Obesity, Type 2 Diabetes, and Cancer Risk

Abstract

Obesity and type 2 diabetes have both been associated with increased cancer risk and are becoming increasingly prevalent. Metabolic abnormalities such as insulin resistance and dyslipidemia are associated with both obesity and type 2 diabetes and have been implicated in the obesity-cancer relationship. Multiple mechanisms have been proposed to link obesity and diabetes with cancer progression, including an increase in insulin/IGF-1 signaling, lipid and glucose uptake and metabolism, alterations in the profile of cytokines, chemokines, and adipokines, as well as changes in the adipose tissue directly adjacent to the cancer sites. This review aims to summarize and provide an update on the epidemiological and mechanistic evidence linking obesity and type 2 diabetes with cancer, focusing on the roles of insulin, lipids, and adipose tissue.

Keywords: IGF-1; Type 2 diabetes; cancer; insulin; leptin; lipids; obesity.

Figure 1

Potential mechanisms linking obesity and type 2 diabetes and cancer. The relationship between type 2 diabetes, obesity, and cancer is potentially mediated by multiple mechanisms, including metabolic conditions such as hyperinsulinemia and dyslipidemia as well as the alteration of adipose tissue which is characterized by inflammation and a tumor growth-promoting secretory profile. Stars indicate factors discussed in this review. Adapted from: Gallagher, E.J., and LeRoith, D (2015). Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality. Physiol. Rev. 95, 727–748.

Figure 2

Role of 27-Hydroxycholesterol in breast cancer. 27-HC is synthesized from cholesterol by CYP27A1 in the liver and other peripheral tissues. It can be further metabolized for bile acid synthesis by CYP7B1. 27-HC can be taken up by tumor cells from the circulation where it exerts ERα agonistic activity, inducing the expression of Cyclin D1 which leads to cell cycle progression and proliferation. It can also enhance the association of tumor suppressor p53 protein with MDM2 leading to its degradation. 27-HC has also been shown to promote EMT by reducing E-Cadherin and β-Catenin expression and by inducing an LXR-mediated increase in Snail and Vimentin expression. It can also activate Stat3 signaling, resulting in increased expression of MMP9 and cell invasion. 27-HC in the lungs can promote the recruitment of polymorphonuclear cells and T cells which favors the development of an immunosuppressive microenvironment that facilitates metastatic seeding and growth of breast cancer cells.