence and death independent of body weight (Jee et al., 2005; Stattin et al.,
2007; Stocks et al., 2009) and cancer site (Crawley et al., 2014). A meta-analysis showed that blood glucose concentration above
110 mg/dL (6.11 mmol/L), increased risk of all cancers by 32% compared to glycemic concentrations below 110 mg/dL

Encyclopedia of Cancer, 3rd Edition https://doi.org/10.1016/B978-0-12-801238-3.65132-2 1

2 Diet and Cancer

(6.11 mmol/L) (Crawley et al., 2014). Fasting blood glucose
140 mg/dL (
7.8 mmol/L) was associated with significantly higher
(23%–29%) death rates from major cancer sites including colorectum, liver and pancreas, compared with blood glucose concen-
tration <90 mg/dL (<5.0 mmol/L) (Jee et al., 2005). Furthermore, hyperglycemia can enhance cancer progression and promotion
(Li et al., 2015), and in a dose–response meta-analysis it was shown that every 10 mg/dL (0.56 mmol/L) increase in blood glucose
concentration corresponded to a 15% increased risk of pancreatic cancer (Liao et al., 2015). Reducing hyperglycemia pharmaco-
logically by use of antihyperglycemic medications (e.g., metformin, acarbose) (Noto et al., 2012; Tseng et al., 2015) and consuming
low GI diets instead of high GI diets has shown benefits in reducing the risk of major cancers especially colorectum, breast and
endometrium (Augustin et al., 2001; Barclay et al., 2008; Turati et al., 2015a; Choi et al., 2012). Some evidence may also suggest
reduced colorectal cancer recurrence (Meyerhardt et al., 2012). The mechanisms involved in increasing risk of cancer with high GI
foods may include at least two pathways, hormonal and oxidative stress.

Potential Mechanisms
Regarding whole grains these carbohydrate foods are rich in dietary fiber, vitamins, minerals and phytochemicals which are
protective against chronic diseases (Slavin, 2003). Dietary fiber down-regulates inflammation, probably through the production
of short chain fatty acids, particularly butyrate and propionate, when fiber is fermented in the colon by gut microbiotia. There are
however other mechanisms of action beyond fiber which have been suggested and include (Fardet, 2010). Furthermore, dietary
fiber may reduce insulin resistance by decreasing the rate of carbohydrate absorption and increasing insulin-like growth factor
binding protein 3 concentrations. These mechanisms are explained further below in relation to the dietary GI.

Insulin-like growth factor—1 (IGF-1)

High GI foods induce higher glycemic and insulinemic responses and insulin is known to have growth promoting and proliferating
effects (Giovannucci, 2003; Kaaks and Lukanova, 2001) and to affect recurrence in breast cancer patients (Goodwin et al., 2002).
Insulin is able to bind to the insulin-like growth factor (IGF)-1 receptor and produce the cascade of reactions typically seen with
IGF-1 activation. IGF-1 is a peptide, similar in molecular structure to insulin, produced mainly by the liver in response to growth
hormone, but can be synthesized by almost any tissue in the body (Olivecrona et al., 1999). IGF-1 is the primary circulating growth
factor in the IGF system, comprising of other IGFs and their binding proteins, regulating cellular proliferation, differentiation and
apoptosis. Meta-analyses of recent studies confirm previous reports regarding elevated serum levels of IGF-I to be associated with an
increased risk of colorectal cancer (Chi et al., 2013; Rinaldi et al., 2010), breast cancer (Endogenous et al., 2010) and prostate cancer
(Rowlands et al., 2009). Studies in healthy people of low versus high GI diets and changes in circulating IGF-1 and its binding
proteins suggest that low GI diets beneficially affect the IGF-1 axis and therefore may lead to an environment that is less conducive
to tumor growth compared to high GI foods (Brand-Miller et al., 2005; Runchey et al., 2012).

Oxidative stress
Damage to DNA by reactive metabolites has been widely accepted as a major cause of cancer (Ames and Gold, 1991; Beckman and
Ames, 1997; Halliwell, 2007). Oxidative stress can activate a variety of transcription factors leading to the expression of over 500
different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and
antiinflammatory molecules (Reuter et al., 2010). Activation of these pathways via oxidative damage has been implicated in the
initiation, promotion, and progression of a normal cell into a tumor cell (Reuter et al., 2010; Valko et al., 2007). Consumption of
high glycemic index foods have been suggested to increase oxidative stress through formation of free radicals that are capable of
damaging biological molecules and hence initiating abnormal cell growth through gene mutation. Hyperglycemia contributes to
increased oxidative stress through an incremental generation of reactive oxygen species (ROS) during the mitochondrial oxidative
metabolism of carbohydrates which depletes antioxidant defenses (Brownlee, 2005; Ceriello et al., 1998; Title et al., 2000).
Reducing the GI of a meal using acarbose has been shown to significantly reduce markers of oxidative stress in individuals with
impaired glucose tolerance (Inoue et al., 2006; Monnier et al., 2006; Quagliaro et al., 2005). Compared to a high GI diet,
consumption of a low GI diet was associated with an increased plasma total antioxidant capacity in overweight and obese men
(Botero et al., 2009) and with a lower marker of oxidative stress in overweight and obese women (Arikawa et al., 2015).

Conclusions and Future Directions

Despite population differences in dietary habits and carbohydrate intakes low GI diets seem to protect from cancer risk compared to
high GI diets particularly for specific cancer sites: colorectum (WHS study) (Higginbotham et al., 2004), breast (ORDET and EPIC
studies) (Sieri et al., 2007; Romieu et al., 2012) and endometrium (NBSS and NHS studies) (Silvera et al., 2005; Cui et al., 2011).
Populations who could benefit the most from consuming low GI diets may be those characterized by a high prevalence of
overweight and/or obesity since the strongest associations have been found in people with higher body weight (Coleman et al.,
2014; Franceschi et al., 2001) and this is possibly due to the underling insulin resistance in people who are overweight or obese
which would result in higher insulin responses for the same dietary GI rank. In an environment characterized by sedentary behavior,
overeating and obesity, higher circulating blood glucose as a result of high GI food consumption, could represent a greater burden
for an already stressed metabolism caused by obesity and lack of physical activity. Lowering the GI of foods may therefore be
 Diet and Cancer 3

particularly relevant in affluent societies and in countries with high consumption of dietary carbohydrates as in the Mediterranean
region (Favero et al., 1997; Slimani et al., 2002; Wirfalt et al., 2002). Regarding prevention of cancer recurrence (secondary
prevention), the guidelines for cancer survivors by the American Cancer Society include foremost maintenance of a healthy body
weight, engaging in physical activity and consuming a healthy diet which are consistent with guidelines for cancer prevention and
heart disease prevention (Kushi et al., 2012). There is no mention of carbohydrate quality beyond whole grains, with regards to
longer survival. At present, there is a lack of clinical trial investigating low GI diets in secondary cancer prevention. Nevertheless,
when summarizing the mechanistic evidence linking glycemia and insulinemia to carcinogenesis and the evidence from primary
prevention studies, there is a general support for cancer protecting effects of lower fluctuations of blood glucose and insulin (Rock
et al., 2012) and hence potentially for low GI diets. Considering the longer survival of people diagnosed with cancer and therefore
their potential risk of developing or worsening other chronic conditions such as diabetes, the inclusion in cancer guidelines for a
preference of low GI whole grains and low GI carbohydrates in general would be a sensible decision.

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A systematic review. Integrative Cancer Therapies 16(1): 32–62. https://doi.org/10.1177/1534735416656052.
Bandera EV, Kushi LH, Moore DF, Gifkins DM, and McCullough ML (2007) Fruits and vegetables and endometrial cancer risk: A systematic literature review and meta-analysis.
Nutrition and Cancer 58(1): 6–21. https://doi.org/10.1080/01635580701307929.
Bloomfield HE, Koeller E, Greer N, MacDonald R, Kane R, and Wilt TJ (2016) Effects on health outcomes of a Mediterranean diet with no restriction on fat intake: A systematic review
and meta-analysis. Annals of Internal Medicine 165(7): 491–500. https://doi.org/10.7326/M16-0361.
Bravi F, Scotti L, Bosetti C, Zucchetto A, Talamini R, Montella M, Greggi S, Pelucchi C, Negri E, Franceschi S, and La Vecchia C (2009) Food groups and endometrial cancer risk:
A case-control study from Italy. American Journal of Obstetrics and Gynecology 200(3) 293 e1–7. https://doi.org/10.1016/j.ajog.2008.09.015.
Buckland G, Travier N, Cottet V, Gonzalez CA, Lujan-Barroso L, Agudo A, Trichopoulou A, Lagiou P, Trichopoulos D, Peeters PH, May A, Bueno-de-Mesquita HB, Bvan Duijnhoven FJ,
Key TJ, Allen N, Khaw KT, Wareham N, Romieu I, McCormack V, Boutron-Ruault M, Clavel-Chapelon F, Panico S, Agnoli C, Palli D, Tumino R, Vineis P, Amiano P, Barricarte A,
Rodriguez L, Sanchez MJ, Chirlaque MD, Kaaks R, Teucher B, Boeing H, Bergmann MM, Overvad K, Dahm CC, Tjonneland A, Olsen A, Manjer J, Wirfalt E, Hallmans G,
Johansson I, Lund E, Hjartaker A, Skeie G, Vergnaud AC, Norat T, Romaguera D, and Riboli E (2013) Adherence to the mediterranean diet and risk of breast cancer in the European
prospective investigation into cancer and nutrition cohort study. International Journal of Cancer 132(12): 2918–2927. https://doi.org/10.1002/ijc.27958.
Capurso C and Vendemiale G (2017) The Mediterranean diet reduces the risk and mortality of the prostate Cancer: A narrative review. Frontiers in Nutrition 4. 38. https://doi.org/
10.3389/fnut.2017.00038.
Davis-Yadley AH and Malafa MP (2015) Vitamins in pancreatic cancer: A review of underlying mechanisms and future applications. Advances in Nutrition 6(6): 774–802. https://doi.
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Dinu M, Pagliai G, Casini A, and Sofi F (2018) Mediterranean diet and multiple health outcomes: An umbrella review of meta-analyses of observational studies and randomised trials.
European Journal of Clinical Nutrition 72(1): 30–43. https://doi.org/10.1038/ejcn.2017.58.
Ferro-Luzzi A and Branca F (1995) Mediterranean diet, Italian-style: Prototype of a healthy diet. The American Journal of Clinical Nutrition 61(6 Suppl): 1338S–1345S.
Filomeno M, Bosetti C, Bidoli E, Levi F, Serraino D, Montella M, La Vecchia C, and Tavani A (2015) Mediterranean diet and risk of endometrial cancer: A pooled analysis of three Italian
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Agnoli C, Mattiello A, Tumino R, Sacerdote C, Bueno-de-Mesquita HB, Peeters PH, Weiderpass E, Gram IT, Gavrilyuk O, Quiros JR, Maria Huerta J, Ardanaz E, Larranaga N, Lujan-
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Plant Based Proteins and Cancer

Introduction 6
Plant Based Protein Sources 6
Evidence for Plant Based Protein Compared to Animal Protein and Cancer Risk 6
Potential Mechanisms of Action: Plant vs. Animal Proteins 7
Conclusions and Recommendations and Future Directions 7
References 7
Further Reading 8

Introduction

Plant based dietary patterns have been associated with reduced risk of developing several chronic diseases, including cancer.
Consistent with these findings, guidelines support dietary patterns lower in animal-based foods and higher in plant-based foods,
emphasizing beans/legumes including soy, whole grains, nuts/seeds, and vegetables, namely sources of plant protein (USDA, 2010;
USDA, 2015; Kushi et al., 2012; Schüz et al., 2015). From a global standpoint, production of plant-based proteins is considered to
have lower environmental burden, land and water requirements coupled with fewer greenhouse gas emissions, as well as having a
lower financial cost compared with animal-based proteins (Pimentel and Pimentel, 2003; Reijnders and Soret, 2003). These
reasons, along with concerns for animal welfare, likely explain the increasing interest in the potential of using plant-based protein
sources. The following focuses on cancer morbidity and mortality related to plant compared with animal protein consumption,
summarizing available evidence and considering implications for future research.

Plant Based Protein Sources

Plant-based proteins can be found in a variety of food sources, including soy beans and other legumes, nuts/seeds, whole grains
containing gluten (e.g., seitan) as well as other vegetables although the amounts are usually small (USDA Food Composition
Database, 2018). In Europe and the United States, cereals are the principal contributors to plant protein intake providing 40%–70%
of plant protein. However, animal products are still the main source of dietary protein providing between 55% and 71%, depending
on the country, with red meats contributing 16%–35% to animal protein intake (Halkjaer et al., 2009; Phillips et al., 2015;
Camilleri et al., 2013).

