The IGF-II-Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives

Pierluigi Scalia; Antonio Giordano; Stephen J Williams

doi:10.3390/cancers12020366

The IGF-II-Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives

Cancers (Basel). 2020 Feb 5;12(2):366. doi: 10.3390/cancers12020366.

Authors

Pierluigi Scalia^{1

2}, Antonio Giordano^{1

3}, Stephen J Williams^{1

4}

Affiliations

¹ Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Biology Department, Temple University, Philadelphia, PA 19122, USA.
² Istituto Somatogene per la Ricerca Onco-Genomica, ISOPROG, 93100 Caltanissetta, Italy.
³ Department of Medical Biotechnology, University of Siena, 53100 Siena, Italy.
⁴ Somatolink Foundation, Inc., Philadelphia, PA 19102, USA.

Abstract

Insulin receptor overexpression is a common event in human cancer. Its overexpression is associated with a relative increase in the expression of its isoform A (IR^A), a shorter variant lacking 11 aa in the extracellular domain, conferring high affinity for the binding of IGF-II along with added intracellular signaling specificity for this ligand. Since IGF-II is secreted by the vast majority of malignant solid cancers, where it establishes autocrine stimuli, the co-expression of IGF-II and IR^A in cancer provides specific advantages such as apoptosis escape, growth, and proliferation to those cancers bearing such a co-expression pattern. However, little is known about the exact role of this autocrine ligand-receptor system in sustaining cancer malignant features such as angiogenesis, invasion, and metastasis. The recent finding that the overexpression of angiogenic receptor kinase EphB4 along with VEGF-A is tightly dependent on the IGF-II/IR^A autocrine system independently of IGFIR provided new perspectives for all malignant IGF2omas (those aggressive solid cancers secreting IGF-II). The present review provides an updated view of the IGF system in cancer, focusing on the biology of the autocrine IGF-II/IR^A ligand-receptor axis and supporting its underscored role as a malignant-switch checkpoint target.

Keywords: HIF; IGF binding protein; IGF(I/II/1R), Insulin-like Growth factor (1 or 2 or receptor); IGFBP; IRA/IR-A; ITN; M6PR; OCT; TF; Transferrin; VHL; VTN; Von Hippel-Lindau gene product; hypoxia-inducible factor; insulin receptor isoform A; integrin; mannose 6 phosphate receptor; off-context targeting; vitronectin.

Publication types

Review