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

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 (IRA), 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 IRA 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/IRA 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/IRA ligand−receptor axis and supporting its underscored role as a malignant-switch checkpoint target.

Keywords

• 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