Figure 5.

Cancer related molecular mechanisms driven by obesity. (A) Obesity causes formation of an expanded compartment of fat-storing cells (adipocytes) and accumulation and activation of immune cells. Signaling from these cells is commonly associated with an increase in TNF-α and IL-6 activity, two important regulators of cell proliferation and inflammation, and is related to immune cell activation. Obesity is also associated with an increase in the level of hormones, such as estrogen, insulin, and leptin, and a decrease in adiponectin, an important negative regulator of metabolism. (B) Excess adipocyte activity increases levels of bioavailable testosterone (T) and estradiol (E2) throughout the body. Within adipocytes, androstenedione (Δ-4A) is modified to testosterone by 17β-hydroxysteroid dehydrogenases (17β-HSD) or to estrone (E1) by aromatase (an enzyme also known as estrogen synthetase). In obesity, elevated aromatase expression is facilitated in part by increased levels of prostaglandin (PGE₂) and TNF-α. In certain tissues (e.g., breast and endometrium), high levels of testosterone and estradiol have been associated with cancer growth and survival. (C) Obesity elevates levels of insulin and IGF1, which bind receptors (INSR and IGF1R) expressed on tumor cells to activate core signaling cascades mediated by RAS and PI3K–AKT–MTOR that strongly drive cell proliferation and survival. (D) In the obese state, low levels of adiponectin reduce activity of AMP kinase (AMPK), a strong regulator of metabolic activity, particularly relevant in terms of the regulation of MTOR. At low levels of adiponectin, MTOR activity contributes to increased cell proliferation, anti-apoptotic activity, and expression of prometastatic genes. Adipocyte-produced leptin and immune cell-produced IL-6 activate JAK–STAT3 signaling to promote cell proliferation and survival. TNF-α inhibits the negative NF-kB regulator IkB, freeing NF-kB to further support a progrowth state.