Figure 3.

Systemic effects of increased adiposity on EC progression. (a) A high level of circulating leptin binds to its receptor OB-R to trigger a signaling pathway as well as recruit pro-angiogenic factors such as VEGF, IL-1β, and LIF to induce cancer progression and metastasis. (b) Increased free fatty acids (FFA), resistin, and decreased adiponectin secretion contribute to insulin resistance, which leads to an increase in insulin synthesis. Hyperinsulinemia is associated with decreased bioavailability of IGFBP and the simultaneous increase in IGF-1 production. Insulin and IGF-1 signal through IR and IGFR respectively to promote EC progression via mTOR activation. (c) Hypertrophied adipocytes secrete an increasing amount of pro-inflammatory cytokines (IL-4, IL-7), ANGPT1, and VEGF to infiltrate endothelial cells, which facilitates angiogenesis. VEGF acts as a key mediator of the EC cell-adipocyte interaction and binds to its receptor, VEGFR2, on the EC cell surface. Phosphorylation of VEGFR2 activates downstream targets and upregulates the mTOR pathway through a high pS6 level.