cancers Review The IGF-II–Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives Pierluigi Scalia 1,2,*, Antonio Giordano 1,3 and Stephen J. Williams 1,4 1 Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Biology Department, Temple University, Philadelphia, PA 19122, USA; [email protected] (A.G.); [email protected] (S.J.W.) 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 * Correspondence: [email protected] Received: 31 December 2019; Accepted: 2 February 2020; Published: 5 February 2020 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); IRA/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 1. The Insulin–IGF Ligand and Receptor System in Cancer 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 (the IGF-IR and the insulin receptor) 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]. This paradigm (the IGF1R mandatory transducer hypothesis) has undergone many changes over time with the realization, first, that the IGFIR is able to form hybrid variants with the insulin receptor [5,6] and, second, that the insulin receptor (IR) could mediate IGF-specific effects. Indeed, genetic evidence of the permissive role of the insulin receptor in a number of developmental and body-size effects mediated by IGF-II had been shown in genetic Cancers 2020, 12, 366; doi:10.3390/cancers12020366 www.mdpi.com/journal/cancers Cancers 2020, 12, 366 2 of 21 studies conducted both in null mice [7] and in transgenic mouse models [8]. However, 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 were not able to reproduce such a result in vitro until a specific isoform of the insulin receptor, lacking view, also presented a distinct role for the insulin receptor far beyond defining it as a pure metabolic 12 aa in the extracellular portion corresponding to exon 11 (IRA), was shown to be the high‐affinity and growthreceptor permissivefor IGF‐II in mediator.both fetal and A number cancer cells of subsequent [9]. This finding, studies besides have changing also demonstrated a long‐rooted insulin A and IGFview, ligand-specific also presented a di distinctfferences role infor their the insulin activation receptor of thefar beyond IR . In defining particular, it as a such pure di metabolicfferences have beenand demonstrated growth permissive at the genemediator. expression A number level of subsequent [10] and at studies the signaling have also level demonstrated [11,12]. Ininsulin this regard, it is worthand IGF noting ligand‐ thatspecific IGF-II differences has been in their found activation to be ableof the to IR bindA. In particular, and transduce such differences signals via have both the homo-tetrameric,been demonstrated high-a atffi thenity gene RTKs expression (IGF1R level and [10] IRA and) and at the via signaling its hetero-tetrameric level [11,12]. In (IGF1R this regard,/IRA) hybrid receptorit is worth in cancer noting [13 that]. This IGF‐II amplifies has been thefound range to be of able cancer-promoting to bind and transduce autocrine signals signalsvia both exerted the by homo‐tetrameric, high‐affinity RTKs (IGF1R and IRA) and via its hetero‐tetrameric (IGF1R/IRA) IGF-II at the cellular level. The ultimate demonstration of the potential of the autocrine IGF-II/IRA axis hybrid receptor in cancer [13]. This amplifies the range of cancer‐promoting autocrineA signals exerted in cancerby IGF came‐II at from the cellular the recent level. finding The ultimate that, demonstration when activated of the by potential IGF-II, the of the IR autocrinevariant isIGF able‐II/IR toA acutely and reversiblyaxis in cancer activate came from a post-translational, the recent finding ubiquitin-dependent, that, when activated by and IGF IGF1R-independent‐II, the IRA variant is able degradation to rescueacutely signal, and causing reversibly EphB4 activate ectopic a post expression‐translational, in malignant ubiquitin‐dependent, mesothelioma and cellIGF1R lines‐independent [14]. Altogether, thesedegradation reports fully rescue disprove signal, the causing old concept EphB4 ectopic of purely expression redundant in malignant biological mesothelioma roles between cell IGFlines ligands and RTKs,[14]. Altogether, and point these at their reports contextual fully disprove co-expression the old concept patterns of purely as key redundant indicators biological of the predominant roles and/orbetween parallel IGF e ligandsffects exerted and RTKs, in and cancer point cells at their according contextual to co the‐expression pre-existing patterns permissive as key indicators or inhibiting of the predominant and/or parallel effects exerted in cancer cells according to the pre‐existing signaling network. These contextual ligand–receptor interactions exerted by autocrine IGF-II and the permissive or inhibiting signaling network. These contextual ligand–receptor interactions exerted by contributionsautocrine IGF of paracrine‐II and the IGFcontributions signals inof cancerparacrine are IGF summarized signals in cancer in Figure are summarized1. in Figure 1. FigureFigure 1. The 1. 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In In particular, particular, the the rolerole ofof IGF-IIIGF‐II and and its its cancer cancer-secreted‐secreted variant variant (Big‐IGF2), (Big-IGF2), as the asmost the most commonlycommonly expressed expressed IGF IGF ligand ligand in in malignantmalignant cancer cancer cells, cells, along along with with the A the variant A variant (exon (exon11) of the 11) of the insulin receptor (IRA), an almost ubiquitously expressed variant of the IR in cancer binding IGF‐II insulin receptor (IRA), an almost ubiquitously expressed variant of the IR in cancer binding IGF-II (and its high molecular form expressed in cancer) with high affinity, has gained additional interest on (andthe its highbasis of molecular its ligand‐ formreceptor expressed‐specific (and in cancer) IGF1R‐ withindependent) high affi abilitynity, hasto tightly gained control additional the protein interest on the basisexpression of its ligand-receptor-specificof an angiogenic invasion metastatic (and IGF1R-independent) factor such as EphB4 ability [14]. 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