MSc Mol Med Lecture on Obesity and Cancer PDF

Obesity and Cancer Dr. Graham Pidgeon, Associate Professor Trinity Translational Medicine Institute / Trinity and St. James’s Cancer Institute Learning Outcomes from the lecture Discuss the mechanisms linking obesity with cancer development or progression Detail cellular and molecular fac...

Obesity and Cancer Dr. Graham Pidgeon, Associate Professor Trinity Translational Medicine Institute / Trinity and St. James’s Cancer Institute Learning Outcomes from the lecture Discuss the mechanisms linking obesity with cancer development or progression Detail cellular and molecular factors associated with adipose tissue signaling that may alter tumour growth Describe how obesity and adipose tissue may affect the various hallmarks of cancer and influence response to therapy Obesity in Ireland Overall: measured § 1% underweight (M 1%; W 1%) § 35% healthy weight (M 31%; W 40%) § 39% overweight (M 47%; W 34%) § 23% obese (M 21%; W 25%) Differential: 22-32% self-report vs measured Causative factors associated with cancer How do we define overweight & obesity? The internationally accepted classification for obesity is the Quetelet's Index, also called the Body Mass Index (BMI) BMI = weight in kilograms = kg/m2 square of height in meters WHO, 2003 WHO classification – Underweight < 18.5 – Normal 18.5-24.9 – Overweight 25-29.9 – Obese Class I 30-34.9 – Obese Class II 35-39.9 – Extreme obesity Class III 40 + Distribution of adipose tissue is hugely important Elevated Cancer Risk Lower Cancer Risk Central obesity more common in men Genetic factors We know that obesity tends to run in families, suggesting a genetic cause. Although, families also share diet and lifestyle, both of which contribute to obesity, research has shown that genetic factors account for as much 65-80% of the link between heredity and obesity. Agouti Mice In mice, a gene known as agouti is associated with coat color, obesity, and the likelihood of developing diabetes and cancer. Diets rich in methyl groups (specifically, diets rich in soy products) could promote the brown phenotype. Asians lag behind those of most other ethnic groups. Could this be due to increased amounts of soy products found in their main food staples? Activation of tumour pathways by adipose tissue: The molecular link between obesity and cancer Obesity research program at TCD SubCut adipose tissue >80% total body fat 1.Abdominal 2.Gluteal 3.Femoral Intra + Retro Peritoneal adipose tissue 10 – 20% body fat. 1.Omental (apron from stomach) 2.Mesenteric (intestine) 3. Epiploic (colon) Research Led Evidence: Obesity is associated with incidence and mortality of specific cancers What are the potential mechanisms where obesity may effect cancer development and/or progression? Physiological - Increased pressure on the stomach, GORD What are the potential mechanisms whereby obesity may effect cancer development and/or progression? Physiological - Increased pressure on the stomach, GORD Hormonal / Paracrine Insulin resistance / IGF Pathway IGF-IR and cell signaling pathways What are the potential mechanisms whereby obesity may effect cancer development and/or progression? Physiological - Increased pressure on the stomach, GORD Hormonal – Insulin resistance / IGF Pathway Immunological – Chronic Inflammation Obesity, which is associated with T cell dysfunction and worse cancer prognosis, also paradoxically induces a better response to anti- PD-1/PD-L1 immunotherapy Are adipose tissue depots molecularly distinct? SubCut Non-obese SubCut Obese A A BB Visceral Non-obese Visceral Obese C C DD ACM from Subcutaneous Adipose Tissue ACM from Visceral Adipose Tissue E E 400 400 ** % Proliferation Relative to Control 350 * % Proliferation Relative to Control 350 300 300 250 * 250 200 200 150 150 100 100 50 50 0 0 Control Normal Weight Viscerally Control Normal Weight Viscerally Obese Obese Are adipose tissue depots molecularly distinct? Does Leptin expression effect tumours in vivo? p=0.013 * Tumour Non-Obese Tumour Obese Can co-culture of human adipose tissue explants with cancer cells alter gene expression profiles ? OE33 tumour cells Visceral adipose tissue/ Adipocytes qPCR / Affymetrix arrays Validations Gene expression analysis qPCR, Western blotting Dr. Zivile Useckaite Impact on cancer diagnosis and treatment Morbidly obese women are significantly less likely to report recent mammography. This relationship appears stronger in white women. Lower screening rates may partly explain the higher breast cancer mortality in morbidly obese women. Impact on cancer diagnosis and treatment Can obesity effect cancer treatment or molecular targeted therapies? Adipose Conditioned Media protects against chemotherapy induced cell death, an effect which is mediated through VEGF 120 ** * 100 % Survival Relative to Control 80 (* p < 0.05, ** p < 0.01) 60 40 20 0 Control 5FU ACM+5FU ACM+5FU+Avastin Summary of mechanisms linking obesity with cancer development and response to treatment  Hallmarks of Cancer Our Research Sustained Evading Growth Proliferation Suppressors Deregulating Cellular Avoiding Immune Energetics Destruction Resisting Enabling Replicative Cell Death Immortality Tumour Promoting Inflammation Genome Instability and Mutation Inducing Metastasis and Angiogenesis Invasion Questions ???