The IGF-II–Insulin Receptor Isoform-A Autocrine Signal in Cancer: <i>Actionable Perspectives</i>

• Main Authors: Pierluigi Scalia, Antonio Giordano, Stephen J. Williams
• Format: Article
• Language: English
• Published: MDPI AG 2020-02-01
• Series: Cancers
• Subjects: igf(i/ii/1r), insulin-like growth factor (1 or 2 or receptor); ir<b>^a</b>/ir-a; insulin receptor isoform a; igfbp; igf binding protein; itn; integrin; m6pr; mannose 6 phosphate receptor; tf; transferrin; vtn; vitronectin; hif; hypoxia-inducible factor; vhl; von hippel-lindau gene product; oct; off-context targeting
• Online Access: https://www.mdpi.com/2072-6694/12/2/366

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<b>^A</b>), 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<b>^A</b> 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&#8722;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<b>^A</b> 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<b>^A</b> ligand&#8722;receptor axis and supporting its underscored role as a malignant-switch checkpoint target.