Evidence for Plant Based Protein Compared to Animal Protein and Cancer Risk

Numerous studies have assessed the impact of animal protein consumption on various types of cancer, however, few have focused
specifically on cancer and consumption of plant protein. Evidence regarding carcinogenic or anticarcinogenic effects of plant
compared with animal protein is mixed. Yet, protein is not consumed in isolation, but as part of a food matrix. Thus, in
epidemiological studies, it can be difficult to attribute any observed benefit solely to protein as the finding may be due to other
nutrients found in the food source. As well, findings from observational studies may be confounded since individuals consuming a
more plant-based diet may also tend to participate in “healthier” lifestyle behaviors, such as being a nonsmokers, consuming less
alcohol, having a lower body weight, being more physically active, and/or consuming a generally healthier diet, all of which may
contribute to decreased cancer risk (Tharrey et al., 2018; Davey et al., 2003). Due to these limitations the following will focus on
research where protein was explicitly the nutrient of interest in the comparison of animal and plant based dietary exposures. Much
of the available evidence for plant protein compared to animal protein in relation to specific cancers pertains to colorectal and
 Diet and Cancer 7

breast cancers. In a meta-analysis of observational studies on colorectal cancer risk, comprising 21 studies and 8187 cases, showed
no evidence of significance between dietary animal protein or vegetable protein intake (Lai et al., 2017). The association between
dietary protein sources and breast cancer risk was assessed in a meta-analysis of 46 prospective cohort studies (60,615 cases and
2,749,307 participants, with a mean follow-up of 3.9–65 years). Findings indicated higher total red meat, fresh red meat, and
processed meat intake were risk factors for breast cancer, whereas evaluation of plant protein sources showed soy protein exhibited a
protective association, and nuts (peanuts and tree nuts) had no adverse association. In terms of cancer mortality, animal and plant
protein intake has been prospectively examined in US health professionals (121,700 women and 51,529 men) followed for up to
32 years with repeated measures of dietary intake. Animal and plant protein consumption comprised 14% (9%–22%) and 4%
(2%–6%) of total energy intake, respectively. Plant protein was inversely associated with cancer mortality when age was taken into
account, however, when the model was further adjusted for dietary and lifestyle factors, such as smoking status, body mass index
and physical activity, this relationship disappeared (Song et al., 2016).

Potential Mechanisms of Action: Plant vs. Animal Proteins

The mechanisms involved require further investigation. Proposed potential mechanisms relate to: (1) the reduction and/or
displacement of animal protein intake with plant protein and (2) the food matrix within which plant protein tends to be contained.
In reducing animal protein intake it is suggested there would be a subsequent reduction of the carcinogenic byproducts from
consumption of red meats, such as heterocyclic amines and polycyclic aromatic hydrocarbons formed during high temperature
cooking (Steck et al., 2007; Zheng and Lee, 2009). Animal protein is also a source of fat and heme iron, which have been implicated
in the production of oxidative stress and inflammation, where experimental data suggest oxidative stress and inflammation have a
pro-carcinogenic role in cancer development (Farvid et al., 2014; Fonseca-Nunes et al., 2014; Hedlund et al., 2008; Negre-Salvayre
et al., 2010; Samraj et al., 2015). Plant protein is found in food matrices that tend to include dietary fiber and antioxidants, thus
possibly playing a role in cancer protection by lessening the negative effects of inflammation, insulin resistance and hyperinsuli-
nemia by reducing IGF-1 concentrations, as well as oxidative damage. Additionally, plant foods are known to contain antioxidants,
including vitamin C, vitamin E, and carotenoids, yet many plant proteins and peptides have also been identified as novel
antioxidant agents, and are thought to contribute to carcinogenic protection by interfering with oxidative damage to DNA, lipids,
and proteins (Lu et al., 2010; Zhang et al., 2010; Xue et al., 2009).

Conclusions and Recommendations and Future Directions

It is important for overall population health to continue to support dietary patterns with lower animal-based foods and higher
plant-based foods (USDA, 2010; USDA, 2015; Kushi et al., 2012; Schüz et al., 2015). Cancer specific recommendations still require
further research, yet, at this time it appears that consumption of plant-based proteins do not have adverse results thus supporting
their intake. Higher quality research is recommended, differentiating cancer types and investigating cancer mortality rates for high
versus low vegetable protein consumption.

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8 Diet and Cancer

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Further Reading

King DE, Egan BM, Woolson RF, et al. (2007) Effect of a high-fiber diet vs a fiber-supplemented diet on C-reactive protein level. Archives of Internal Medicine 167: 502–506.

Soy Foods and Cancer

Mechanisms of Action 9
Conclusions and Recommendations 10
Future Directions 10
References 10
Further Reading 11

Over the years epidemiological studies have consistently shown health benefits of soy foods related to the prevention of chronic
diseases, including cancer (Messina, 2010). Of particular interest for human health are soy isoflavones, bioactive compounds in
soybeans, that have shown anticancer properties due to their estrogen-like activity, as well as their ability to modulate cell cycle,
apoptosis, differentiation, proliferation, and cell signaling (Rizzo and Baroni, 2018). Breast cancer incidence rates are lower in soy
food consuming countries such as Asian populations (Pisani et al., 1999). Asian epidemiologic studies show that higher soy
consumption is associated with an approximate one-third reduction in breast cancer risk (Chen et al., 2014). Opposite, in last
decades, as Westernization of Asian cultures has occurred, breast cancer rates among Asian populations have steadily increased.
In 1995 the “early intake” hypothesis emerged, in animal models, that exposure to soy isoflavones early in life reduce breast cancer
risk (Lamartiniere et al., 1995a, b, 2000). Data from epidemiological studies indicate that higher soy intake early in life, such as
during childhood and/or adolescence, is associated with 25%–60% reductions in risk (Wu et al., 2002; Shu et al., 2001; Lee et al.,
2009). The “early-intake” hypothesis could also explain discrepancies in epidemiologic data from different countries. The estrogen-
like activity of isoflavones by soybeans is at the base of data reporting soy isoflavones adversely affect the prognosis of breast cancer
patients. Results from animal studies indicate that isoflavones activity stimulates the growth of existing mammary tumors (Ju et al.,
2001; Allred et al., 2001; Helferich et al., 2008). However, results from in vitro and animal studies are controversial and not in line
with human studies. The European Prospective Investigation into Cancer and Nutrition Study cohort (EPIC) reported no increase in
cancer risk with higher soy isoflavone intake (Zamora-Ros et al., 2013). Regarding the association between soy food intake in breast
cancer patients, clinical and prospective epidemiological data clearly show that soy consumption after breast cancer diagnosis was
associated with reductions in breast cancer recurrence and beneficial effects were similar in Asian and non-Asian populations (Guha
et al., 2009; Caan et al., 2011; Shu et al., 2009; Kang et al., 2010; Zhang et al., 2012). A meta-analysis of five cohort studies showed
 Diet and Cancer 9

that soy isoflavones intake might be associated with lower recurrence in ER negative, ER þ/PR þ breast cancer (Chi et al., 2013).
Furthermore, it is reported that exposure to soy isoflavones was associated with reduced mortality and reduced cancer recurrence
also in women with ER(þ) and ER() breast cancer (Messina, 2016a, b; Shu et al., 2009). Results from in vivo studies shown that
isolated isoflavones possibly interfere with the efficacy of tamoxifene, an antiestrogen prescribed to women with ER þ tumors
(Ju et al., 2008; Jones et al., 2002), whereas other studies in humans report benefits of combined soy food intake and tamoxifen
therapy use on the inhibition of breast cancer growth improving pharmacological efficacy (Kang et al., 2010; Nechuta et al., 2012).
As for breast cancer, prostate cancer incidence varies throughout the world and it appear higher in Western countries than in the
Asian population. Specifically, the higher soy food intake in Asian population is associated with as much as a 50% reduction in
prostate cancer risk (Zhang et al., 2016) even if prostate cancer has a lower incidence rate in Asian population and this phenomenon
has been linked to difference in intestinal bacteria responsible for conversion of daidzein to equol in the gut (Akaza, 2012). Clinical
studies indicate that isoflavone exposure has beneficial effects in prostate cancer patients (Messina et al., 2006; Kwan et al., 2010; Ide
et al., 2010). A recent meta-analysis supports the existing evidence which indicates that the total soy food intake is associated with
reduced prostate cancer risk (Applegate et al., 2018). Nevertheless, some studies reported controversial results on the effects of soy
on prostate cancer (Bosland et al., 2010; Fleshner et al., 2011). Differences in study designs limit the implications of results.
The European Food Safety Agency (EFSA) commented on the possible association between the intake of isoflavones and adverse
effect on sex-hormone responsive tissues (such as breast and endometrium), after reviewing 25 clinical studies and concluded that
35–150 mg per day of isoflavones from supplements do not adversely affect the endometrium (EFSA Panel on Food Additives and
Nutrient Sources added to Food ANS, 2015). No effect of oral isoflavone supplementation on endometrial thickness overall was found
in a meta-analysis of 23 randomized controlled trials in peri- and postmenopausal women (Liu et al., 2016). Moreover, data from a
meta-analysis of 10 observational studies found that dietary soy isoflavones from soy beans and soy foods were inversely associated
with endometrial cancer risk, and the protective effects were found for both Asian and non-Asian populations.
Evidence reported from a meta-analysis of 17 epidemiologic studies (including case-control and prospective cohort studies)
revealed that soy isoflavone consumption, particularly with soy foods/products, was significantly associated also with reduced risk
of colorectal cancer in Asian populations (Yu et al., 2016). Another meta-analysis of prospective studies showed higher isoflavone
intakes significantly decreased the risk of stomach and lung cancer while nearly significantly decreased the risk of breast and
colorectal cancer (Grosso et al., 2017).

Mechanisms of Action

Many biological explanations have been proposed for the cancer protective effects of soy foods (Grosso et al., 2017). Soy isoflavones
play a competitive role with endogenous estrogens for binding of estrogen receptors (ERs) and stimulate cell proliferation (Trock
et al., 2006; Taylor et al., 2009; Guha et al., 2009). Isoflavones act as weak ER agonists or antagonists, depending on the cell type and
estrogen environment (Larkin et al., 2008). ER agonist/antagonist properties of isoflavones have been widely studied and because of
their tissue-selective effects isoflavones are classified as selective ER modulators. Soy may act as an ER antagonist (Dorjgochoo et al.,
2011) and soy isoflavones intake was associated with protective effects in both ER  and ER þ breast cancer patients (Chi
et al., 2013).
The mechanisms by which soy intake may improve the prognosis of breast cancer patients is not obvious, taking into account
also data showing a lack of effect of isoflavones on breast cancer markers. To date, neither soy protein nor isoflavones supplements
seem to affect markers of breast cancer including mammographic density and breast cell proliferation (Hooper et al., 2010; Wu
et al., 2015; Sartippour et al., 2004; Palomares et al., 2004; Cheng et al., 2007; Khan et al., 2012). Different mechanisms have been
proposed to explain the role that isoflavones may play in prostate cancer prevention and modulation. Clinical and animal studies
report that isoflavones are able to inhibit metastasis (Xu et al., 2009; Jin et al., 2013). Also, cell-based studies show that
phytoestrogens exert a chemopreventive effect through binding ERb, expressed in prostate epithelial cells, regulating genes that
control cell cycle and apoptosis (Applegate et al., 2018; Mahmoud et al., 2014).
Several mechanisms for the protective role of early isoflavone exposure have been proposed (Messina and Hilakivi-Clarke,
2009). The protective effect of early isoflavone exposure may be related to isoflavones ability to impact mammary gland
development, changing cells in ways that make them permanently less likely to be transformed into cancer cells. Early life exposure
to phytoestrogens has been demonstrated to impact mammary gland development through accelerated terminal end bud differ-
entiation. Furthermore, many similarities between the protective effect of early isoflavone exposure and early pregnancy have been
observed (De Assis et al., 2011; Rahal and Simmen, 2011; Mishra et al., 2011).
Soy isoflavones also act independently of ER activity exhibiting antiproliferative, antioxidant and antiinflammatory properties
in vitro and in vivo (Guha et al., 2009; Rizzo and Baroni, 2018; Zaheer and Humayoun Akhtar, 2017). Isoflavones act as
antioxidants and reduce the long-term cancer risk by preventing DNA damage. Genistein in particular is a potent antioxidants
and it seems to increase the production of SOD which removes free radicals from cells (Zaheer and Humayoun Akhtar, 2017).
Isoflavones interact with epigenetic modifications, such as hypermethylation of tumor suppressor genes. In vitro studies have
demonstrated that phytoestrogens act on chromatin and modify transcription through the demetylation and acetylation of histones
in breast cancer cell lines (Dagdemir et al., 2013; Zaheer and Humayoun Akhtar, 2017; Grosso et al., 2017).
10 Diet and Cancer

Conclusions and Recommendations

Evidence indicates that soy foods, mainly by virtue of their isoflavones content, as having a number of health benefits. Despite the
many benefits, soy foods have not been embraced by the medical community. Mainly the estrogen-like properties of isoflavones has
led to concerns that soy may exert untoward effects in some subpopulation (e.g., postmenopausal women), increasing breast cancer
risk and getting worse the prognosis of breast cancer patients. As a result, clinicians treating breast cancer patients frequently caution
them to either avoid soy foods or use them in moderation. However, evidence published over the past decades indicates the safety of
isoflavones exposure with respect to breast and endometrial cancer. The position of AICR and WFRC are that soy foods are safe and
even beneficial if consumed by women with a breast cancer diagnosis (American Institute for Cancer Research (AICR); World Cancer
Research Fund International (WCRF). In 2015, after a literature evaluation, EFSA concluded that isoflavones do not adversely affect
the breast, uterus and thyroid (the three organs that were investigated) in peri and postmenopausal women (EFSA Panel on Food
Additives and Nutrient Sources added to Food ANS, 2015). Clinical studies did not support the hypothesis of an increased risk of
breast cancer and supplementation with 150 mg/day of soy isoflavones (up to 30 months) of had no adversely effect on
endometrial thickness and in the uterus (EFSA Panel on Food Additives and Nutrient Sources added to Food ANS, 2015).
As suggested by the early hypothesis, it could be reasonable to encourage young women to consume one serving per day of soy
foods because epidemiological data suggest it may be protective. However, the consumption of a variety of soy foods, such as soy
flour and tofu, should be encouraged rather than purified forms of phytoestrogens. A moderate consumption of soy foods, such as
one to two standard servings daily of soy foods (one serving averages approximately 25 mg isoflavones) is not links to increased
breast cancer risk.

