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 16 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.
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 $\uparrow$.