Microenvironmental Regulation of Tumor Resistance to Anti-IGF-1R Monoclonal Antibody

Abstract

Drug resistance is a major impediment to a large repertoire of anticancer therapies. Hence, the rational design of anticancer therapies should include strategies that circumvent treatment-associated drug resistance. Recent studies have demonstrated the importance of the tumor microenvironment (TME) to innate resistance to molecularly targeted therapies. In this study, I investigated the role of the TME in innate resistance to insulin like growth factor receptor-1 (IGF-1R) targeting therapy based on monoclonal antibody (mAb) that has shown limited clinical efficacy. Anti-IGF-1R mAb treatment stimulated tumor progression with distant cancer metastasis and decreased survival in mouse models harboring orthotopic tumors of human cancer cell lines. In this models, increased tumor angiogenesis and stromal cell infiltration within the TME were concomitantly observed. Next I performed co-culture experiments with human cancer, vascular endothelial (VE) cells, fibroblasts and monocytes and found that IGF-1R ablated cancer cells recruited fibroblast and monocytes. Once fibroblasts and monocytes recruited to cancer cells, they were shown to stimulate angiogenic abilities of VE cells. From the signaling pathway array using protein lysates from IGF-1R blocked cancer cells, we found that anti-IGF-1R mAb treatment stimulated signal transducer and activator of transcription 3 (STAT3)-dependent transcriptional up-regulation of IGF-2 in cancer cells, enabling communication with fibroblast and monocytes through their insulin like growth factor receptor 2 (IGF-2R). Upon the interaction with IGF-1R ablated cancer cells, fibroblasts and monocytes produced potent proangiogenic cytokine, CXCL8. Silencing IGF-2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells markedly inhibited communication between cancer and stromal cells and vascular endothelial cells angiogenic activities. Moreover, tumor tissue derived STAT3 knocked down cancer cells revealed impairment of anti-IGF-1R mAbs ability to recruit stromal cells. In conclusion, IGF-1R blockade reprograms cancer cells to produce IGF-2, which alters the TME, thereby stimulating tumor angiogenesis and metastasis. Targeting the STAT3/IGF2/IGF-2R/CXCL8 intercellular signaling loop may overcome the adverse consequences of anti-IGF-1R mAb-based therapies.