Future Directions

Although soy and isoflavones offer health benefits to humans, controversial results from different studies have raised doubts about
the validity of such health claims. More studies are therefore needed to clarify the controversial results. Nutraceutical values of
soybean, including isoflavone content of soy foods, can vary considerably due to the soybean type, cultivar and food processing.
Labeling of soy foods with isoflavones concentrations could be a helpful information for consumers and scientists. Dietary
guidelines for soy foods and soy isoflavones consumption may improve cancer prevention and management.

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Further Reading

American Institute for Cancer Research (AICR). (2018) Soy is Safe for Breast Cancer Survivors. Available online: http://www.aicr.org/press/press-releases/soy-safe-breast-cancer-
survivors.html (accessed on 14 April 2018).
12 Diet and Cancer

Macias V, Kajdacsy-Balla A, Lumey LH, et al. (2013) Effect of soy protein isolate supplementation on biochemical recurrence of prostate cancer after radical prostatectomy:
A randomized trial. JAMA 310: 170–178.
World Cancer Research Fund International (WCRF). Breast cancer survivors. Available online: http://www.wcrf.org/int/research-we-fund/continuous-update-project-findings-reports/
breast-cancer-survivors (accessed on 14 April 2018).

Dietary Fats

Dietary Fats and Cancer Prevention 12

Saturated Fatty Acids 12
Monounsaturated Fat (MUFA) 13
Polyunsaturated Fat PUFA 13
Trans-Fatty Acid 13
Cholesterol 13
Mechanisms of Action 14
Guidelines and Recommendations 14
References 14
Further Reading 15

Dietary fats include oils, butter and lard. They are composed of a 3-carbon backbone to which fatty acids are attached. Fatty acids are
formed by long, short or medium hydrocarbon or aliphatic chain linked to a carboxylic acid end. The aliphatic chain of fatty acids
can present double or single bonds between their carbon molecules, indicating unsaturated fats or saturated fats (SFA), respectively.
Fatty acids with one double bound are called monounsaturated fats (MUFA), while polyunsaturated fats (PUFA) are fatty acids with
more than one double bound. A type of unsaturated fat that occurs in small amounts in nature are trans-unsaturated fatty acids,
with one or more of their double bonds in the “trans” rather than the common “cis” configuration. Cholesterol is not a fat but an
organic molecule of the sterol family (similar to wax) and it is not used for calorie production hence it is not oxidized. Fats and oils
are most abundant lipids in nature. They represent the major component of storage fat or adipose tissue in the human body and the
major contributor to energy intake in diet. The fatty acids profile in serum and tissues reflects the composition of dietary fats. Fat-
rich foods are formed by SFA (with no double-bond), MUFA (e.g., oleic acid) and PUFA (n  3, n  6 fatty acids, e.g., linolenic acid,
omega 3 fatty acids). SFAs are found in dairy products such as butter, cream, cheese and milk, in meat and certain plants (e.g., palm
oil, coconut oil). Dietary sources of MUFAs are olives, rapeseed, peanuts, sesame and safflower oil. Specific types of fish contain
abundant levels of n  3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA). Linoleic acid (LA, n  6
PUFAs) is present in oil of safflower, grape seed, hemp, corn, wheat germ, cotton-seed and soybean, while a-linoleic acid (ALA,
n  3 PUFAs) is in flaxseed, walnuts, some vegetables and canola oils (Burdge, 2004). Trans-fatty acids are found especially in dairy
products and meat, but in high amounts in baked foods (biscuits, crackers, cookies, etc.) and margarines. Cholesterol dietary
sources are mainly egg yolk, organ meat, shrimp, squid and shell.

Dietary Fats and Cancer Prevention

Many studies have suggested that a high consumption of fat through diet is related to an increased incidence of breast, colon,
pancreatic and prostate cancer (Othman, 2007). Independently from type of fat, excess dietary fat intake has been associated with
cancer recurrence (Dal Maso et al., 2008; McEligot et al. 2006; Vernieri et al. 2018). However, when intervention studies with low fat
diets were conducted in the USA no effect on primary (Prentice et al. 2006) or secondary prevention of breast cancer were observed
(Pierce et al. 2007) unless the dietary change involved weight loss (Chlebowski et al. 2006).

Saturated Fatty Acids

Direct associations between SFAs intake and risk of breast cancer in postmenopausal breast cancer have been found but not in
premenopausal women (Cao et al., 2016; Xia et al., 2015). Higher intakes of total fat and SFAs compared to lower intakes were
associated with higher risk of breast cancer subtypes, in particular ER and PR positive breast cancer (Sieri et al., 2014). When
investigating exposure to SFA consumption and mortality incidence, a recent meta-analysis of four studies found 50% higher risk of
breast cancer mortality in the highest compared to the lowest SFA intakes.
In colorectal cancer total fat and SFAs did not show any significant associations in an Asian population (Zhong et al., 2013) but
in a large European population SFA was directly and significantly associated with colorectal cancer risk (May-Wilson et al. 2017).
A meta-analysis of endometrial cancer studies and dietary fat a 45% increased risk was found in case-control studies only (Zhao
et al., 2016a, b). Evidence from observational studies (both case-control and prospective) indicate that there is no apparent
 Diet and Cancer 13

relationship between SFAs and pancreatic cancer risk. Case-controls study on prostate cancer and dietary fats shows that high
consumption of SFAs was associated with a higher aggressiveness of prostate cancer (PC) which seemed to be related mainly to the
SFA effects on serum cholesterol levels. Other studies confirmed a role of dietary cholesterol on PC aggressiveness (Allott et al.,
2017; Mensink et al. 2003; Platz et al., 2006; Platz et al., 2009).

Monounsaturated Fat (MUFA)

Most recent epidemiologic evidence has shown that foods rich in MUFAs could reduce breast cancer risk (Pelucchi et al., 2011) but
others do not support these results. High versus low consumption of MUFAs to SFAs ratio was associated with a significantly
reduced risk of colorectal cancer in three case–control studies (Rosato et al., 2016). Inverse associations were observed between
MUFAs and endometrial cancer risk in cohort studies, while nonsignificant associations were observed in case-control studies (Zhao
et al., 2016b). No significant relationship between MUFAs and pancreatic cancer risk were observed in cohort studies (Yao and
Saturated, 2015) and conflicting results were seen for prostate cancer.
MUFAs are found both in vegetable oils especially olive oil and canola oil but also in meat. This could explain the heterogeneity
of results in international studies particularly between North American populations with high meat to olive oil intakes and
Mediterranean populations who tend to consume larger amounts of olive oil and less meat. Indeed, when investigating vegetable
oil and olive oil a protection is seen in breast cancer risk of 12% and 26%, respectively, in a meta-analysis of cohort and case-control
studies (Xin et al. 2015). This protection was supported by results of the PREDIMED clinical trial conducted in Spain where the arm
consuming higher extra virgin olive oil showed a 68% reduction in breast cancer risk after 4 years of intervention compared to the
control group (Toledo et al. 2015).

Polyunsaturated Fat PUFA

Numerous studies (epidemiological, clinical, animal model and in vitro) confirm a preventive role of n  3 PUFAs in different types
of cancer sites, including breast, colon and prostate (Berquin et al., 2008; Huerta-Yépez et al., 2016) while high dietary intake of
n  6 PUFAs could increase risk of cancer development (Lawrence, 2013). In vitro and in vivo recent studies indicate positive
association between n  3 PUFAs and cancer risk (Sawada et al., 2012), moreover data from epidemiologic studies confirm a
protective role of this type of fats on cancer risk (Huerta-Yépez et al., 2016). Colorectal cancer is most widely developed in
populations who consume a Western diet which is characterized by high fat and are especially rich in n  6 PUFAs particularly
arachidonic acid (AA) which is associated with cancer promotion (Huerta-Yépez et al., 2016). Overall, n  3 PUFAs fats and fish
may have positive effects on carcinogenesis and lower risk of colorectal cancer (Hall et al., 2008; Ronco et al., 2010). Results from
meta-analysis indicate that high intakes of PUFAs was associated to reduced risk of pancreatic cancer, especially in case-control
studies but not clearly in prospective studies while a high n  6/n  3 PUFA ratio was correlated with higher risk of high-grade
prostate cancer (Williams et al., 2011). In recent meta-analysis, consumption of foods rich in n  3 PUFAs such as marine fish, EPA
and DHA, was associated with lower risk of breast cancer (Yang et al., 2014). Meta-analysis on endometrial cancer risk indicate a
relationship between intake of fish and lower risk of cancer in European studies (Hou et al., 2017). Results from prospective cohort
studies confirm the benefit of n  3 PUFAs on breast cancer incidence (Zheng et al., 2013) which may be due to improvements in
immune system for EPA/DHA in supplementation studies (Paixão et al., 2017).

Trans-Fatty Acid
Intakes of commercially produced trans-fatty acid are associated with several diseases, including several types of cancers (Thompson
et al., 2008; Mozaffarian et al., 2006; Stender and Dyerberg, 2004). Data from correlational studies on trans-fatty acid intake and
breast cancer indicate a positive correlation between intake and risk in premenopausal women (Hu et al., 2011) but studies on
ruminant-derived trans-fatty acids do not confirm this association (Kolahdouz Mohammadi et al., 2017). However trans fatty acids
in ruminants are different than those in industrial products, they are 10-fold lower in concentration and the position of the double
bond is located on different carbons. Only few studies observed direct associations between intakes of trans-fatty acids and colon
cancer or prostate cancer (Hu et al., 2010).

Cholesterol

Dietary cholesterol is found only in animal foods. There is an increased evidence of an important role of dietary cholesterol in
increasing breast cancer risk (Li et al., 2016) and this may be due partly to the cholesterol metabolite, 27-hydroxycholesterol, which
has estrogenic activity increasing proliferation of ER þ breast cancer cells (Nelson et al., 2013). High dietary cholesterol may also
increase risk of pancreatic (Chen et al., 2015) and colorectal cancers in some studies (Järvinen et al., 2001; Lee et al., 2009), but not
all (Nagata et al., 2001) and of endometrial and prostate cancers (Allott et al., 2017).
14 Diet and Cancer

Mechanisms of Action

Potential mechanisms of dietary fats in the etiology of cancer include pathways linked to excess adiposity, reactive oxygen species
(ROS), hyperinsulinemia, adipokine secretion and other key mechanism of inflammation which could induce an environment
favorable to tumor growth (Austin et al., 2011; Sung et al., 2011). Dietary fats affect eicosanoids synthesis which are involved in the
inflammatory cascade which in turn may stimulate cancer growth (Larsson et al., 2004; Escrich et al., 2011). ROS production is
linked to higher consumption of dietary fat and induce oxidative stress that may promote carcinogenesis (Kang, 2002, Baracos et al.,
2004). Fatty acids regulate transcription and expression of genes influencing cancer (Jump, 2004; Mandal et al., 2010). Different
fatty acids can differently induce cell growth, proliferation, differentiation and motility of cancer cells (Zadra et al., 2013; Navarro-
Tito et al., 2008). N  3 PUFAs for example reduce inflammation and seem to be protective against tumor growth (Schley
et al., 2005).

Guidelines and Recommendations

The recommendations are to limit the intake of red meat and processed meats as much as possible since they are rich sources of SFA,
AA, cholesterol and increase inflammation. It is important to avoid excess dietary fat which would lead of positive energy balance
and therefore to overweight and obesity. The preferred sources of fats linked to better health and lower cancer risk are MUFA and
PUFAs (ACS, American Cancer Society; WCRF, World Cancer Research Fund International).

