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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.
Highlights
The family of the insulin and IGF ligands and receptors are known for their central metabolic and growth-related functions spanning throughout phylogenetically distant organisms [1,2]
Up to the late 90s, the working model for the role of insulin, IGFs, and their receptors in cancer was based on a scenario dominated by two cousin receptors used by their own ligands (IGF-I for the IGF-I receptor and insulin for the insulin receptor), with the IGF-I receptor being considered the sole active mediator of the IGF-I and IGF-II effects, making the latter a favorite target for halting the actions of IGFs in cancer [3,4]
Cellular studies were not able to reproduce such a result in vitro until a specific isoform of the insulin receptor, lacking 12 aa in the extracellular portion corresponding to exon 11 (IRA), was shown to be the high-affinity receptor for IGF-II in both fetal and cancer cells [9]
Summary
The family of the insulin and IGF ligands and receptors are known for their central metabolic and growth-related functions spanning throughout phylogenetically distant organisms [1,2]. Cellular studies were not able to reproduce such a result in vitro until a specific isoform of the insulin receptor, lacking 12 aa in the extracellular portion corresponding to exon 11 (IRA), was shown to be the high-affinity receptor for IGF-II in both fetal and cancer cells [9]. This finding, besides changing a long-rooted view,w1a2elarseaonipnortteahsbeelenexttoterdraecpaerldloudilsautricnepcsoturtrcioholnaercfeoosrrurelttshipneovinnidtsriuongluinntotirleeaxcosepnpet1co1ifri(cIfRaisAro)b,fowerymaosnosfdhtohdweenifintsnouinlbinge rtiehtceaeshpitagohrp,‐ualafrcfeiknimintygetabolic and grercoewpttohr pfoerrmIGiFs‐sIiIvienmboetdhiafettoarl.aAndncuamncbererceollfss[u9b].sTehqius efnintdsintugd, bieessihdeasvcehaalnsgoindgema loonngst‐rroaoteteddinsulin and IvGieFwl,igalasnodp-rsepseenctiefidcaddiiffsetirnecnt croelseifnorththeeirinascutliivnarteicoenptoofr tfahrebIeRyAon. dIndepfainritnicguitlaars,asupuchredmiffetearbeonlicces have beenadnedmgoronwstrhaptedrmaitsstihve gmeendeiaetoxrp. The finding that cancer-secreted IGF-II (big-IGF-II) skips the binding control exerted on mature IGF-II by the IGFBPs (as graphically summarized in Figure 2) suggests that more specific targeting strategies should be considered in order to target this factor in its cancer-specific context
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