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Cancer and Obesity

Learning Objectives

  • Definitions and prevalence of obesity.
  • Obesity and cancer risk.
  • Cellular and molecular mechanisms linking obesity and cancer.
  • Role of adipocyte-secreted adipokines in cancer.
  • Metabolic symbiosis between cancer and obesity.
  • Role of hyperglycemia and Insulin-IGF1 axis in cancer.
  • Adipocytes as endocrine organs: the role of sex hormones in cancer.
  • Prevention and treatment of obesity-induced cancers.

Definitions and Prevalence of Obesity

  • Obesity is defined as a condition of excess body fat that increases the risk of health problems.
  • Measured using Body Mass Index (BMI).
  • BMI of 30 or higher indicates obesity.
  • Overweight: BMI between 25 and 29.9.
  • Prevalence in Australia (2017–18):
    • 1 in 4 (25%) children and adolescents aged 2–17 were overweight or obese.
    • 2 in 3 (67%) Australians aged 18 and over were overweight or obese.
  • Worldwide obesity has nearly tripled since 1975.
  • In 2016, more than 1.9 billion adults (18+) were overweight; over 650 million were obese.
  • Obesity is a major risk factor for cancer.
  • Strongest association with endometrial cancer.

Obesity and Cancer Risk

  • Cancers associated with overweight & obesity, including:
    • Colorectal (men and women)
    • Female breast (postmenopausal)
    • Adenocarcinoma of the esophagus
    • Endometrial
    • Kidney (renal-cell)
    • Multiple myeloma
    • Oesophageal (adenocarcinoma)
    • Kidney
    • Pancreatic
    • Liver
    • Gallbladder
    • Endometrium
    • Gastric cardia (adenocarcinoma)
    • Ovary
    • Meningioma
    • Thyroid
  • Relative risk increases with higher BMI.
  • Population Attributable Fraction (PAF) indicates the percentage of cancer cases attributable to overweight and obesity in the US and EU populations.

Obesity and Cancer: Molecular Landscape

  • Plausible links between obesity and cancer:
    • Obesity-related inflammation.
    • Metabolic symbiosis between stromal adipocytes and cancer cells.
  • Three main factors connecting obesity and cancer:
    • The insulin–IGF-1 axis.
    • Sex hormones.
    • Adipocyte-derived cytokines (adipokines), such as leptin.
  • These factors are linked to endocrine and paracrine dysregulation of adipose tissue in obesity.
  • Adipocytes function as endocrine cells, shaping the tumor microenvironment and contributing to tumor development and progression.

Adipocytes: Components of the Tumour Stroma

  • Adipose tissue actively contributes to tumor growth and metastasis by:
    • Functioning as an endocrine organ, secreting signaling molecules:
      • Adipokines.
      • Proinflammatory cytokines.
      • Proangiogenic factors.
      • Extracellular matrix constituents.
    • Acting as an energy reservoir (fat) for cancer cells.

Adipose Tissue Microenvironment

  • Hypertrophic expansion of adipose tissue shares features with solid tumor growth.
  • Provides a tumor-permissive niche.
  • Adipose tissue expansion:
    • Hypoxia.
    • Compensatory angiogenesis.
    • HIF1a expression.
    • Upregulation of a profibrotic pathway.
      • Involving extracellular matrix proteins: Collagens, Matrix metalloproteinases, Tissue inhibitors of metalloproteinases.
    • Upregulates proinflammatory cytokines: IL-6, Tumour necrosis factor [TNF], C-C motif chemokine 2.
    • Tumor growth and metastasis.

Pro-tumorigenic Microenvironment

  • Increased visceral adiposity creates a pro-tumorigenic environment.
  • Visceral adipose tissue secretes bioactive compounds into systemic circulation.
  • Macrophage and T-cell infiltration occurs.
  • Tumor-adjacent adipose tissue functions in a paracrine manner.
  • Effects:
    • Increased leptin, TNF-α, and insulin levels.
    • Increased levels of free IGF-1.
    • Pro-tumorigenic state of inflammation.
    • Increased insulin resistance.
    • Increased Angiogenesis.
  • Tumor microenvironment is influenced by adipose-derived factors secreted into systemic circulation.

Cancer-Associated Adipocytes (CAA)

  • Adipose tissue: adipocytes + stromal cells (endothelial cells, pericytes, macrophages, and adipocyte progenitor cells).
  • For breast, prostate, ovarian, gastric, renal, and colon cancers, the degree of adipose tissue invasion reflects the aggressiveness of the tumor.
  • In the presence of cancer cells (especially at the tumor invasive front), CAAs undergo delipidation and acquire a fibroblast-like phenotype, accompanied by increased secretion of proinflammatory cytokines.

Cancer Cells and Adipocytes Interaction

  • Cancer cells reprogram adipocytes into CAAs to support tumor growth and survival.
  • Cancer cells release paracrine signals, leading to lipolysis in adipocytes, resulting in free fatty acids.
  • Cancer-associated adipocytes and cancer cells communicate.
  • Adipocyte-rich tissue surrounding tumor cells provides an easily accessible reservoir of lipid.

Adipocytes and Cancer Stem Cells (CSC)

  • Various cytokines (such as leptin) released from adipose tissue in obese states stimulate CSC growth and survival.
  • Obese patients display more resistance to chemotherapy or radiotherapy than lean individuals, partly due to the increased number of CSCs.

