Editors' ChoiceCancer

Cancer cells harness insulin for performance enhancement

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Science Translational Medicine  10 Jun 2020:
Vol. 12, Issue 547, eabc8942
DOI: 10.1126/scitranslmed.abc8942

Abstract

Hyperinsulinemia and insulin receptor signaling allow cancer cells to evade cell competition.

Endogenous hyperinsulinemia has been proposed as one of the causal factors contributing to the association between obesity, diabetes, and increased cancer risk and mortality. Previous studies have examined the mechanisms through which hyperinsulinemia promotes cancer progression, but it is not understood how hyperinsulinemia contributes to cancer incidence. Disruption of cell polarity is an early event in epithelial cancers, and cells that lose polarity are usually eliminated through tumor-suppressive cell competition. Sanaki and colleagues used Drosophila with scrib (scribble planar cell polarity protein) mutant cell clones in the eye disc to understand the mechanisms underlying tumor-suppressive cell competition. They discovered that hyperinsulinemia gives epithelial cancer cells a competitive advantage.

Loss-of-function mutations in scrib disrupt cell polarity, but tumors do not usually form due to cell competition. By introducing heterozygous chromosomal deficiencies in Drosophila, the researchers found that scrib mutant clones developed tumors in chico (insulin receptor substrate)–deficient backgrounds. However, neither knocking down chico in the scrib mutant cells nor in the wild-type cells affected tumorigenesis. Instead, knocking down chico in the insulin-producing cells in the brain led to increased tumor development as well as elevated circulating Drosophila insulin-like peptides (Dilps). Increasing circulating Dilps by dietary modification also increased tumorigenesis. Scrib mutant cells had greater protein synthesis rates in the setting of elevated Dilps. As metformin is a treatment for diabetes, which has been reported to have anti-cancer effects, Sanaki et al. next examined whether metformin would prevent the ability of scrib mutant cells to evade competitive suppression. Indeed, metformin treatment inhibited protein synthesis and reduced tumor size.

Overall, the study provides potential mechanisms to explain the links between hyperinsulinemia and increased cancer incidence. It is important to recognize that the Drosophila insulin/insulin-like growth factor (IGF) system has eight Dilps and one receptor, whereas the human system consists of insulin, IGF-1, IGF-2, along with two insulin receptor isoforms, the IGF-1 receptor and hybrid receptors. However, insulin and IGF-1 are known to be anabolic hormones in humans, sometimes used as performance enhancers for sports; therefore, it is not unexpected that cancer cells may use this system to gain a competitive edge in humans.

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