Hyperinsulinemia and the insulin-like growth factor axis

One of the cardinal changes of the obese phenotype is hyperinsulinemia, and this has also been proposed as a procarcinogenic mechanism in patients with excess adipose tissue.Insulin resistance is highly correlated with increased body weight and is reversed with weight loss.79


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The mechanisms by which obesity causes insulin resistance are not fully elucidated, but it appears that inflammatory events are of central importance. Raised circulating free fatty acids, due to increased lipolysis in obese subjects, are a factor in the development of insulin resistance as they affect hepatic glucose production.80

Insulin is a mitogen and is central to the maintenance of cells in the in vitro setting.81 Epidemiological studies report a consistent association between the presence of type 2 diabetes and cancers of the liver, pancreas, endometrium, breast, colorectal, bladder, non-Hodgkin’s lymphoma, and kidney.82

Confounding factors such as obesity, diet, socioeconomic status, physical activity, and smoking make it difficult to unpick how insulin resistance translates into the upregulation of cancer cell growth.

Studies to clarify this have often used supraphysiological doses of insulin to promote tumorigenesis in animal studies,83 but these doses are not clinically relevant in humans. So it is hypothesized that the coregulated and largely homologous insulin-like growth factor (IGF) system may mediate the cancer risk as activation of the IGF 1 receptor (IGF1R) leads to decreased apoptosis and increased invasiveness.84,85 Increased expression of IGF1R are reported in a number of cancer subtypes.86–88

Visceral obesity may influence the IGF1R expression in tumor tissue – in tumor samples from patients with esophageal adenocarcinoma, patients with abdominal obesity were more likely to have increased IGF1R mRNA expression and protein expression in their tumors.88

Peritumoral adipose tissue

While there are a number of systemic alterations that occur within the obese state which may putatively impact tumor growth and metastasis, there is also cross-talk between cancer cells within a tumor and the peritumoral adipocytes.

Tumor cells induced lipolysis in cancer-associated adipocytes, which induces them to undergo differentiation into fibroblast-like cells.63 These cells produced proinflammatory cytokines, which in turn support tumor cells development.

Potential therapeutic avenues

Understanding mechanisms promoting cancer development in obese patients may lead to potential development of new anticancer targets.

The role of bariatric surgery in delivering sustained large-volume weight loss is well established, with most procedures leading to excess weight loss of 60%–70% within 2 years of surgery.89,90

Whether this translates into a reduced cancer-related mortality is not clear. As previously mentioned, the largest single study of bariatric procedures (the SOS study) has shown mixed results with respect to decreased cancer incidence.91 Reductions in IL-6, TNF-α, and CRP are reported following weight loss in cohort studies.92

Disclosure

The authors report no conflicts of interest in this work.