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Further Reading

Agnoli C, Grioni S, Sieri S, Palli D, Masala G, Sacerdote C, Vineis P, Tumino R, Giurdanella MC, Pala V, Berrino F, Mattiello A, Panico S, and Krogh V (2013) Italian Mediterranean index
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Bamia C, Lagiou P, Buckland G, et al. (2013) Mediterranean diet and colorectal cancer risk: Results from a European cohort. European Journal of Epidemiology 28(4): 317–328.
https://doi.org/10.1007/s10654-013-9795-x. Epub 2013 Apr 12.
Berrino F (2016) Mediterranean diet and its association with reduced invasive breast cancer risk. JAMA Oncology 2(4): 535–536.
16 Diet and Cancer

Brennan SF, Woodside JV, Lunny PM, Cardwell CR, and Cantwell MM (2017) Dietary fat and breast cancer mortality: A systematic review and meta-analysis. Critical Reviews in Food
Science and Nutrition 57(10): 1999–2008.
Buckland G et al. Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. International Journal of
Cancer 132 (12), 2918–2927.
Chao A, Thun MJ, Connell CJ, McCullough ML, Jacobs EJ, Flanders WD, Rodriguez C, Sinha R, and Calle EE (2005) Meat consumption and risk of colorectal cancer. Journal of the
American Medical Association 293(2): 172–182.
Farnetti S, Malandrino N, Luciani D, Gasbarrini G, and Capristo E (2011) Food fried in extra-virgin olive oil improves postprandial insulin response in obese, insulin-resistant women.
Journal of Medicinal Food 14: 316–321.
Filomeno M, Bosetti C, Bidoli E, Levi F, Serraino D, Montella M, La Vecchia C, and Tavani A (2015) Mediterranean diet and risk of endometrial cancer: A pooled analysis of three Italian
case-control studies. British Journal of Cancer 112(11): 1816–1821. https://doi.org/10.1038/bjc.2015.153 Epub 2015 May 12.
Gong TT, Li D, Wu QJ, and Wang YZ (2016) Cholesterol consumption and risk of endometrial cancer: A systematic review and dose-response meta-analysis of observational studies.
Oncotarget 7(13): 16996–17008. https://doi.org/10.18632/oncotarget.7913.
Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, and Hebbel RP (2002) Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling
and promotes breast tumor growth. Cancer Research 62(15): 4491–4498.
Di Sebastiano KM and Mourtzakis M (2014) The role of dietary fat throughout the prostate Cancer trajectory. Nutrients 6(12): 6095–6109. Published online 2014 Dec 22. https://doi.
org/10.3390/nu6126095.
Khodarahmi M and Azadbakht L (2014) The association between different kinds of fat intake and breast cancer risk in women. International Journal of Preventive Medicine 5: 6–15.
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26(4): 303–311. https://doi.org/10.1016/j.jnutbio.2014.11.001. Epub 2014 Dec 3.
Parekh N, Chandran U, and Bandera EV (2012) Obesity in cancer survival. Annual Review of Nutrition 32: 311–342.
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https://doi.org/10.1265/ehpm.2002.95.

Relevant Websites
http://www.heart.org/HEARTORG/—American Heart Association.
https://www.dietitians.ca/—Dietitians of Canada.

Cruciferous Vegetables and Related Sulphoraphane

Raw vs Cooked 17
Evidence That Cruciferous Vegetables Can Reduce Cancer Risk 17
Prostate Cancer 17
Colorectal Cancer 17
Breast Cancer 17
Overall 18
Mechanisms 18
Dietary Fiber 18
Mechanisms Modulating Estrogen Receptor-a Expression 18
GST Polymorphism and Colorectal Cancer 18
Epigenetic Modulation 18
Recommendations 18
References 19
Further Reading 20

Cruciferous vegetables are part of the Brassica genus of plants and include arugula, broccoli, Brussels sprouts, cabbage, cauliflower,
kale, turnip greens and mustard, among others. Cruciferous vegetables have been associated with protection against a range of
cancers (AICR’S Foods That Fight Cancer—Broccoli and Cruciferous Vegetables; NIH—Cruciferous Vegetables and Cancer Preven-
tion). They are a rich source of carotenoids (beta-carotene, lutein, zeaxanthin), vitamins C, dietary fiber and a major source of
glucosinolate-derived bioactive compounds which have been shown to have anticarcinogenic properties. Glucosinolates are present
in almost every member of Cruciferae family and these sulfur-containing compounds are responsible for the pungent aroma and
bitter flavor that distinguish cruciferous vegetables from other vegetables (Verhoeven et al., 1996; Higdon et al., 2007). Chemically,
glucosinolates are composed of thiohydroximate-O-sulfonate group linked to glucose, and an alkyl, aralkyl, or indolyl side chain
(R) (Agerbirk and Olsen, 2012). Glucosinolates (Glucoraphanin) undergo hydrolysis upon contact with the enzyme myrosinase,
which is present within plant tissues, and they form biologically active compounds such as indoles (indole-3-carbinol) and
isothiocyanates (sulforaphane) that have well known anticarcinogenic properties in in vitro and animal studies (Bosetti et al.,
2012; Zhang et al., 1992). Isothiocyanates (ITCs) in plants have antibacterial and antifungal activity and provide important
protection from insect and herbivore attack (Rosa et al., 1997).
 Diet and Cancer 17

Glucoraphanin glucosinolate is found in the vacuoles of intact plant cells and it is spatially separated from myrosinase, which is
in the cytoplasm cells. After cell rupture, induced by chewing during human consumption or by tissue damage during freezing,
thawing, and chopping of edible plants, glucoraphanin comes into contact with myrosinase and is converted into sulforaphane and
sulforaphane nitrile.

Raw vs Cooked

Storage, processing and cooking can change ITCs formation from glucosinolate and affect the cruciferous vegetables anticancer
activity (Barba et al., 2016; Jones et al., 2010). Intake of raw cruciferous vegetables provides two to nine times the amount of ITCs in
humans compared with similar intakes of their cooked counterparts (Rouzaud et al., 2004; Getahun and Chung, 1999; Conaway
et al., 2000; Shapiro et al., 1998). Studies demonstrated that inverse association between cruciferous vegetable intake and cancer risk
appear to be stronger with raw vegetable consumption than with their cooked counterparts. It is notable that ITCs may be largely
reduced by cooking procedures due to heat-inactivating myrosinase, reducing the formation of sulforaphane (Rouzaud et al., 2004;
Getahun and Chung, 1999; Conaway et al., 2000). Human intestinal microflora also possess myrosinase activity and is able to
partially hydrolyze ingested glucosinolates, but studies have shown that isothiocyanate exposure after the consumption of cooked
cruciferous vegetables is 60%–90% less than that after the ingestion of raw cruciferous vegetables (Rouzaud et al., 2004; Getahun
and Chung, 1999; Conaway et al., 2000; Shapiro et al., 1998). Among thermal processing, steaming is preferred over boiling
because glucosinolates can leach into the boiling water and because the action of myrosinase at internal temperatures exceeding
70 C is inhibited (Jones et al., 2010).
Freezing at 20 C is one way to preserve the content of nutrients and improve health benefits of cruciferous vegetables. Freezing
at 20 C resulted in the formation of more sulforaphane of broccoli sprouts which was probably due to the enhancement of
myrosinase activity and to the damage caused by ice crystals that brings glucoraphanin into contact with myrosinase (Guo et al.,
2015). However, freezing at 20 C and  40 C had a negative impact on the ascorbic acid content in broccoli leading to the
enhancement of myrosinase activity (Guo et al., 2015).

Evidence That Cruciferous Vegetables Can Reduce Cancer Risk

There is substantial evidence from human studies that cruciferous vegetable consumption may reduce the risk of several common
cancer (IARC 2004, WCRF/AICR 2007; Verhoeven et al., 1997; Turati et al., 2015).

Prostate Cancer

A meta-analysis of 13 studies found that high intakes of cruciferous vegetables were associated with the decreased risk of prostate
cancer (Liu et al., 2012). Cohort studies have examined a wide range of daily cruciferous vegetable intakes and found little or no
association with prostate cancer risk (Schuurman et al., 1998; Giovannucci et al., 2003; Key et al., 2004). However, some case-
control studies have found that people who ate greater amounts of cruciferous vegetables had a lower risk of prostate cancer
(Kolonel et al., 2000; Jain et al., 1999).

Colorectal Cancer

Results from cohort studies have generally found no association between cruciferous vegetable intake and colorectal cancer risk
(McCullough et al., 2003; Flood et al., 2002; Michels et al., 2000). Two meta-analysis reported consistent findings on the protective
effects of cruciferous vegetables for colorectal cancer suggesting that intake of cruciferous vegetables may reduce the risk of colorectal
cancer in humans (Wu et al., 2013; Tse and Eslick, 2014). In an updated report from the World Cancer Research Fund and the
American Institute for Cancer Research (WCRF/AICR), dietary fiber intake, including cruciferous vegetables, has been upgraded as a
convincing protective dietary factor for CRC (WCRF Colorectal cancer).

Breast Cancer

Data from a meta-analysis of 13 studies suggest that cruciferous vegetables consumption may reduce the risk of breast cancer with a
significantly reduced risk in postmenopausal but not in premenopausal women (Liu and Lv, 2013). Despite strong evidence of a
protective role of cruciferous vegetables in breast cancer in animal and in in-vitro studies, data in human studies are often
inconsistent. Some epidemiological studies reported no association (Smith-Warner et al., 2001) or a weak association with breast
cancer risk (Zhang et al., 1999). No evidence of association between cruciferous vegetables consumption and breast cancer
prognosis has been observed in breast cancer patients (Nechuta et al., 2013; Peng et al., 2017).
18 Diet and Cancer

Overall

Significant reductions of colorectal and breast cancer risk in subjects consuming cruciferous vegetables at least once a week
(compared to non-consumers) were reported from an analysis of a large network of case-control studies while no significant
associations were seen in prostate cancer risk (Bosetti et al., 2012). Similar findings have been reported from a systematic review of
Mediterranean countries (Turati et al., 2015).

Mechanisms

Similar to other plants, cruciferous vegetables contain various protective compounds including dietary fiber, several antioxidants
and vitamins (i.e., carotenoids, polyphenols, vitamin C, and folate) (IARC 2004; Verhoeven et al., 1997; Higdon et al., 2007).
In addition, cruciferae are rich unique sources of glucosinolates whose major breakdown products (indoles and ITCs) have shown
anticarcinogenic properties. Indoles and ITCs may protect against cancer by modulating Phase I and Phase II enzymes, inhibiting
carcinogenesis, stimulating cell cycle arrest and apoptosis, and by reducing inflammation and angiogenesis (Navarro et al., 2011;
Lenzi et al., 2014).

Dietary Fiber

Cruciferous vegetables are good sources of dietary fiber which may play a protective role in colorectal cancer (Aune et al., 2011).

Mechanisms Modulating Estrogen Receptor-a Expression

There is strong evidence from cell and animal experiments of a preventive role of cruciferous vegetables in breast carcinogenesis by
regulating the expression of estrogen receptor, altering the metabolism of estrogen, or suppressing cyclooxygenase 2 (COX-2) (Lin
et al., 2017; Fowke et al., 2000; Kang et al., 2009). The chemopreventive effect of indole-3-carbinol on breast cancer may be linked
to its ability of decreasing estrogen receptor-a expression (Bosetti et al., 2002; Fowke et al., 2000). Indeed indole-3-carbinol are able
to bind to the estrogen receptor (ER), repressing ER signaling, downregulating the expression of estrogen-responsive genes (Meng
et al., 2000) and thus preventing the development of estrogen-dependent cancers including breast, endometrial and cervical cancers.
Besides indole-3-carbinol also ITCs can modulate expression of sex hormones and their receptors. ITCs function as ERa disruptors
to abrogate mitogenic estrogen signaling in ER-positive breast cancer cells, which provides a molecular explanation for the growth
inhibitory function of ITCs in breast cancer development, and a rational for further exploration of ITCs as chemopreventive agents
for human mammary carcinogenesis. (Kang et al., 2009).

GST Polymorphism and Colorectal Cancer

Several studies have investigated the different capacity of individuals to metabolize and eliminate glucosinolate byproducts of
hydrolysis and this theory may help explain the differential health benefits of cruciferous vegetables (Lampe and Peterson, 2002; Lin
et al., 1998). Approximately half of the population lacks GSTM1 (a variant of glucosinolate enzymes) due to gene deletion (Lin
et al., 1998) and the homozygous deletion of GSTM1 gives rise to the null phenotype in which there is no expression of GSTM1
protein. The hypothesis is that individuals with the null genotype of GSTM1 or GSTT1 polymorphisms would have less conjugation
activity, and thus permitting ITCs to remain biologically active potentially providing greater protection against cancer (Cotton et al.,
2000). Findings from a meta-analysis suggest a positive correlation between glucosinolate polymorphism and the protective effects
of cruciferous vegetables consumption against colorectal cancer risk in individuals with a single null GSTT1 genotype (Tse and
Eslick, 2014).

Epigenetic Modulation
Cruciferous vegetables may have epigenetic properties modulating cancer prevention. Most cancers are characterized by the
overexpression of histone deacetylases and DNA methyltransferases, and the mis-expression of micro RNAs. Sulforaphane and
indole-3-carbinol from cruciferous vegetables may regulate micro RNAs and inhibit histone deacetylases and DNA methyltrans-
ferases (Royston and Tollefsbol, 2015).

Recommendations

Dietary Guidelines generally recommend consuming a variety of vegetables each day because of their different content of bioactive
compounds (USDA Choose my Plate). Usually cruciferous vegetables fall into the “dark-green vegetables” category. It is suggested to
 Diet and Cancer 19

eat cruciferous vegetables as part of a healthy diet and to prefer eating them raw or after steaming and that sulforaphane appears to
be an effective and safe chemopreventive molecule and a promising tool to fight cancer (Lenzi et al., 2014).