Obesity and Cancer Cell Signaling

  • Increased visceral adipose tissue leads to increased circulation of bioactive compounds (IL-6, TNF-α, leptin, and IGF-1).
  • Binding of these compounds to their receptors on tumor cells leads to the activation of cell signaling pathways:
    • Phosphatidylinositol 3-kinase (PI3K).
    • Mitogen-activated-protein-kinase (MAPK).
    • Signal transducer and activator of transcription 3 (STAT3).
    • IKB kinase (IKK).
  • The cascade of downstream signaling leads to increased cell survival and proliferation, promoting tumor progression.

Obesity, Inflammation, and Cancer

  • Tumor necrosis factor-alpha (TNF-alpha) is a key mediator of both obesity-induced inflammation and colon cancer development.
  • Local inflammation, primarily mediated by TNF, has a key role in tumor initiation in obese rodents.

Adipocyte-Derived Cytokines (Adipokines): Leptin

  • Leptin is a 16kDa16 kDa hormone produced by adipocytes.
  • Regulates food intake.
  • Leptin receptors are expressed in almost every tissue.
  • Dynamic role in cancer growth.
  • Pivotal role at the interface of obesity and cancer development.

Leptin and Colorectal Cancer

  • Leptin activates the PI3K–AKT pathway and Jak2–STAT3 pathway, resulting in increased colon cancer cell proliferation.

Leptin and Ovarian Cancer

  • Up to 60% of ovarian tumors showed overexpression of leptin receptor, correlated with reduced progression-free survival.
  • Leptin signaling inhibits apoptosis and stimulates cell division via inhibition of p21 and increased expression of cyclin D1.
  • Bisphenol A increases leptin receptor expression and inhibits caspase-3 expression and activity in ovarian cancer cell lines.

Leptin and Breast Cancer

  • Women with breast cancer frequently exhibit significantly elevated circulating levels of leptin, indicating cancer progression and poor prognosis.
  • Leptin induced growth of breast tumor cells through activation of the JAK–STAT and PI3K signaling pathways.
  • Leptin activates the migration and motility of breast cancer cells.
  • Leptin signaling maintained CSC-like properties in triple-negative breast cancer cells, enabling CSCs with self-renewal capacity.

Metabolic Symbiosis

Insulin-IGF1 Axis
  • IGF-1 and Insulin activate mitogenic pathways and inhibit cell apoptosis.
  • Obesity contributes to carcinogenesis by activating the IGF-1–insulin pathway, stimulating intracellular signaling through mitogen-activated protein kinases (MAPKs) or the PI3K–AKT cascade.
  • Insulin-receptor-mediated signaling regulates metabolic pathways.
  • IGF-1-receptor-mediated signaling stimulates proliferation and cell growth.
Sex Hormones
  • Cytochrome P450 aromatase, encoded by CYP19 gene, converts androgens to estrogens.
  • The ovarian follicle is a major site for producing aromatase in premenopausal women.
  • In postmenopausal women, aromatase is predominantly produced in adipose tissues and skin.
  • The rate of conversion of androgens to estrogens is elevated in postmenopausal women with obesity, increasing the risk of breast cancer.
  • Obesity is a chronic inflammatory state, so pro-inflammatory cytokines such as TNF and IL-6 are elevated, and TNF can induce aromatase expression in human adipose stromal cells.

Obesity and Insulin Resistance

  • Excess weight/adiposity leads to:
    • Increased Free Fatty Acids (FFA) and TNFα.
    • Increased Resistin, decreased Adiponectin.
  • Results in insulin resistance and increased insulin.
  • The blood and tissue shows:
    • Decreased IGFBP1 and IGFBP2.
    • Increased IGF1 bioavailability.
  • Which leads to increased cell proliferation and decreased Apoptosis via Insulin receptors (IR) and IGF-I receptor (IGF1R), leading to Tumor development.

Prevention and Treatment of Obesity-Induced Cancers

  • Metformin
  • Thiazolidinediones
  • Exercise
  • Weight loss
  • Understanding the heterotypic interactions between adipocytes and cancer cells could lead to identifying further novel targets for cancer therapies.

Summary

  • Obesity leads to dysfunctional adipose tissue, producing abundant levels of proinflammatory cytokines, sex hormones, and lipid metabolites, along with altered adipokine profiles.
  • The altered adipose tissue is a source of various ECM proteins, cancer stem cells, cancer-associated adipocytes, and adipocyte progenitors.
  • Each of these factors contributes to various stages of tumor progression, including initiation, growth, and recurrence.
  • Obesity-associated systemic metabolic changes (hyperinsulinemia and hyperglycemia) also contribute to a tumor-permissive environment.
  • \textbf{Obesity} $\rightarrow$ Adipose tissue dysfunction, \uparrow Aromatase activity, \uparrow Levels of ECM proteins, Hormones (estrogen), Adipocyte progenitors, Lipid metabolites, Inflammatory cytokines, Adipokines, Hyperinsulinaemia, Hyperglycaemia $\rightarrow$ Tumour initation, Tumour progression,
    Drug resistance and cancer recurrence.

Cellular Mechanisms Linking Obesity and Cancers

  • The Adipocyte secretome includes:
    • Adipokines: Leptin \uparrow, Adiponectin $\downarrow$, Other Adipokines $\uparrow$.
    • Cytokines: TNFα, IL6, PAI-1.
    • Metabolites/molecules: Free fatty acids (FFA), Adipose fatty acid-binding protein (A-FABP) Fatty acid transporter CD36.
    • Hormones: Insulin, IGF-1, Fibrosis.
  • The Adipose tissue ECM shows:
    • Stiffness, Fiber alignment, Interstitial pressure, Myofibroblast abundance, Desmoplasia
  • Microbiome shows:
    • Altered microbial abundance and composition, Short-chain fatty acids, Deoxycholic acid
  • The Cancer cell phenotypes:
    • Stemness, Initiation, Tumour progression, cell stress, metabolism