Promotion and selection by serum growth factors drive field cancerization, which is anticipated in vivo by type 2 diabetes and obesity.

Abstract

Individuals suffering from type 2 diabetes or obesity exhibit a significant increase in the incidence of various types of cancer. It is generally accepted that those conditions arise from overnutrition and a sedentary lifestyle, which lead to insulin resistance characterized by overproduction of insulin acting as a growth factor. There is a consensus based largely on epidemiological data that chronic overproduction of insulin is responsible for the increased incidence of cancer. A model system in culture of NIH 3T3 cells induces the collective effects of serum growth factors on progression through the stages of field cancerization. It shows that the driving force of progression is promotion of cell growth under selection at high cell density, with no requirement for exogenous carcinogenic agents. The early effect is gradual selection among many preexisting, low-penetrance preneoplastic mutations or stable epigenetic variants, followed by sporadic, high-penetrance transforming variants, all dependent on endogenous processes. The significance of the results for cancer in diabetic and obese individuals is that the initial stages of the process involve multiorgan metabolic interactions that produce a systemic insulin resistance with chronic overproduction of insulin and localized field cancerization. Hypomagnesemia is prevalent in the foregoing metabalo/systemic disorders, and may also provide a selective microenvironment for tumor development.