Lecture 29; Obesity and Cancer

Question 1

How does obesity relate to cancer?

Answer 1

BMI is associated with increased risk of several common and less common cancers in a sex- and site-specific manner

Question 2

What has meta-analysis shown regarding cancer and obesity?

Answer 2

quantifying associations between a 5- kg/m2 BMI increase and risk of incident cancer.

Question 3

What are some common cancers with obesity?

Answer 3

Endometrial
Esophageal adenocarcinoma
ColorectalPost-menopausal breast
Prostrate
Renal cancer

Question 4

What are some less common cancers associated with obesity?

Answer 4

Leukemia
Non-Hodgkin’s lymphoma
Melanoma
thyroid

Question 5

Does losing weight reduce risk of cancer? What does a follow up bariatric surgery show?

Answer 5

Long-term follow-up of patients undergoing bariatric surgery for morbid obesity point to a reduction in cancer incidence (limited to women) associated with weight loss – supports a causal association between obesity and cancer risk. Swedish obese subjects study showed that 20 years after surgery the overall rate of cancer in women was around 50% lower in people who had undergone surgery compares to controls.

Question 6

What does obesity provide for cancers?

Answer 6

Note that its not currently thought that obesity/diabetes increases mutation rate but that it provides a good environment for tumours to grow in.

Question 7

What are the possible biological mechanisms of obesity induced cancer growth? 1->3

Answer 7

1. Insulin and insulin-like growth factors (IGFs) associated with insulin resistance might drive tumours.
2. High glucose levels associated with diabetes may drive tumourgrowth.
3. Raised levels of sex steroids might be be directly driving some tumours (e.g. estrogen).

Question 8

What are the possible biological mechanisms of obesity induced cancer growth? 4 & 5

Answer 8

4. Dysregulated cholesterol metabolism might play a role. Statin treatments know to decrease risk of developing some cancers
5. Adipokines and cytokines produced in the low grade inflammation in obesity might be affect the tumour environment in cancers and assist tumour cell growth or allow them to evade immune detection.

These factors enhance the growth of cancers and allows their survival rather than causing them.

Question 9

How does insulin and IGF1 relate to cancer?

Answer 9

Circulating insulin levels positively correlate with increasing BMI, and many obese persons are insulin resistant.

Hypothesis:Prolonged hyperinsulinemia reduces production of IGF binding proteins (IGFBP-1 and IGFBP2) which results in increased levels of free or bioactive IGF-1.

The high insulin levels may also directly drive cancer in some cases.

Question 10

In what cancers are high levels of IGF used as a prognostic marker?

Answer 10

High insulin levels and insulin resistance are an adverse prognostic factor for breast, colorectal and prostate cancer-related mortalities.

Question 11

What can insulin machinary do?

Answer 11

Insulin signaling has the machinery to be mitogenic and anti-apoptotic: triggers intracellular signaling cascades in both the extracellular-signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI-3K) pathways.

Question 12

How does insulin mediate its proliferative effects that may relate to cancer?

Answer 12

Thought that insulin is mitogenic only at supraphysiological levels and its main proliferative effects are probably mediated through IGF-1 receptors.

Question 13

How does IGF1 relate to cancer?

Answer 13

Relationship between BMI and circulating IGF-1 and IGF-1 binding proteins are complex and non-linear but elevated free IGF-1 in obese individuals is a consistent observation.

Meta-analyses support relationships between total IGF-1 levels and risk of colorectal, prostate, and premenopausal breast cancer.

Signaling processes downstream of IGF-1R activation are similar to those for insulin and include ERK and PI-3K pathways.

Question 14

What is the first Inconsistencies associated with Insulin-IGF-1and obesity hypothesis?

Answer 14

1.IGF-1 levels do not increase with increasing fatness in humans like they do in mice. Total levels of human IGF-1 increase to a pivotal point BMI = 27 kg/m2 and then decline with increasing weight.

Question 15

What is the second Inconsistencies associated with Insulin-IGF-1and obesity hypothesis?

Answer 15

2.Total IGF-1 levels tend to increase in humans who intentionally lose weight.

Question 16

What is the third Inconsistencies associated with Insulin-IGF-1and obesity hypothesis?

Answer 16

3.Drugs targeting IGF1R haven’t really been effective in human clinical trials

Question 17

How does obesity, sex hormones and cancer interplay?

Answer 17

Increased adipose tissue results in increased expression of the enzyme aromatase, which is responsible for converting androgens to estrogens.

Question 18

How come postmenopausal women who are obese are at higher risk?

Answer 18

For postmenopausal breast cancer, the increased risk observed in obese women is generally explained by the higher rates of conversion of androgens to estradiol.

Question 19

What are the effects of sex hormones?

Answer 19

Estrogens are mitogenic in normal and neoplastic mammary tissues.

Question 20

How are testosterone levels and obesity related?

Answer 20

Adiposity is inversely related to testosterone concentrations in men but positively related in women.

Question 21

What does obesity and insulin resistance lead to in terms of bioavailability of estrogen?

Answer 21

Obesity and insulin resistance lead to decreased production of sex hormone-binding globulin (SHBG) resulting in increased bioavailability of estrogen

Question 22

How does estradiol and IGF1 relate?

Answer 22

Proliferative actions of estradiol on endometrial tissue are mediated by an increase in the local production of IGF-1.

Progesterone diminishes estrogenic action in the endometrium by stimulating metabolism of estradiol and inducing synthesis of IGFBP-1, which inhibits IGF-1 action.

Question 23

How does the estrogen and IGF1 receptor work together to stimulate tumor growth in the endometrium?

Answer 23

The estrogen receptor and IGF1R can work together to activate MAPK thus stimulating tumor proliferation.

Epidemiology studies how that higher levels of plasma estradiol are associated with increased endometrial cancer risk in postmenopausal women.

Question 24

What do adipose tissue produce?

Answer 24

50+ different adipokines

Question 25

How does leptin relate to insulin?

Answer 25

Leptin is intrinsically associated with insulin. Insulin acts as a positive feedback on leptin expression. Both short and long forms of the leptin receptor are present in cancers and the short forms mainly activate MAPK and proliferation with little effect on STAT activation.

Question 26

What has studies shown regarding leptin and cancer?

Answer 26

However, epidemiology studies relating serum leptin with cancer risk have reported inconsistent findings

Question 27

What are newer hypotheses regarding obesity and cancer?

Answer 27

1. Obesity-related hypoxia
2. Shared genetic susceptibility
3. Migrating adipose stromal cells

Question 28

What is obesity related hypoxia?

Answer 28

Oxygen levels are substantially lower in white adipose tissue of obese mice compared to lean mice and this may be a relevant paracrine effect in the tumour environment.

Question 29

What is shared genetic susceptibility?

Answer 29

Genetic factors that predispose to obesity may also predispose to the development of certain tumours. Genome wide association studies – now possible to superimpose the “obesity” gene map onto the “Cancer” gene maps and explore likely mutual candidate genes in associated areas. Potential overlap for colorectal cancer with a SNP around the MC4R associated with obesity.

Question 30

What is migrating adipose stromal cells?

Answer 30

Mesenchyml stromal cells are a potential source of progenitor cells for the formation of neovasculature – promote angiogenesis and drive tumour progression. Adipose stromal cells and adipose endothelial cells may be recruited to the tumour and support tumour development.

Question 31

What does he want us to think about?

Answer 31

What happenss when you give someone a drug (think about all the diseases)

i.e Statins, reduces heart disease. But long term these reduce cancer risk. but could be bad.