Sei sulla pagina 1di 35

BMS5012

Cancer Biology and Therapeutics

BMS5012 Cancer Biology and Therapeutics

Cancer and Metabolism

Renea Taylor Department of Physiology

Unless otherwise indicated, the following notice may apply to content within this lecture:

COMMONWEALTH OF AUSTRALIA

Copyright Regulations 1969 WARNING

This material has been reproduced and communicated to you by or on behalf of Monash University pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice.

© Monash University

material by you may be the subject of copyright protection under the Act. Do not remove
material by you may be the subject of copyright protection under the Act. Do not remove
Overview of the lecture

Overview of the lecture

Overview of the lecture

What is Cancer Metabolism?

The link between cancer and obesity

Obesity driven cancer progression

Learning objectives

Learning objectives

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

Hallmarks of Cancer

Hallmarks of Cancer
Hallmarks of Cancer Hanahan & Weinberg, Cell, 2011
Hallmarks of Cancer Hanahan & Weinberg, Cell, 2011
Hallmarks of Cancer Hanahan & Weinberg, Cell, 2011
Hallmarks of Cancer Hanahan & Weinberg, Cell, 2011
Hallmarks of Cancer Hanahan & Weinberg, Cell, 2011

Hanahan & Weinberg, Cell, 2011

What is Cancer Metabolism?

What is Cancer Metabolism?

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.

the alterations in cellular metabolism pathways that are evident in cancer cells compared with most normal
Metabolism in Cancer: Warburg Effect

Metabolism in Cancer: Warburg Effect

Metabolism in Cancer: Warburg Effect
Metabolism in Cancer: Warburg Effect Cancer cells produce energy by a high rate of glycolysis followed

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

Metabolism in Cancer: Warburg Effect

Metabolism in Cancer: Warburg Effect
Metabolism in Cancer: Warburg Effect Liberti and Locasale, Trends in Biological Sciences, 2016

Liberti and Locasale, Trends in Biological Sciences, 2016

Signalling pathways that regulate Cancer Metabolism

Signalling pathways that regulate Cancer Metabolism

Signalling pathways that regulate Cancer Metabolism
Signalling pathways that regulate Cancer Metabolism DeBerardinis and Chandel Sci. Adv. 2016; 2 : e1600200

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

Metabolism in Cancer – Fatty acids Periprostatic adipose tissue VLDL Systemic circulation Fatty acid CD36

Metabolism in Cancer – Fatty acids

Metabolism in Cancer – Fatty acids Periprostatic adipose tissue VLDL Systemic circulation Fatty acid CD36 Glucose
Metabolism in Cancer – Fatty acids Periprostatic adipose tissue VLDL Systemic circulation Fatty acid CD36 Glucose

Periprostatic adipose tissue

in Cancer – Fatty acids Periprostatic adipose tissue VLDL Systemic circulation Fatty acid CD36 Glucose Lactate
in Cancer – Fatty acids Periprostatic adipose tissue VLDL Systemic circulation Fatty acid CD36 Glucose Lactate

VLDL

in Cancer – Fatty acids Periprostatic adipose tissue VLDL Systemic circulation Fatty acid CD36 Glucose Lactate

Systemic circulation

Fatty acid CD36
Fatty acid
CD36

Glucose

Lactate

G-6-P ATP Pyruvate
G-6-P
ATP
Pyruvate
Fatty acid
Fatty acid

Triglyceride

ACC1 Citrate Acetyl CoA
ACC1
Citrate
Acetyl CoA

Phospholipid

Sterol lipid

Signalling molecules

Pyruvate Fatty acid Triglyceride ACC1 Citrate Acetyl CoA Phospholipid Sterol lipid Signalling molecules ATP Glutamine

ATP

Glutamine

https://www.youtube.com/watch?v=kYmLQP2M-qo

Therapeutic Approaches to Cancer

Therapeutic Approaches to Cancer

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

getting therapeutic window accurate to as to not interfere with normal cell processes Hanahan & Weinberg,

Hanahan & Weinberg, Cell, 2011

Cancer Imaging

Cancer Imaging

Cancer Imaging

¨ Glycolysis and other metabolic activity allows tumours to be detected by PET scanning (non-invasive diagnosis)

¨ Glycolysis and other metabolic activity allows tumours to be detected by PET scanning (non-invasive diagnosis)
¨ Glycolysis and other metabolic activity allows tumours to be detected by PET scanning (non-invasive diagnosis)
Multiple choice question (MCQ)

Multiple choice question (MCQ)

Multiple choice question (MCQ)

ŸA

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

ŸA

ŸA

ŸA

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
Obesity and Cancer

Obesity and Cancer

Overweight and obesity predictions

Overweight and obesity predictions

Overweight and obesity predictions
Overweight and obesity predictions Inescapable conclusion is that clinicians will be treating more obese patients in

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

Obesity and Cancer

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)

Obesity and Cancer Incidence (meta-analysis)

Obesity and Cancer Incidence (meta-analysis)
Obesity and Cancer Incidence (meta-analysis) Renehan et al Lancet 371: 569–78, 2008.