References

Agerbirk N and Olsen CE (2012) Glucosinolate structures in evolution. Phytochemistry 77: 16–45.
Aune D, Chan DS, Lau R, et al. (2011) Dietary fibre, whole grains, and risk of colorectal cancer: Systematic review and dose-response meta-analysis of prospective studies. BMJ
343: d6617.
Barba FJ, Nikmaram N, Roohinejad S, Khelfa A, Zhu Z, and Koubaa M (2016) Bioavailability of Glucosinolates and their breakdown products: Impact of processing. Frontiers in Nutrition
3: 24.
Bosetti C, Filomeno M, Riso P, Polesel J, Levi F, Talamini R, Montella M, Negri E, Franceschi S, and La Vecchia C (2012) Cruciferous vegetables and cancer risk in a network of case-
control studies. Annals of Oncology 23: 2198–2203.
Bosetti C, Negri E, Kolonel L, et al. (2002) A pooled analysis of case-control studies of thyroid cancer. VII. Cruciferous and other vegetables (International). Cancer Causes & Control
13: 765–775.
Conaway CC, Getahun SM, Liebes LL, et al. (2000) Disposition of glucosinolates and sulforaphane in humans after ingestion of steamed and fresh broccoli. Nutrition and Cancer
38: 168–178. 26.
Cotton SC, Sharp L, Little J, and Brockton N (2000) Glutathione S-transferase polymorphisms and colorectal cancer: A HuGE review. American Journal of Epidemiology 151: 7–32.
Flood A, Velie EM, Chaterjee N, et al. (2002) Fruit and vegetable intakes and the risk of colorectal cancer in the breast Cancer detection demonstration project follow-up cohort. The
American Journal of Clinical Nutrition 75: 936–943.
Fowke JH, Longcope C, and Hebert JR (2000) Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal women. Cancer Epidemiology, Biomarkers &
Prevention 9: 773–779.
Getahun SM and Chung FL (1999) Conversion of glucosinolates to isothiocyanates in humans after ingestion of cooked watercress. Cancer Epidemiology, Biomarkers & Prevention
8: 447–451.
Giovannucci E, Rimm EB, Liu Y, and Stampfer MJ (2003) Willett WC. A prospective study of cruciferous vegetables and prostate cancer. Cancer epidemiology. Biomarkers & Prevention
12: 1403–1409.
Higdon JV, Delage B, Williams DE, and Dashwood RH (2007) Cruciferous vegetables and human cancer risk: Epidemiologic evidence and mechanistic basis. Pharmacological Research
55: 224–236.
IARC. Cruciferous vegetables, isothiocyanates and indoles. IARC Handbooks of Cancer Prevention Vol. 9. Lyon: IARC Press, 2004 (accessed on 14 April 2018).
Jain MG, Hislop GT, Howe GR, and Ghadirian P (1999) Plant foods, antioxidants, and prostate cancer risk: Findings from case-control studies in Canada. Nutrition and Cancer
34: 173–184.
Jones RB, Frisina CL, Winkler S, Imsic M, and Tomkins RB (2010) Cooking method significantly effects glucosinolate content and sulforaphane production in broccoli florets. Food
Chemistry (2): 237–242.
Kang L, Ding L, and Wang ZY (2009) Isothiocyanates repress estrogen receptor alpha expression in breast cancer cells. Oncology Reports 21: 185–192.
Key TJ, Allen N, Appleby P, et al. (2004) Fruits and vegetables and prostate cancer: No association among 1104 cases in a prospective study of 130544 men in the European
prospective investigation into Cancer and nutrition (EPIC). International Journal of Cancer 109: 119–124.
Kolonel LN, Hankin JH, Whittemore AS, et al. (2000) Vegetables, fruits, legumes and prostate cancer: A multiethnic case-control study. Cancer epidemiology. Biomarkers & Prevention
9: 795–804.
Lampe JWand Peterson S (2002) Brassica, biotransformation and cancer risk: Genetic polymorphisms alter the preventive effects of cruciferous vegetables. The Journal of Nutrition
132: 2991–2994.
Lenzi M, Fimognari C, and Hrelia P (2014) Sulforaphane as a promising molecule for fighting cancer. Cancer Treatment and Research 159: 207–223.
Lin HJ, Probst-Hensch NM, Louie A, Kau IH, Witte JS, et al. (1998) Glutathione transferase null genotype, broccoli, and lower prevalence of colorectal adenomas. Cancer Epidem
Biomar 7: 647–652.
Guo L, Yang R, Wanga Z, and Zhenxin G (2015) Effect of freezing methods on sulforaphane formation in broccoli sprouts. RSC Advances 5: 32290.
Liu B, Mao Q, Cao M, and Xie L (2012) Cruciferous vegetables intake and risk of prostate cancer: A meta-analysis. International Journal of Urology 19: 134–141.
Liu X and Lv K (2013) Cruciferous vegetables intake is inversely associated with risk of breast cancer: A meta-analysis. Breast 22: 309–313.
McCullough ML, Robertson AS, Chao A, et al. (2003) A prospective study of whole grains, fruits, vegetables and colon cancer risk. Cancer Causes & Control 14: 959–970.
Meng Q, Yuan F, Goldberg ID, Rosen EM, Auborn K, and Fan S (2000) Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. The Journal
of Nutrition 130: 2927–2931.
Michels KB, Giovannucci E, Joshipura KJ, et al. (2000) Prospective study of fruit and vegetable consumption and incidence of colon and rectal cancers. Journal of the National Cancer
Institute 92(21): 1740–1752.
Navarro SL, Li F, and Lampe JW (2011) Mechanisms of action of isothiocyanates in cancer chemoprevention: An update. Food & Function 2: 579–587.
Nechuta S, Caan BJ, Chen WY, Kwan ML, Lu W, Cai H, Poole EM, Flatt SW, Zheng W, Pierce JP, and Shu XO (2013) Postdiagnosis cruciferous vegetable consumption and breast
cancer outcomes: A report from the after breast Cancer pooling project. Cancer Epidemiology, Biomarkers & Prevention 22: 1451–1456.
Peng C, WP1 L, and Zhang CX (2017) Fruit and vegetable intake and breast cancer prognosis: A meta-analysis of prospective cohort studies. The British Journal of Nutrition 117(5):
737–749.
Rosa EAS, Heaney RK, Fenwick GR, and Portas CAM (1997) Glucosinolates in crop plants. Horticultural Reviews 19: 99–215.
Rouzaud G, Young SA, and Duncan AJ (2004) Hydrolysis of glucosinolates to isothiocyanates after ingestion of raw or microwaved cabbage by human volunteers. Cancer Epidemiology,
Biomarkers & Prevention 13: 125–131.
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epidemiology. Biomarkers & Prevention 7(8): 673–680.
Shapiro TA, Fahey JW, Wade KL, Stephenson KK, and Talalay P (1998) Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous
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Smith-Warner SA, Spiegelman D, Yaun SS, et al. (2001) Intake of fruits and vegetables and risk of breast cancer: A pooled analysis of cohort studies. JAMA 285(6): 769–776.
Lin T, Zirpoli GR, McCann SE, Moysich KB, Christine B, and Tang AL (2017) Trends in cruciferous vegetable consumption and associations with breast Cancer risk: A case-control
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Turati F, Rossi M, Pelucchi C, Levi F, and La Vecchia C (2015) Fruit and vegetables and cancer risk: A review of southern European studies. The British Journal of Nutrition
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Biological Interactions 103: 79–129.
20 Diet and Cancer

Verhoeven DTH, Goldbohm RA, vanPoppel G, Verhagen H, and vanden-Brandt PA (1996) Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiology,
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Annals of Oncology 24: 1079–1087.
Zhang S, Hunter DJ, Forman MR, et al. (1999) Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. Journal of the National Cancer Institute 91(6): 547–556.
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National Academy of Science USA 89: 2399–2403.

Further Reading

AICR’S Foods That Fight Cancer—Broccoli & Cruciferous Vegetables. 2018. http://www.aicr.org/foods-that-fight-cancer/broccoli-cruciferous.html (accessed on 14 April 2018).
Economopoulos KP and Sergentanis TN (2010) GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: A comprehensive meta-analysis. European Journal of Cancer
31: 1617–1631.
Li Y, Li S, Meng X, Gan RY, Zhang JJ, and Li HB (2017 Jul 8) Dietary natural products for prevention and treatment of breast Cancer. Nutrients 9: E728.
NIH-Cruciferous Vegetables and Cancer Prevention. https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/cruciferous-vegetables-fact-sheet. Accessed 14 April 2018.
USDA 2018 Choose my plate. https://www.choosemyplate.gov/vegetables (accessed on 14 April 2018).
World Cancer Research Fund/American Institute for Cancer Research. 2018 Colorectal cancer. https://wcrf.org/int/continuous-update-project/cup-findings-reports/colorectal-cancer
(accessed on 15 April 2018).

Pro-Inflammatory Vegetables: Is There Any Evidence?

High plasma levels of C reactive protein (CRP) are expression of chronic inflammatory status and are associated with poor
prognosis of tumors. The inflammatory cytokines are released into the blood by the tumor and by the tumor-associated macro-
phages, their presence in the blood and the presence of high levels of CRP may indicate that the tumor is more aggressive.
It is a common belief that the Solanaceae plants (tomatoes, eggplants, peppers, and potatoes) may increase inflammation however
there seems to be a lack of evidence (Berrino, 2016). In order to keep inflammation low, it is preferable to consume a diet rich in
plant foods such as vegetables, fruit and whole grains with some omega-3 fats (flaxseeds, soybeans, wild herbs). Evidence of a
possible association between the intake of tomatoes and tomato juice and inflammation has given mixed results: reduction in CRP
levels in some studies (Jacob et al., 2008) or no significant change in CRP and other inflammatory mediators in others (Blum et al.,
2007). Furthermore, isolated lycopene supplementation has not shown antiinflammatory effect (Markovitis et al., 2009). Toma-
toes, eggplants, peppers, and potatoes are rich the glycoalkaloids a- solanine and a—chaconine which are plants’ natural defenses.
These compounds however may stimulate the formation of polyamines, metabolites that induce cell proliferation, reduce immune
defenses against tumors and promote metastatic migration of tumor cells and angiogenesis (Soda, 2011).

References
Berrino F (2016) I quattro pilastri alimentari della dieta adiuvante le terapie oncologiche. In: Berrino F (ed.) Il cibo dell’uomo. La via della salute tra conoscenza scientifica e antiche
saggezze, pp. 121–135. FrancoAngeli/Self-help.
Jacob K, Periago MJ, Bohm V, and Berruezo GR (2008) Influence of lycopene and vitamin C from tomato juice on biomarkers of oxidative stress and inflammation. The British Journal of
Nutrition 99: 137–146.
Blum A, Monir M, Khazim K, Peleg A, and Blum A (2007) Tomato-rich (Mediterranean) diet does not modify inflammatory markers. Clinical and Investigative Medicine 30: E70–E74.
Markovitis N, Ben Amotz A, and Levy Y (2009) The effect of tomato-derived lycopene on low carotenoids and enhanced systemic inflammation and oxidation in severe obesity. The
Israel Medical Association Journal 11: 598–601.
Soda K (2011) The mechanisms by which polyamines accelerate tumor spread. Journal of Experimental & Clinical Cancer Research 30: 95.
 Diet and Cancer 21

Supplements: Soy Isoflavones

Sources 21
Health Effects 21
Concerns 22
Recommendations 22
References 22
Further Reading 24

Soy isoflavones are phytochemical compounds that are found in soybeans. These bioactive compounds are also known as
phytoestrogen because of their chemical structure similar to animal endogenous estrogens which allows them to bind to the
estrogen receptor (Setchell, 1998; Cabot, 2003). Mean isoflavone intake among adults range from 30 to 50 mg/day in Asian
countries consuming traditional soy foods whereas is less than 3 mg/day in United States, Canada and Europe (Goodman-Gruen
and Kritz-Silverstein, 2001; Bai et al., 2014; Van Erp-Baart et al., 2003; Van der Schouw et al., 2005).
Soy isoflavones occur mainly as glycosides form, bound to a sugar molecule (Murphy et al., 2002). After food fermentation
during processing or gut digestion the sugar moiety is hydrolyzed, thereby allowing absorption to occur (Rowland et al., 2003).
Breaking of this glycosidic bond leaves the isoflavones in their simple aglycone form (Murphy et al., 1999, 2002; Yamabe et al.,
2007; Otieno et al., 2007). It is still not clear whether the effects are due only to the aglycone or its glucosidic portion or both. Soy
isoflavones occur mostly in the form of genistein, daidzein and glycitein which account for approximately 50%, 40%, and 10%,
respectively, of the total soy isoflavones content (Murphy et al., 2002).
Some human studies reported a wide inter-individual variability in isoflavones metabolism (Jackson et al., 2011) which
depends primarily on intestinal flora polymorphisms (Moon et al., 2006; Nechuta et al., 2012a,b). Some individuals host intestinal
bacteria that convert the isoflavone daidzein into the isoflavonoid equol (Jackson et al., 2011; Setchell, 1998; Setchell and Clerici,
2010) and this may explain some of the discrepancies in results seen for the health effects of soy foods in human studies (Bolca
et al., 2007). It has been suggested that individuals with equol-producing intestinal bacteria may benefit from soy food consump-
tion more than those without (Setchell et al., 2002; Setchell and Clerici, 2010; Setchell, 1998).

Sources

Plants synthetize isoflavones through environmental stresses, such as infections or paucity of nutrients (Lozovaya et al., 2005). Also,
different climatic conditions and different cultivation practices lead to variable bean dimension as well as isoflavone content
(Howitz and Sinclair, 2008). Isoflavones content can vary depending on temperature and soil moisture. During plant growth, the
highest isoflavone concentrations occurring at low temperatures and high soil moisture (Rizzo and Baroni, 2018). Isoflavones are
contained in different legumes, such as soy, kidney beans, navy beans, red clover and Japanese arrowroot called kudzu, but only soy
beans and soy foods provide the main dietary sources of isoflavones in the human diet (Messina, 1999; Mazur et al., 1998). Soy
foods include traditional Asian foods such as tofu, soy milk, tempeh and edamame.
Each gram of soy protein in soybeans and traditional soy foods is associated with approximately 3.5 mg of isoflavones (Messina
et al., 2006a,b,c). One serving of a traditional soy food, such as 100 g of tofu or 250 mL soymilk, typically provides about 25 mg
isoflavones. In 1999 USDA in conjunction with Iowa State University created a database providing data on the isoflavone (including
daidzein, genistein, glycitein and total isoflavones) content of selected food items (USDA).

