BMS5012

Cancer Biology and Therapeutics

Cancer and Metabolism

Renea Taylor
Department of Physiology

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 Overview of the lecture

What is Cancer Metabolism?

The link between cancer and obesity

Obesity driven cancer progression

 Learning objectives

Upon the conclusion of this lecture and relevant reading, you should be able to:

Obj 1: Identify the major substrates of metabolism and understand the Warburg effect

Obj 2: Identify the association between obesity and cancer

Obj 3: Describe the main adipocyte-related factors of obesity that contribute to cancer progression
Hallmarks of Cancer

Hanahan & Weinberg, Cell, 2011

 What is Cancer Metabolism?

Cancer metabolism refers

to the alterations in
cellular metabolism
pathways that are evident
in cancer cells compared
with most normal tissue
cells.

higher requirement of energy —>

increase the supply
 Metabolism in Cancer: Warburg Effect

cancer cell will always use this

pathway

Cancer cells produce energy by a high rate of glycolysis followed by lactic

acid fermentation rather than glycolysis followed by oxidation of pyruvate
(even in the presence of sufficient oxygen)
Metabolism in Cancer: Warburg Effect

Liberti and Locasale, Trends in Biological Sciences, 2016

Signalling pathways that regulate Cancer
Metabolism

DeBerardinis and Chandel Sci. Adv. 2016; 2 : e1600200

Metabolism in Cancer – Fatty acids

Periprostatic adipose tissue VLDL Systemic circulation

Fatty acid

CD36

Fatty acid Triglyceride

Glucose G-6-P
ACC1
ATP Phospholipid
Sterol lipid
Citrate

Lactate Pyruvate Signalling molecules

Acetyl CoA

ATP
Glutamine
https://www.youtube.com/watch?v=kYmLQP2M-qo
 Therapeutic Approaches to Cancer

1. Glycolysis inhibitors

2. Other substrates in
different tumor types

3. Other cancer treatments

also effect metabolism

4. Importance of getting
therapeutic window
accurate to as to not
interfere with normal cell
processes

Hanahan & Weinberg, Cell, 2011

 Cancer Imaging

¨ Glycolysis and other metabolic activity allows tumours to

be detected by PET scanning (non-invasive diagnosis)
 Multiple choice question (MCQ)

ŸA
The Warburg Effect states
ŸA that cancer cells
predominantly produce energy
ŸA
ŸA
by:

a)Fatty acid uptake and oxidation

b)Glycolysis followed by lactic acid fermentation
c) Oxidative breakdown and metabolism of pyruvate
d)Replicating mitochondrial DNA
Obesity and Cancer
 Overweight and obesity predictions

Inescapable conclusion is that clinicians will be treating more obese

patients in the future.

Source: Haby M M et al. Health Promot. Int. 2012;27:250-260

 Obesity and Cancer

• Incidence - do people get cancer because

they’re fat?

“Being overweight or obese increases your risk

of developing certain types of cancer, including
common forms such as bowel and (post-
menopausal) breast cancer, as well as cancers of
the endometrium, kidney and oesophagus”.

Cancer Council Australia

https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet
Obesity and Cancer Incidence (meta-analysis)

Renehan et al Lancet 371: 569–78, 2008.

 Obesity and Cancer Incidence (meta-analysis)

§ Endometrial: higher all-cause mortality hazard ratio =

1.85 (95% CI 1.19-2.88).
§ Ovarian: marginal, higher all-cause mortality hazard
ratio = 1.15 (95% CI 0.92-1.41)
§ Prostate: marginal, higher biochemical recurrence
hazard ratio = 1.16 (RR 1.16, 95 % CI 1.08–1.24)

Most likely that obesity should be viewed as an

aggressive tumour promoter, rather than a cause of
cancer.
 Prostate Cancer Progression

Faster the progressive of cancer

General Population: 10-15 years / Obese men: 4-8 years

Androgen Castrate-Resistant
Surgery Death
Ablation Therapy Prostate Cancer
Radiation Therapy
Tumour Burden

Active Surveillance

Normal Localised Advanced Castration Resistant

 Multiple choice question (MCQ)

ŸA
Epidemiological evidence
ŸA indicates that:
ŸA
ŸA
a)Obesity and cancer are unrelated
b)Cancer is caused by people being overweight
c) Obese patients often have worse outcomes
compared to lean patients
d)Obesity causes patients to respond poorly to
cancer treatments
Obesity driven cancer progression
 Features of Obesity

• Defined as excess accumulation of adipose tissue

• Adipose tissue stores excess energy as triglyceride
– Excess lipid in obesity
– Dysregulated lipid biology in obesity
– Active endocrine organ
• Associated with secondary metabolic effects
– E.g. Insulin resistance
– Inflammatory
Obesity and Cancer – Possible mechanisms

4 female
1. Fatty acid action in Cancer
major fuel substrate for cancer cell

Proliferation,
Second
survival,
Messengers
migration/invasion

Signalling
Wnt
Others
 2. Adipocytes and Inflammation

thiss region does not supply with oxygen

because not attacht in blood vessel

Healthy TNF-α, IL-6, IL1ß

Obese
lean Obesity induces:
Hypertrophy
Hypoxia
Cell death
Tumour Inflammation
ECM remodelling
2. Cytokines and Cancer
2. Cytokines and Cancer
 2. Inflammation and Cancer

• Immune infiltration into adipose tissue includes macrophages

– Tumour associated macrophages
• Tissue invasion
• Angiogenesis
• Metastasis
• Chronic inflammation is proposed to be a ‘causative’ factor for
cancer
– Pre-malignancy
 3. Insulin and IGF-1

• Most obese people have some degree of insulin resistance.

• Elevated (but ineffective) circulating insulin.
• Diabetes is also associated with poor cancer progression.
• Insulin stimulates proliferation and metastasis.
• Hyperinsulinemia also increases production of IGF1 and IGF2.
3. Insulin and IGF-1
 Metabolism-based therapies

• Metformin – anti-diabetic drug

• Suppresses the actions of insulin and insulin-like growth factors - two
molecules that support cancer growth
• Data have shown mixed results – appears to stimulate AMPK, which is also
growth stimulatory
• Highlights importance of understanding biology in drug development
Overview of Mechanisms
 Multiple choice question (MCQ)

ŸA
_________ are a major cell
ŸA type in obese patients
that promote cancer growth
ŸA
ŸA
are:

a) Cancer cells
b) Adipocytes
c) Cancer-associated fibroblasts
d) Blood vessels
 Summary

Lipids Fatty Acids

Steroids Obesity Cytokines

(Pro-tumorigenic)
Insulin / IGF1 Inflammatory cells