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

Obesity and Cancer Incidence (meta-analysis)

Obesity and Cancer Incidence (meta-analysis)

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

Prostate Cancer Progression

Prostate Cancer Progression

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

General Population: 10-15 years / Obese men: 4-8 years Surgery Radiation Therapy Active Surveillance Androgen
Surgery Radiation Therapy Active Surveillance Androgen Ablation Therapy Castrate-Resistant Prostate Cancer Death
Surgery
Radiation Therapy
Active Surveillance
Androgen
Ablation Therapy
Castrate-Resistant
Prostate Cancer
Death
Tumour Burden

Normal

Localised

Advanced

Castration Resistant

Multiple choice question (MCQ)

Multiple choice question (MCQ)

Multiple choice question (MCQ)

ŸA

Epidemiological evidence indicates that:

ŸA

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
Obesity driven cancer progression

Obesity driven cancer progression

Obesity driven cancer progression
Features of Obesity

Features of Obesity

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

– Active endocrine organ • Associated with secondary metabolic effects – E.g. Insulin resistance – Inflammatory
Obesity and Cancer – Possible mechanisms

Obesity and Cancer – Possible mechanisms

Obesity and Cancer – Possible mechanisms
1 2 3 4
1
2
3
4
1. Fatty acid action in Cancer

1. Fatty acid action in Cancer

1. Fatty acid action in Cancer
Proliferation, Second survival, Messengers migration/invasion Signalling Wnt Others
Proliferation,
Second
survival,
Messengers
migration/invasion
Signalling
Wnt
Others
2. Adipocytes and Inflammation

2. Adipocytes and Inflammation

2. Adipocytes and Inflammation
2. Adipocytes and Inflammation TNF-α, IL-6, IL1ß Healthy Obese lean Hypertrophy Hypoxia Cell death Inflammation ECM
2. Adipocytes and Inflammation TNF-α, IL-6, IL1ß Healthy Obese lean Hypertrophy Hypoxia Cell death Inflammation ECM

TNF-α, IL-6, IL1ß

2. Adipocytes and Inflammation TNF-α, IL-6, IL1ß Healthy Obese lean Hypertrophy Hypoxia Cell death Inflammation ECM
Healthy Obese
Healthy
Obese

lean

and Inflammation TNF-α, IL-6, IL1ß Healthy Obese lean Hypertrophy Hypoxia Cell death Inflammation ECM

Hypertrophy Hypoxia Cell death Inflammation ECM remodelling

Obesity induces:
Obesity induces:

Tumour

2. Cytokines and Cancer

2. Cytokines and Cancer

2. Cytokines and Cancer
2. Cytokines and Cancer
2. Cytokines and Cancer

2. Cytokines and Cancer

2. Cytokines and Cancer
2. Cytokines and Cancer
2. Inflammation and Cancer

2. Inflammation 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

• Metastasis • Chronic inflammation is proposed to be a ‘causative’ factor for cancer – Pre
3. Insulin and IGF-1

3. Insulin and IGF-1

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

3. Insulin and IGF-1

3. Insulin and IGF-1
3. Insulin and IGF-1
Metabolism -based therapies

Metabolism-based therapies

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

to stimulate AMPK, which is also growth stimulatory • Highlights importance of understanding biology in drug
Overview of Mechanisms

Overview of Mechanisms

Overview of Mechanisms
Overview of Mechanisms
Multiple choice question (MCQ)

Multiple choice question (MCQ)

Multiple choice question (MCQ)

ŸA

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

ŸA

ŸA

ŸA

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

Summary

Summary

Summary
Lipids Fatty Acids Obesity Steroids Cytokines (Pro-tumorigenic) Insulin / IGF1 Inflammatory cells
Lipids
Fatty Acids
Obesity
Steroids
Cytokines
(Pro-tumorigenic)
Insulin / IGF1
Inflammatory cells