Health Effects

Beneficial effects have been associated with soy consumption, some of which may depend on phytoestrogen content (Rizzo and
Baroni, 2018; Messina et al., 2006a,b,c). Epidemiological studies in Asian countries showed that a traditional diet rich in
phytoestrogens was associated with a lower risk of chronic diseases and report on possible benefits in hormone-dependent prostate
cancer (Applegate et al., 2018; Zuniga et al., 2013), colon cancer (Yu et al., 2016; Grosso et al., 2017a,b), breast and ovarian cancers
(Loibl et al., 2011; Magee et al., 2004; Patisaul and Jefferson, 2010; Peeters et al., 2002; Grosso et al., 2017a), endometrial cancer
(Zhong et al., 2018) and stomach cancer (Grosso et al., 2017b).
Some common potential mechanisms of action through which isoflavones could exert protective effects in carcinogenesis have
been reported. Isoflavones are structurally similar to 17b-estradiol, the primary endogenous estrogen (Tham et al., 1998; Guha et al.,
2009). These molecules play a competitive role with endogenous estrogens for binding to ERa and ERb although they have lower
estrogenic potency compared to estradiol (Breinholt and Larsen, 1998). Isoflavones possessed mixed ER agonist and antagonist
properties, depending on the cell type and concentration of estrogen present in the surroundings (Larkin et al., 2008). It has been
22 Diet and Cancer

suggested that soy isoflavones may act as selective tissue estrogenic activity regulators and selective estrogen receptor modulator also
with different mechanisms than direct receptor interactions (Nilsson and Gustafsson, 2002; Meegan and Lloyd, 2003; Riggs and
Hartmann, 2003; Smith and O’Malley, 2004). ERa and ERb display distinct expression patterns in men and women, thus
phytoestrogens do not exert their activity as classical estrogen agonists (Matthews and Gustafsson, 2003; Hooper et al., 2009).
For example, the ability of genistein to bind to ERb may be a key factor in the inhibition of prostatic carcinogenesis but other
mechanisms include cellular proliferation, apoptosis and differentiation (Mahmoud et al., 2014). Indeed, in addition to
ER-depending activity, anticancer effects of soy have been largely ascribed to isoflavones which can modulate cell cycle, apoptosis,
differentiation, proliferation and cell signaling (Messina et al., 2006a,b,c; Zhou et al., 1999; Vitale et al., 2016). Soy isoflavones, as a
polyphenol subclass, also act exhibiting antioxidant, anti-proliferative and anti-inflammatory properties in vitro and in vivo (Tham
et al., 1998; Guha et al., 2009; Patel et al., 2001).
Newly discovered anticarcinogenic mechanisms of action of phytoestrogens include epigenetic modifications. In breast cancer
cell lines phytoestrogens modulated chromatin transcription through epigenetic modifications such as methylation and acetylation
of histones (Dagdemir et al., 2013; Grosso et al., 2017a,b).
A protective action of soy isoflavones during the cancer promotion phase may explain the reduced breast cancer risk and reduced
recurrence in Asian women exposed to soy since infancy.
In 1995 the “early intake” hypothesis emerged showing that early isoflavone exposure may be protective against breast cancer in
adulthood in animal studies. This effect may be related to isoflavones ability to impact on mammary gland development, changing
cells in ways that make them permanently less likely to be transformed into cancer cells. Animal studies and epidemiological
evidence support this hypothesis (Russo et al., 2005; Brown et al., 2010; De Assis et al., 2011; Rahal and Simmen, 2011; Mishra
et al., 2011).

Concerns

The estrogen-like properties of isoflavones have been a concern suggesting it may increase estrogenic activities and thus cancer cell
proliferation particularly in those who already had breast cancer. This concern stems mainly from animal studies where pharma-
cological doses of isoflavones were able to stimulate the growth of existing tumors in athymic ovariectomized mice implanted with
estrogen-sensitive human breast cancer (Messina, 2016). However clinical and epidemiological studies in humans indicate that
isoflavone exposure is safe for all women and it improves the prognosis of breast cancer patients (Grosso et al., 2017a,b; Rizzo and
Baroni, 2018). This may be due partly to the selective nature of isoflavones in binding to estrogen receptors and to their other
anticancer properties mentioned above. In 2015, after a comprehensive and multiyear evaluation of the literature, the European
Food Safety Authority (EFSA) concluded that in postmenopausal women, intakes of 35–150 mg per day of isoflavones from food
supplements do not adversely affect sex hormones-responsive tissues such as breast and utero after 2.5 years of treatment (EFSA
Panel on Food Additives and Nutrient Sources added to Food ANS, 2015). Data from this systematic review does not support the
hypothesis of an increased risk of breast cancer nor of an effect on mammographic density or proliferation marker Ki-67 expression
(Wu et al., 2015). Moreover, higher isoflavone intakes in breast cancer patients were associated with reduced mortality and cancer
recurrence in women with ER (þ) and ER(-) breast cancer (Shu et al., 2009) and no contro-indications have been observed for
women under treatment with tamoxifeen or anastrozole, two antihormonal drugs commonly used to treat breast cancer (Guha
et al., 2009; Nechuta et al., 2012a,b; Kang et al., 2010).

Recommendations

Up to three servings/day (up to 100 mg/day of isoflavones) as consumed by Asian populations for thousands of years do not seem
to be associated to increased breast cancer risk (American Institute for Cancer Research, AICR). Considering one serving averages
about 7 g of protein and 25 mg isoflavones, a moderate soy isoflavone consumption is achieved with 1–2 standard servings daily of
soybeans or soy foods.

References
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10(1).
Bai W, Wang C, and Ren C (2014) Intakes of total and individual flavonoids by US adults. International Journal of Food Science 65: 9–14.
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Breinholt V and Larsen JC (1998) Detection of weak estrogenic flavonoids using a recombinant yeast strain and a modified MCF7 cell proliferation assay. Chemical Research in
Toxicology 11: 622–629.
Brown NM, Belles CA, Lindley SL, Zimmer-Nechemias LD, Zhao X, Witte DP, Kim MO, and Setchell KD (2010) The chemopreventive action of equol enantiomers in a chemically
induced animal model of breast cancer. Carcinogenesis 31: 886–893.
Cabot W (2003) Phytoestrogens. Journal of the American Academy of Orthopaedic Surgeons 11: 153–156.
Dagdemir A, Durif J, Ngollo M, Bignon YJ, and Bernard-Gallon D (2013) Histone lysine trimethylation or acetylation can be modulated by phytoestrogen, estrogen or anti-HDAC in breast
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 Diet and Cancer 23

De Assis S, Warri A, Benitez C, Helferich W, and Hilakivi-Clarke L (2011) Protective effects of prepubertal genistein exposure on mammary tumorigenesis are dependent on BRCA1
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Patisaul HB and Jefferson W (2010) The pros and cons of phytoestrogens. Frontiers in Neuroendocrinology 31: 400–419.
Peeters PHM, Keinan-Boker L, van der Schouw YT, and Grobbee DE (2002) Phytoestrogens and breast cancer risk: Review of the epidemiological evidence. IARC Scientific Publications
156: 331–336.
Rahal OM and Simmen RC (2011) Paracrine-acting adiponectin promotes mammary epithelial differentiation and synergizes with genistein to enhance transcriptional response to
estrogen receptor beta signaling. Endocrinology 152: 3409–3421.
Riggs BL and Hartmann LC (2003) Selective estrogen-receptor modulators—Mechanisms of action and application to clinical practice. The New England Journal of Medicine
348: 618–629.
Rizzo G and Baroni L (2018) Soy, soy foods and their role in vegetarian diets. Nutrients 5: 10. Review.
Rowland I, Faughnan M, Hoey L, Wahala K, Williamson G, and Cassidy A (2003) Bioavailability of phyto-oestrogens. The British Journal of Nutrition 89: S45–S58.
Russo J, Mailo D, Hu YF, Balogh G, Sheriff F, and Russo IH (2005) Breast differentiation and its implication in cancer prevention. Clinical Cancer Research 11: 931s–936s.
Setchell KD (1998) Phytoestrogens: The biochemistry, physiology, and implications for human health of soy isoflavones. The American Journal of Clinical Nutrition 68: 1333S–1346S.
Setchell KD, Brown NM, and Lydeking-Olsen E (2002) The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. The Journal of Nutrition
132: 3577–3584.
Setchell KD and Clerici C (2010) Equol: Pharmacokinetics and biological actions. The Journal of Nutrition 140: 1363S–1368S.
Smith CL and O’Malley BW (2004) Coregulator function: A key to understanding tissue specificity of selective receptor modulators. Endocrine Reviews 25: 45–71.
Tham DM, Gardner CD, and Haskell WL (1998) Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological, and mechanistic evidence. The Journal of
Clinical Endocrinology and Metabolism 83: 2223–2235.
Van der Schouw YT, Kreijkamp-Kaspers S, Peeters PH, Keinan-Boker L, Rimm EB, and Grobbee DE (2005) Prospective study on usual dietary phytoestrogen intake and cardiovascular
disease risk in western women. Circulation 111: 465–471.
24 Diet and Cancer

Van Erp-Baart MA, Brants HA, Kiely M, Mulligan A, Turrini A, Sermoneta C, Kilkkinen A, and Valsta LM (2003) Isoflavone intake in four different European countries: The VENUS
approach. The British Journal of Nutrition 89: S25–S30.
Vitale SG, Laganà AS, Nigro A, La Rosa VL, Rossetti P, Rapisarda AMC, La Vignera S, Condorelli RA, Corrado F, Buscema M, et al. (2016) Peroxisome proliferator-activated receptor
modulation during metabolic diseases and cancers: Master and minions. PPAR Research 2016: 6517313.
Wu AH, Spicer D, Garcia A, Tseng CC, Hovanessian-Larsen L, Sheth P, Martin SE, Hawes D, Russell C, MacDonald H, et al. (2015) Double-blind randomized 12-month soy intervention
had no effects on breast MRI Fibroglandular tissue density or mammographic density. Cancer Prevention Research 8: 942–951.
Yamabe S, Kobayashi-Hattori K, Kaneko K, Endo H, and Takita T (2007) Effect of soybean varieties on the content and composition of isoflavone in rice-koji miso. Food Chemistry
100: 369–374.
Yu Y, Jing X, Li H, Zhao X, and Wang D (2016) Soy isoflavone consumption and colorectal cancer risk: A systematic review and meta-analysis. Scientific Reports 6: 25939.
Zhong XS, Ge J, Chen SW, Xiong YQ, Ma SJ, and Chen Q (2018) Association between dietary Isoflavones in soy and legumes and endometrial cancer: A systematic review and meta-
analysis. Journal of the Academy of Nutrition and Dietetics 118(4): 637–651.
Zhou JR, Gugger ET, Tanaka T, Guo Y, Blackburn GL, and Clinton SK (1999) Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor
angiogenesis in mice. The Journal of Nutrition 129: 1628–1635.
Zuniga KE, Clinton SK, and Erdman JW (2013) The interactions of dietary tomato powder and soy germ on prostate carcinogenesis in the TRAMP model. Cancer Prevention Research
6: 548–557.

Further Reading

Adlercreutz H, Markkanen H, and Watanabe S (1993) Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342: 1209–1210.
American Institute for Cancer Research (AICR). 2018 Soybeans, soy nuts and edamame contain fiber. After a systematic review of the global scientific literature, AICR/WCRF weighed
the strength of the evidence linking these factors to lower risk for several cancers. Available online: http://www.aicr.org/foods-that-fight-cancer/tab-content/soy-research-1.html.
(accessed on 14 April 2018).
Boker LK, Van der Schouw YT, De Kleijn MJ, Jacques PF, Grobbee DE, and Peeters PH (2002) Intake of dietary phytoestrogens by Dutch women. The Journal of Nutrition
132: 1319–1328.
De Kleijn MJ, van der Schouw YT, Wilson PW, Adlercreutz H, Mazur W, Grobbee DE, and Jacques PF (2001) Intake of dietary phytoestrogens is low in postmenopausal women in the
United States: The Framingham study (1–4). The Journal of Nutrition 131: 1826–1832.
Faulkner-Hogg KB, Selby WS, and Loblay RH (1999) Dietary analysis in symptomatic patients with coeliac disease on a gluten-free diet: The role of trace amounts of gluten and non-
gluten food intolerances. Scandinavian Journal of Gastroenterology 34: 784–789.
Kapiotis S, Hermann M, Held I, Seelos C, Ehringer H, and Gmeiner BM (1997) Genistein, the dietary-derived angiogenesis inhibitor, prevents LDL oxidation and protects endothelial cells
from damage by atherogenic LDL. Arteriosclerosis, Thrombosis, and Vascular Biology 17: 2868–2874.
Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, and Gustafsson JA (1998) Interaction of estrogenic chemicals and phytoestrogens with
estrogen receptor beta. Endocrinology 139: 4252–4263.
Levy RM, D’Anna R, et al. (2008) Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: A follow-up study. The Journal of Clinical Endocrinology and
Metabolism 93: 4787–4796.
Messina MJ and Wood CE (2008) Soy isoflavones, estrogen therapy, and breast cancer risk: Analysis and commentary. Nutrition Journal 7: 17. Review.
USDA Database for the Isoflavone Content of Selected Food, Release 2.1 (November 2015). https://data.nal.usda.gov/dataset/usda-database-isoflavone-content-selected-foods-
release-21-november-2015 (accessed on 14 April 2018).

