Hyperglycemia as a risk factor for cancer progression

Abstract

As the prevalence of diabetes mellitus is substantially increasing worldwide, associated diseases such as renal failure, cardiovascular diseases, fatty liver, and cancers have also increased. A number of cancers such as pancreatic, liver, breast, and female reproductive cancers have shown an increased prevalence and a higher mortality rate in diabetic patients compared to healthy subjects. Thus, this suggests an association between diabetes, especially type 2 diabetes and cancer incidence and progression. Recent studies have suggested that hyperinsulinemia, chronic inflammation and hyperglycemia, all frequently seen in diabetics, may lead to increased tumor growth; the underlying molecular mechanisms of this association are not fully understood. In particular, chronic hyperglycemic episodes could serve as a direct or indirect mediator of the increase in tumor cell growth. Here, we will discuss our current understanding how hyperglycemia and cancer risk may be linked, and what the implications are for the treatment of diabetic cancer patients.

Keywords: Cancer risk; Diabetes; Hyperglycemia; Therapeutics.

Fig. 1

Impact of hyperglycemia on tumor progression. A hyperglycemic environment contributes to tumor progression through multiple pathways. Cancer cell proliferation is promoted by the up-regulation of glucose transporters (GLUT1 and GLUT3), epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR), and other growth promoting signals such as protein kinase C-α (PKC-α), peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ, glial cell line-derived neurotophic factor (GDNF), and its receptor, rearranged during transfection (RET) receptor. The levels of hypoxia inducible factor-1α (HIF1α), prolyl hydroxylase (PHD) enzyme and cytochrome c regulated by hyperglycemia are associated with antiapoptotic activity of cancer cells. Cancer cell migration and invasiveness is acquired by the up-regulation of superoxide dismutase (SOD), urokinase plasminogen activator (uPA), ZRT/IRT-like protein 6 (ZIP6), and ZRT/IRT-like protein 10 (ZIP10). Moreover, hyperglycemic memory, i.e., epigenetic regulation of cancer cells by hyperglylcemia, increases the expression of nuclear factor-κB (NF-κB) and neuregulin-1 (Nrg1), both are well-established oncogenic signals.