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

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.

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“…INS is one of the key growth factors for many types of neoplastic cells [32][33][34][35][36][37][38][39][40], and it is a potent growth factor for myeloma cells [20]. Our data fully confirm these dates and show that INS enhances serum-induced proliferation of RPMI8226 and IM9 cells (Figure 2A and Figure 2B).…”

Overactivation of the IGF signalling pathway in osteosarcoma: a potential therapeutic target?

“…Later, it was demonstrated that both IGF ligands could initiate a mitogenic response via hybrid receptors such as IGF1R/IR or IGF1R/EGFR. Even in the absence of IGF1R, activation of the RAS‐MAPK–ERK signalling cascades can still be triggered by IGF2 through a specific isoform of the insulin receptor (IR A ) [14,24]. Therefore, any therapeutic strategy solely targeting IGF1R or IGF1R/EGFR and/or IGF1R/IR (main isoform) is likely insufficient to prevent the activation of downstream signalling pathways.…”

“…Escape mechanisms involving the heterodimerisation of IGF1R with either the human epidermal growth factor receptor (EGFR) or the insulin receptor (IR) have been described as underlying causes [11,12]. Alternative strategies are currently under investigation to prevent IGF1R activation, such as targeting its ligands (IGF1 and IGF2) with neutralising antibodies or combining anti‐IGF1R treatment with additional inhibitors of the PI3K/AKT and/or the RAS/MAP kinase cascades to avoid adaptive responses [13,14]. It seems crucial to identify biomarkers that can help to discriminate potential responders from non‐responders to IGF1R inhibition.…”

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

“…In epidemiological studies, there is no clear association between IGF2 serum levels and cancer risk [43,44]. However, IGF2 is commonly upregulated in cancer and secreted by a broad range of tumor cell types [45][46][47][48]. Notably, IGF2 systemic effects modulate the syndrome known as non-islet cell tumor hypoglycemia [47,48].…”