Green Tea and Green Tea Extracts (GTEs)

Next to water, tea is the beverage most widely consumed worldwide, consisting of an infusion or decoction made from the leaves of
a woody plant, Camellia sinensis (L.) Kuntze, belonging to the family Theaceae. The varieties of tea, derived from the leaves of the
same plant, are created through different treatments and have different degrees of enzymatic oxidation of polyphenols by
polyphenol oxidase (fermentation). Green tea is a nonoxidized nonfermented product which has similar phenolic compounds
to unprocessed tea leaves. To preserve the polyphenols present in green tea, the leaves are arranged on bamboo surfaces and are
exposed to the sun for a few hours, then they are steamed (Japanese Style Green Tea) or heated dried (Chinese Style Green Tea) to
inactivate enzymes involved in the modification of polyphenols. Drying phases are alternated with folding or rolling allowing water
to evaporate. When the leaves are well dried they are ready to be refined (dust and debris are eliminated) and packaged (Kosinska
and Andlauer, 2014). The most common polyphenols present in green tea are catechins: (-)-epigallocatechin-3-gallate (EGCG) ffi
59% of total catechins, (-)-epigallocatechin (EGC) (ffi 19%), (-)-epicatechin-3-gallate (ECG) (ffi 13.6%), (-)-epicatechin (EC), (þ)-
catechin (C), (-)-gallocatechin gallate (GCG) (ffi 6.4%) and glycosylated flavonols (Lin et al., 2008). They contribute to a higher
antioxidant capacity of green tea and its sensory properties. Green tea products are also available as highly concentrated extracts
(GTEs) for reconstituted tea drinks (in liquid and powdered forms) or supplements.
Recently, the EFSA ANS Panel provided a scientific opinion on the safety of green tea catechins from dietary sources including
food supplements and infusions as a result of concerns about the possible hepatotoxicity, concluding that the catechins contained
in green tea infusion and reconstituted drinks are risk-free. However, there is evidence from interventional clinical trials that intake
of doses above 800 mg EGCG/day as a food supplement, may be a health concern due to increased serum transaminases (EFSA,
Opinion 2018).
Previously peculiar to Asia, green tea is now gaining popularity in Western countries because its consumption seems to be linked
to health benefits, especially for its potential anticancer effects in primary and secondary prevention (Cabrera et al., 2006) and in
cancer therapy (Lecumberri et al. 2013). Several preclinical evidences have shown that EGCG is a multipotent chemopreventive and
anticancer agent in vitro and in various animal models (Fujita et al., 1989; Fujiki and Suganuma, 2002; Gupta et al., 2001; Yamane
 Diet and Cancer 25

et al., 1995; Yang et al., 2009; Yiannakopoulou, 2014). The mechanisms involved include inhibition of NF-kB signaling, protection
from intracellular oxidation and DNA damage and apoptosis in tumor cells (Roy et al., 2010; Sadava et al., 2007). However, in
contrast to the consistent results in in vitro and animal models, results from human studies are mixed (Johnson et al., 2012; Yuan,
2013). Two high quality systematic reviews assessed the link between green tea consumption and the risk of incidence, mortality
and recurrence of all cancer types (Bohem et al., 2009; Sturgeon et al., 2009). The authors concluded that despite the associations
between green tea consumption and decreased risk for some cancers, the overall evidence is limitated in quantity and quality.
In intervention studies an inhibitory role of oral supplementation of green tea on a precancerous lesion of the oral cavity was shown
(Li et al., 1999). A limited moderate to strong evidence has been investigated for lung cancer and seem inversely associated with
green tea intake among never smokers but not among smokers, probably due to the potential confounding effect of smoking that
cancel out the potential protective effect of green tea (Zhong et al., 2001). In prostate cancer, observational studies do not support a
role of tea intake in reducing risk but some phase II clinical trials suggested that green tea catechins may have chemopreventive
properties against prostate carcinogenesis (Bettuzzi et al., 2006).
The role of green tea infusion on cancer of the liver, colorectal and breast is not yet clear. However, two case control studies
investigated the role of genotypes and suggested that differing angiotensin converting and folate metabolism activity genotypes in
women probably play a role in the risk reduction of breast cancer with green tea (Inoue et al., 2008; Yoan et al., 2007).
A field to be investigate is the interaction between green tea/GTEs supplementation and cancer drug treatments. Studies showed
an interference between green tea supplementation and the chemotherapy drug Bortezomib (Golden et al., 2009) and Sunitinib
(Ge et al., 2011).
Until now, very little research has been done on the use of green tea or green tea extracts in treating cancer. Phase I and II trials of
daily oral somministration of a green tea extract to patients with a chronic lymphocytic leukemia, who did not take any other
treatment, showed that the number of leukemic cells and the size of their lymphones were reduced in a third of the participants
(Shanafelt et al., 2009, 2013). More evidence is needed to confirm these preliminary results. At present there is no conclusive
evidence that green tea helps to prevent or treat cancer in people because the number of studies especially randomized controlled
trials are lacking and studies conducted thus far have utilized different amounts and types of green tea in different settings which
makes it difficult to compare results.

References

Kosinska A and Andlauer W (2014) Antioxidant capacity of tea: Effect of processing and storage. In: Preedy V (ed.) Processing and impact on antioxidants in beverages, pp. 109–120.
Elsevier.
Lin LZ, Chen P, and Harnly JM (2008) New phenolic components and chromatographic profiles of green and fermented teas. Journal of Agricultural and Food Chemistry
56: 8130–8140.
European Food Safety Authority (EFSA) Panel on Food Additives and Nutrient Sources added to Food (ANS) (2018) Scientific opinion on the safety of green tea catechins. EFSA Journal
16: 5239.
Cabrera C, Artacho R, and Giménez R (2006) Beneficial effects of green tea: A review. Journal of the American College of Nutrition 25: 79–99.
Lecumberri E, Dupertuis YM, Miralbell R, and Pichard C (2013) Green tea polyphenl epigallocatechin-3-gallate (EGCG) as adjuvant in cancer therapy. Clinical Nutrition 32: 894–903.
Fujita Y, Yamane T, Tanaka M, et al. (1989) Inhibitory effect of (-)-epigallocatechin gallate on carcinogenesis with N-ethyl-N’-nitro-N-nitrosoguanidine in mouse duodenum. Japanese
Journal of Cancer Research 80: 503–505.
Fujiki H and Suganuma M (2002) Green tea and cancer prevention. Proceedings of the Japan Academy 78: 263–270.
Gupta S, Hastak K, Ahmad N, Lewin JS, and Mukhtar H (2001) Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proceedings of the
National Academy of Sciences of the United States of America 98: 10350–10355.
Yamane T, Takahashi T, Kuwata K, et al. (1995) Inhibition of N-methyl-N’-nitro-N-nitrosoguanidine-induced carcinogenesis by (-)-epigallocatechin gallate in the rat glandular stomach.
Cancer Research 55: 2081–2084.
Yang CS, Wang X, Lu G, and Picinich SC (2009) Cancer prevention by tea: Animal studies, molecular mechanisms and human relevance. Nature Reviews. Cancer 9: 429–439.
Yiannakopoulou EC (2014) Effect of green tea catechins on breast carcinogenesis: A systematic review of in-vitro and in-vivo experimental studies. European Journal of Cancer
Prevention 23: 84–89.
Roy P, Nigam N, Singh M, et al. (2010) Tea polyphenols inhibit cyclooxygenase-2 expression and block activation of nuclear factor-kappa B and Akt in diethylnitrosoamine induced lung
tumors in Swiss mice. Investigational New Drugs 28(4): 466–471.
Sadava D, Whitlock E, and Kane SE (2007) The green tea polyphenol, epigallocatechin 3- gallate inhibits telomerase and induces apoptosis in drug-resistant lung cancer cells.
Biochemical and Biophysical Research Communications 360(1): 233–237.
Johnson R, Bryant S, and Huntley LA (2012) Green tea and gree tea catechin extracts: An overview of the clinical evidence. Maturitas 73: 280–287.
Yuan JM (2013) Cancer prevention by green tea: Evidence from epidemiologic studies. The American Journal of Clinical Nutrition 98: 1676S–1681S.
Bohem K, Borrelli F, Ernst E, et al. (2009) Green tea (Camellia sinensis) for the prevention of cancer. Cochrane Database of Systematic Reviews 3: CD005004.
Sturgeon JL, Williams M, and van Servellen G (2009) Efficacy of green tea in the prevention of cancers. Nursing and Health Sciences 11: 436–446.
Li N, Sun Z, Han C, and Chen J (1999) The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proceedings of the Society for Experimental Biology and
Medicine 220: 218–224.
Zhong L, Goldberg MS, Gao YT, et al. (2001) Population-based case-control study of lung cancer and green tea consumption among women living in Shanghai, China. Epidemiology
12: 695–700.
Bettuzzi S, Brausi M, Rizzi F, et al. (2006) Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial
neoplasia: A preliminary report from a one-year proof-of-principle study. Cancer Research 66: 1234–1240.
Inoue M, Robien K, Wang R, et al. (2008) Green tea intake, MTHFR/TYMS genotype and breast cancer risk: The Singapore Chinese health study. Carcinogenesis 29: 1967–1972.
Yoan JM, Koh WP, Sun CL, Lee HP, and Yu MC (2007) Green tea intake, ACE gene polymorphism and breast cancer risk among Chinese women in Singapore. Carcinogenesis
28: 1074–1078.
Golden EB, Lam PY, Kardosh A, et al. (2009) Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood 113(23):
5927–5937.
26 Diet and Cancer

Ge J, Tan BX, Chen Y, et al. (2011) Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: Potential risk of dimin- ished sunitinib bioavailability. Journal of
Molecular Medicine (Berl) 89(6): 595e602.
Shanafelt TD, Call TG, Zent CS, et al. (2009) Phase I trial of daily, oral polyphenol E in patients with asymptomatic rai stage 0 to II chronic lymphocytic leukemia. Journal of Clinical
Oncology 27: 3808–3814.
Shanafelt TD, Call TG, Zent CS, et al. (2013) Phase I trial of daily, oral polyphenol E in patients with asymptomatic rai stage 0 to II chronic lymphocytic leukemia. Cancer 119: 363–370.

Mediterranean Diet

Mediterranean Diet in Breast Cancer 26

Mediterranean Diet in Colorectal Cancer 27
Mediterranean Diet in Prostate Cancer 27
Mediterranean Diet in Endometrial Cancer 27
Mediterranean Diet in Pancreatic Cancer 27
Guidelines and Future Perspectives 27
References 27
Further Reading 29

The traditional Mediterranean diet represents the dietary pattern of the Mediterranean countries in 1960s (Kromhout et al., 1989;
Sofi et al., 2008; Sofi et al., 2013). The traditional Mediterranean diet is characterized by a high intake of vegetables, legumes, fruits,
nuts, unprocessed cereals and extra virgin olive oil as the main source of fat, it is also characterized by a low intake of saturated fats,
meat and poultry, moderately high intake of fish, moderately low intake of dairy products and ethanol, mainly wine and generally
during meals (Willett et al., 1995; Sofi et al., 2014). The Mediterranean diet contributes to the intake of important vitamins and
phytochemicals including b-carotene, vitamins B, C, and E, folic acid, polyphenols and it contains on average: 55%–60%
carbohydrates (80% complex carbohydrates and 20% simple sugars mainly from fruit), 10%–15% proteins (40% plant protein),
and 25%–30% fats (mainly monousaturated fat from olive oil). The traditional Mediterranean diet received a great attention in the
1970s by the American physiologist Ancel Keys who lived for many years in Southern Italy and conducted the Seven Countries
Study, the first major epidemiological study to investigate the relationship between diet and lifestyle in cardiovascular disease across
countries and cultures (Menotti et al., 1989; Serra-Majem et al., 2006). This study suggested that the Mediterranean diet is protective
against cardiovascular disease and cancer (Ferro-Luzzi and Branca, 1995). Numerous epidemiological studies showed that the
Mediterranean diet is associated with a risk reduction of overall mortality, cardiovascular disease incidence and mortality, total
cancer incidence and mortality, 25% reduction in colorectal cancer, 15% in breast cancer, and 10% in prostate, pancreas and
endometrial cancers (Bloomfield et al., 2016).

