Obesity, Diabetes, and Increased Cancer Progression

Abstract

Rates of obesity and diabetes have increased significantly over the past decades and the prevalence is expected to continue to rise further in the coming years. Many observations suggest that obesity and diabetes are associated with an increased risk of developing several types of cancers, including liver, pancreatic, endometrial, colorectal, and post-menopausal breast cancer. The path towards developing obesity and diabetes is affected by multiple factors, including adipokines, inflammatory cytokines, growth hormones, insulin resistance, and hyperlipidemia. The metabolic abnormalities associated with changes in the levels of these factors in obesity and diabetes have the potential to significantly contribute to the development and progression of cancer through the regulation of distinct signaling pathways. Here, we highlight the cellular and molecular pathways that constitute the links between obesity, diabetes, cancer risk and mortality. This includes a description of the existing evidence supporting the obesity-driven morphological and functional alternations of cancer cells and adipocytes through complex interactions within the tumor microenvironment.

Keywords: Adipokines; Adipose tissue; Diabetes mellitus, type 2; Hyperlipidemia; Insulin resistance; Neoplasms; Obesity.

Fig. 1.

Proposed role of obesity-associated dysfunctional adipose tissue in tumor development and progression. Obesity-associated systemic metabolic disorders in adipose tissue contribute to the initiation and progression of cancer by producing endocrine and paracrine factors and alternation of tumor microenvironment. IGF, insulin-like growth factor; IGFR, insulin-like growth factor receptor; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; IKK, IkB kinase; STAT3, signal transducer and activator of transcription 3; IL, interleukin; PAI-1, plasminogen activator inhibitor 1; TNF-α, tumor necrosis factor-α; ECM, extracellular matrix.

Fig. 2.

Adipocyte/cancer cell crosstalk in the obese state. Obesity increases the risk of developing of cancer by promoting multiple metabolic abnormalities of adipose tissue. In turn, cancer cells also induce morphological and functional changes in adipose tissue, which promote invasive and metastatic phenotypes of cancer. ECM, extracellular matrix.

Fig. 3.

Possible molecular mechanisms for a direct link between diabetes and cancer. Diabetes-associated metabolic disturbances including hyperinsulinemia and dyslipidemia have been proposed as a causal link between diabetes and cancer. MF, metformin; DM, diabetes mellitus; IGF, insulin-like growth factor; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; NEFA, non-esterified fatty acid; PKC, protein kinase C; mTOR, mammalian target of rapamycin; GSK3β, glycogen synthase kinase 3β; ATP, adenosine triphosphate.