Potent Inhibition of Angiogenesis by the IGF-1 Receptor-Targeting Antibody SCH717454 Is Reversed by IGF-2

Abstract

Previously, we reported that a predominant action of an IGF-1R-targeted antibody was through inhibiting tumor-derived VEGF, and indirectly, angiogenesis. Here we examined the direct anti-angiogenic activity of the IGF-1R-targeted antibody SCH717454 that inhibits ligand-receptor binding, and the mechanism by which tumors circumvent its anti-angiogenic activity. Inhibition of ligand stimulated activation of IGF-1R, insulin receptor (IN-R) or downstream signaling (phosphorylation of Akt [Ser473]) was determined by receptor-specific immunoprecipitation and immunoblotting. Inhibition of angiogenesis was determined by proliferation and tube formation using human umbilical vein endothelial cells (HUVECs) in vitro and in Matrigel plugs implanted in mice. SCH717454 blocked IGF-1 but not IGF-2 stimulated phosphorylation of Akt in sarcoma cells. Immunoprecipitation using anti-IGF-1R and anti-IN-R antibodies revealed that SCH717454 equally blocked IGF-1 and IGF-2 stimulated IGF-1R phosphorylation, but not IGF-2 stimulated phosphorylation of IN-R. SCH717454 completely blocked VEGF-stimulated proliferation and tube formation of HUVECs, but exogenous IGF-2 and insulin circumvented these inhibitory effects. Co-culture of HUVECs with IGF-2-secreting tumor cells completely abrogated SCH717454 inhibition of VEGF-stimulated HUVEC tube formation. In mice SCH717454 inhibited angiogenesis in VEGF-infused Matrigel plugs, but had no inhibitory activity when plugs contained both VEGF+IGF-2. These results reveal for the first time, a role for IGF-1R signaling in VEGF-mediated angiogenesis in vitro and indicate direct anti-angiogenic activity of SCH717454. Both in vitro and in vivo IGF-2 circumvented these effects through IN-R signaling. Many childhood cancers secrete IGF-2, suggesting that tumor-derived IGF-2 in the microenvironment maintains angiogenesis in the presence of IGF-1R-targeted antibodies allowing tumor progression.

Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways

“…Our findings are supported by a recent study that IGF-1R-targeted antibody SCH717454 completely blocked VEGF-A-induced HUVEC proliferation, migration, tube formation, and in vivo vessel formation (39). Interestingly, the blocking effect of the antibody on VEGF-A signaling could be reversed by exogenous IGF-2 or insulin, but not by exogenous IGF-1, suggesting that the antibody might directly neutralize IGF-1 ligand released into the extracellular space or cause degradation of transmembrane IGF-1R (39). Nevertheless, the study did not address how the IGF-1R antibody affects VEGF-A signaling, directly or indirectly.…”

Growth factors and their receptors derived from human amniotic cells in vitro

“…Also, our experiment showed that IGF-2 was continually released into the culture media of cultured hAM over the 48 h time period. Bid et al suggested role for IGF-2 in angiogenesis on HUVECs culture model [30]. We propose that the observed migratory effect on HUVEC may be due to the IGF-2 presence in the 24 h hAM culture medium or appearance of other released, however, not tested factors.…”

Serum Insulin-Like Growth Factor-1 Levels Predict Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy

“…IGF-1 has been shown to stimulate hypoxia-inducible factor-1a activity and VEGF expression in several cancer models (25)(26)(27)(28). Blockade of the IGF-1 pathway inhibited angiogenesis and tumor growth in experimental animals (29)(30)(31)(32). It is plausible that our HCC patients who had high serum IGF-1 levels might have tumors with higher angiogenic activity, which renders them more likely to benefit from antiangiogenic therapy.…”