Mediterranean Diet in Breast Cancer

High adherence to Med Diet has been shown to reduce incidence and recurrence of breast cancer (Bloomfield et al., 2016). A large
European observational study supports a protective role of the Med Diet and its components in breast cancer risk (Buckland et al.,
2013). In international studies outside the Mediterranean basin, reductions in breast cancer risk have been observed with higher
consumption of components of the Med Diet such as dietary fiber, low glycemic index carbohydrates, whole grains, fruit and
vegetables and dietary marine o – 3 (Farvid et al., 2016; Kushi et al., 2012; Nicodemus et al., 2001; Zheng et al., 2013). The
intervention study PREDIMED (Prevención con Dieta Mediterránea), showed that a Spanish Med Diet supplemented with at least
20% of calories as extra virgin olive oil reduced the incidence of breast cancer by 68% after 4.8 years (Toledo et al., 2015). Possible
mechanisms seem to be linked to reduced inflammation, higher antioxidant, antiproliferative and apoptosis-inducing properties of
specific compounds present in vegetables, fruit, nuts, extra virgin olive oil and fish, flavonoids such as polyphenols present in olive
oil and red wine, dietary fiber and vitamin C present in vegetables and fruit, lignans in whole grains and seeds, monounsaturated fat
and squalene in olive oil, and omega-3 fatty acids in fish (Dussaillant et al., 2016; Jing et al., 2013) improving insulin sensitivity and
decreasing insulin-like growth factors (Barnard et al., 2006; Breneman and Tucker, 2013). In addition the antioxidant content in
extra virgin olive oil (Carruba et al., 2006) may decrease endogenous estrogens, increase sex-hormone binding globulin levels
(Wu et al., 2009), neutralize free radicals, prevent DNA damage and reduce oxidative stress (Mitjavila et al., 2013; Visioli et al.,
2004). These results are confirmed also by the DIANA-5 study (Diet and Androgens) (Villarini et al., 2012).
 Diet and Cancer 27

Mediterranean Diet in Colorectal Cancer

The Med diet seems to be implicated also in a decreased risk of colorectal cancer although some studies are discordant. It seems that
the positive effects of the Med Diet are more evident for the distal colon rather than the proximal colon (Donovan et al., 2017).
Possible mechanisms are the antinflammatory effects as reported by preclinical studies. In vitro studies attributed this effect to the
phenolic fraction and o – 3 content of olive oil and partly also to oleic acid, polyphenols from grapes, red wine, fruits and
vegetables (Llor et al., 2003). Other studies assess that butyrate, produced from fiber by microorganisms in the gut, contribute to the
oncoprotective effect. Future studies will focus on the role of the Med diet on epigenetic regulation and on changes of the
microbiome as means of reducing colorectal cancer risk.

Mediterranean Diet in Prostate Cancer

Approximately 10% of the incidence of prostate cancer can be prevented following a traditional Mediterranean dietary pattern
(Capurso and Vendemiale, 2017), reducing risk by 4% (Bloomfield et al., 2016). Possible protective compounds may be flavonoids
in fruit and vegetables which exert antiinflammatory, antioxidant, antimutagenic and antiproliferative activities (Vance et al., 2013).
Important is the antioxidation ativity of lycopene from tomatoes which modulate inflammatory mechanisms of carcinogenesis
(Gann et al., 1999; Graff et al., 2016). Numerous studies are also investigating the antiflammatory action of o – 3 derived from fish
in prostate cancer prevention and progression (Thompson et al., 2014; Aucoin et al., 2017).

Mediterranean Diet in Endometrial Cancer

Evidence associating endometrial cancer risk and specific dietary components are limitated. Howewer a 10% protection was found
with the highest adherence to the Med Diet (Schwingshackl et al., 2017). Bioactive compounds and fiber of vegetables and fruit, as
well as monounsatured fatty acid of extra virign olive oil, seem to modulate the estrogen levels and the inflammatory response.
(Bravi et al., 2009; Filomeno et al., 2015; Lampe, 1999; Bandera et al., 2007; Fortner et al., 2017; Wang et al., 2011; Rose, 1990).

Mediterranean Diet in Pancreatic Cancer

Studies on the association between the Med Diet and pancreatic cancer are scanty and discordant. Howewer some studies suggest a
protection of 10% for an high adherence to the Med Diet (Trichopoulou et al., 2000) possibly due to the high consumption of
vegetables and fruit because of vitamin C, D, E, and K, folate and phenolic compounds (Larsson et al., 2006; Nothlings et al., 2007;
Rossi et al., 2012; Trichopoulou et al., 2000; Buckland et al., 2013; Giacosa et al., 2013; Davis-Yadley and Malafa, 2015).

Guidelines and Future Perspectives

Scientific evidence supports healthy benefits of Mediterranean dietary pattern in primary and secondary prevention for the most
common types of cancer. The World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR), based
on scientific evidence, including the European code against cancer, provided lifestyle recommendations aimed to reduce the
incidence and recurrence of the most common cancers worldwide. The recommendations are to avoid sugared beverages and
processed meat and to limit calorie-dense and salty food, alcoholic beverages and red meat. The central recommendation is to “Eat
mostly food of plant origin, with a variety of nonstarchy vegetables and of fruit every day and with unprocessed cereals and/or
pulses within every meal”. these recommendations are at the base of the Med diet characteristics.(WCRF/AICR, 2007, www.iarc.it).

References
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28 Diet and Cancer

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www.iarc.ithttps://cancer-code-europe.iarc.fr/index.php/it/.

Fasting and Intermittent Fasting Diet

Evidence in Cancer 29
Mechanisms 30
Future Directions 30
References 31
Further Reading 31

In the last decades a range of dietary interventions have gained considerable popularity for the prevention and treatment of age-
related diseases, including cancer. Calorie restriction (CR) as well as fasting regimens are both dietary interventions of reduced
caloric intake without malnutrition and have demonstrated a wide range of beneficial effects potentially able to prevent cancer and
increase the efficacy of cancer therapies (Varady and Hellerstein, 2007; Mattson et al., 2017; Buono and Longo, 2018). Calorie
restriction (CR) is a term commonly used to refer to a 20%–40% reduction in caloric intake without malnutrition (e.g., with an
adequate micronutrient intake) (Mirzaei et al., 2016; Varady and Hellerstein 2007). As CR is not well tolerated by cancer patients
and contraindicated for those at risk of weight loss, cachexia and sarcopenia, other caloric restricted approaches have been
investigated, such as intermittent fasting (IF) which may be more suitable (Varady and Hellerstein, 2007; Rizza et al., 2014)
Fasting refers to a complete absence of food intake. The fasting period for the organism is a time for standby and repair in order
to harvest energy when food becomes available (Longo and Panda, 2016). Alternate cycle of feeding and fasting are at the base of
fasting physiology. Fasting can be administered at various time frames and can be repeated many times. Both reducing daily energy
intake and restricting the time of food intake to a few hours may trigger the fasting physiology (Longo and Panda, 2016). IF
comprises different forms of fasting including alternate day fasting (ADF), periodic fasting (PF), time-restricted feeding (TRF) and
Ramadan fasting (Longo and Mattson, 2014; Varady, 2016). ADF regimens generally involve a 24-h fast followed by a 24-h non-
fasting period (Horne et al., 2015). PF only requires participants to fast two or more consecutive days per week, every 2 or more
weeks (Hutchison and Heilbronn, 2016). TRF requires individuals to confine the period of food intake to a set period of time during
the day, for example an 8-h feeding window where all food is consumed between 10:00 am and 6:00 pm (Rothschild et al., 2014).
The Islamic ritual of Ramadan fasting is a form of time-restricted feeding, where food consumption is only permitted during the
night time (Mazidi et al., 2015).

Evidence in Cancer

Data from epidemiological and experimental studies suggest that calorie intake, the timing of food intake (e.g., fasting cycles), and
dietary composition (e.g., protein, aminoacid, fat, mineral, vitamin and phytochemical intakes) are implicated in the pathogenesis
of chronic diseases, including common types of cancer (Fontana et al., 2010; Mattson, 2005; Eyre et al., 2004).
30 Diet and Cancer

Chronic CR provides both beneficial and detrimental effects as well as major compliance challenges, whereas different fasting
regimens, without malnutrition, are emerging as interventions with the potential to be widely used to prevent and treat cancer
(Patterson and Sears, 2017; Buono and Longo, 2018; Lee et al., 2012b; O’Flanagan et al., 2017).
First experiments in animal models demonstrated that fasting exerts a protective effect against DNA damage and promotes
longevity (Longo and Fontana, 2010; Varady and Hellerstein, 2007). IF reduces the incidence of spontaneous tumors (Berrigan
et al., 2002; Descamps et al., 2005), while PF can delay cancer progression as effectively as chemotherapy in animal models (Lee
et al., 2012b). No data are available on the effects of IF on cancer rates in humans. Surrogate evidence that IF may reduce cancer risk
can be derived from its effects on cancer risk factors. For example, most studies of ADF show benefits in weight reduction (Tinsley
and La Bounty, 2015) and weight control is associated with a reduced risk of cancer (Renehan et al., 2008). IF has a beneficial effect
on insulin resistance and diabetes which are cancer prognostic factors (Goodwin et al., 2015). Some studies have investigated the
effect of fasting on the effectiveness of cancer therapy. Preliminary studies in 10 cancer patients fasted voluntarily during their
chemotherapy and showed a decrease in the range of self-reported common side effects caused by chemotherapy compared to when
they were on a standard diet (Safdie et al., 2009; Raffaghello et al., 2010b).

Mechanisms

CR and fasting have been shown to promote stress resistance as well as longevity in a wide variety of animal models. These dietary
regimens affect cellular metabolism and growth by down regulating conserved nutrient-signaling proteins and by activating stress
resistance transcription factors (Fontana et al., 2010). Metabolic and molecular antitumorigenic mechanisms of CR are well
established. Accumulating data have showed that CR tumor suppressive effects are mediated by enhanced apoptosis, modulation
of systemic signals such as IGF-1, insulin, metabolic and inflammatory pathways, and reduced angiogenesis (O’Flanagan et al.,
2017; Fontana et al., 2010). Indirect evidence suggests that CR and fasting regimens may share common mechanisms. To date no
data from human studies on the effect of IF or PF in cancer prevention are available. However their effect on reducing IGF-1, insulin
and glucose levels, and increasing IGFBP1 and ketone body levels could generate a protective environment that reduces DNA
damage and carcinogenesis, while at the same time creating hostile conditions for cancer and pre-cancerous cells (Longo and
Mattson 2014). Elevated circulating IGF-1 is associated with an increased risk of developing several cancers (Chan et al., 2000;
Giovannucci et al., 2000) and individuals with severe IGF-1 deficiency caused by growth hormone receptor deficiency, rarely
develop cancer (Guevara-Aguirre et al., 2011; Shevah and Laron, 2007). Findings in IGF-1 deficient subjects suggest that fasting may
protect from cancer by reducing cellular and DNA damage but also by enhancing the programmed cell death of precancerous cells
(Guevara-Aguirre et al., 2011). However, the effect of IF on IGF-1 levels in human studies has been variable. Some studies reported
no changes in IGF-1 with weight loss due to intermittent fasting (Harvie et al., 2011), and others showed an increase in both IGFBP1
and IGFBP2 (Harvie et al., 2011; Fontana et al., 2010; Thissen et al., 1994). It is well established that a positive energy balance, as
well as an increasing adiposity contributes to an increased risk of developing several types of cancer, including cancer of the colon,
breast, prostate, endometrium, pancreas, liver and kidney, whereas weight loss lowers risk (Longo and Fontana, 2010; Calle and
Kaaks, 2004).
Evidence demonstrates the important role of dysregulation in signal transduction and metabolic pathway in tumor initiation
and progression. Cancer cells are characterized by an abnormally high level of glucose requirements necessary to produce the
glycolytic ATP, as well as by accumulation of a variety of mutations (e.g., the IGF-1 receptor) (Buono and Longo, 2018) making
them potentially sensitive to the changes in growth factors and circulating nutrients. Furthermore, a differential stress resistance
(e.g., cell mechanism used during fasting to protect normal cells but not cancer cells from chemotherapy) and differential stress
sensitization (e.g., cell mechanism used during fasting to preferentially kill cancer cells and other damaged cells in combination
with chemotherapy or other cytotoxic agents) of fasting conditions in normal and cancer cells have been showed in in vitro and
animal models (Buono and Longo, 2018; Raffaghello et al., 2008). Fasting conditions can be protective in normal cells because they
are capable of adapting to starvation (Raffaghello et al., 2008) whereas cancer cells are characterized by inability to adapt to multi-
stressed environments (Cheng et al., 2014; Lee et al., 2012b).

Future Directions

Several epidemiological studies clearly demonstrated that diet plays an important role in the initiation, promotion and progression
of many common cancers (Kushi et al., 2006; Renehan et al., 2010). To date, there are no specific guidelines on the type of nutrition
for each cancer type or cancer stage. According to the American Cancer Society, cancer patients receiving chemotherapy should
increase calorie and protein intake (Doyle et al., 2006).
Findings from in vitro and animal studies have reported beneficial effects of combined fasting regimens with the standard-of-
care pharmacotherapy. Dietary interventions mimicking CR can also be viewed as adjuvant anticancer strategies to be combined to
standard cancer therapy (chemotherapeutic agents, ionizing radiation, and drugs with specific molecular targets). Clinical studies
on the potential use of dietary treatments alongside conventional treatments are ongoing however the preliminary evidence suggests
that these approaches may be a valid integrated therapy in cancer patients.
 Diet and Cancer 31

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Further Reading
Lee C and Longo VD (2011) Fasting vs dietary restriction in cellular protection and cancer treatment: From model organisms to patients. Oncogene 30(30): 3305–3316.
Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, et al. (2012a) Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to
chemotherapy. Science Translational Medicine 4: 124–127.
Raffaghello L and Longo V (2017) Metabolic alterations at the crossroad of aging and oncogenesis. International Review of Cell and Molecular Biology 332: 1–42.
Raffaghello L, Safdie F, Bianchi G, Dorff T, Fontana L, and Longo VD (2010a) Fasting and differential chemotherapy protection in patients. Cell Cycle 9(22): 4474–4476.
Varady KA (2011) Intermittent versus daily calorie restriction: Which diet regimen is more effective for weight loss? Obesity Reviews 12(7): e593–e601.