Insulin/Insulin-Like Growth Factors in Cancer: New Roles for the Aryl Hydrocarbon Receptor, Tumor Resistance Mechanisms, and New Blocking Strategies

Abstract

The insulin-like growth factor 1 receptor (IGF1R) and the insulin receptor (IR) are receptor tyrosine kinases that are expressed in cancer cells. The results of different studies indicate that tumor proliferation and survival is dependent on the IGF1R and IR, and that their inhibition leads to reductions in proliferation and increases in cell death. Molecular targeting therapies that have been used in solid tumors include anti-IGF1R antibodies, anti-IGF1/IGF2 antibodies, and small molecule inhibitors that suppress IGF1R and IR kinase activity. New advances in the molecular basis of anti-IGF1R blocking antibodies reveal they are biased agonists and promote the binding of IGF1 to integrin β3 receptors in some cancer cells. Our recent reports indicate that pharmacological aryl hydrocarbon receptor (AHR) ligands inhibit breast cancer cell responses to IGFs, suggesting that targeting AHR may have benefit in cancers whose proliferation and survival are dependent on insulin/IGF signaling. Novel aspects of IGF1R/IR in cancer, such as biased agonism, integrin β3 signaling, AHR, and new therapeutic targeting strategies will be discussed.

Preoperative Metabolic Syndrome Is Predictive of Significant Gastric Cancer Mortality after Gastrectomy: The Fujian Prospective Investigation of Cancer (FIESTA) Study

“…Mounting evidence suggests that insulin plays a pivotal role in the regulation of cell proliferation, differentiation, and apoptosis through insulin receptor and insulin-like growth factor 1 receptor, both of which are expressed in gastric cancer cells (Godsland, 2010, Salisbury and Tomblin, 2015, Bardou et al, 2013). The inhibition of these two receptors reduces cancer cell proliferation and accelerates cell death (Mu et al, 2012, Suda et al, 2014).…”

Circulating Insulin-Like Growth Factor-1 Level and Ovarian Cancer Risk

“…Besides, some agents targeting IGF-1 signaling are also promising in the treatment of some cancers [13,35,36]. Other factors in the IGF system are also likely to be potential therapeutic targets, and anticancer therapies aiming to target those factors are currently under investigation [13,35,36].…”

Understanding STAT3 signaling in cardiac ischemia

“…STAT activation is rapid, transient and lasts at most a few hours in a non-pathological setting [92]. Signal decay requires dephosphorylation of three signaling intermediates; the receptor, JAK, and STAT [85]. STAT monomers are then re-located back to the cytoplasm where they can again partake in signaling.…”