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Tumor Microenvironment: A New Treatment Target to overcome Resistance to Anticancer Therapy Ho-Young Lee College of Pharmacy, Seoul National University, Seoul, Republic of Korea Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumor microenvironment (TME) to innate resistance to molecular targeted therapies. The type 1 insulin-like growth factor receptor (IGF-1R)-mediated signaling is known to be crucial for cell growth, survival and has been considered as an attractive target for developing molecularly targeted anticancer therapy. Several clinical trials have been conducted to evaluate the efficacy of IGF-1R-targeted anticancer agents such as monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs); however, most of these trials did not show clinical benefits and the further clinical development of many IGF-1R targeted drugs has halted. Recently, we discovered a novel molecular mechanisms underlying resistance to cixutumumab, a fully humanized mAb against IGF-1R, in relation to modulation of TME. In orthotopic and subcutaneous tumor xenograft models using human non-small cell lung cancer (NSCLC) and breast cancer cells, we observed that cixutumumab treatment displayed either no change or increased tumor growth with recruitment of surrounding stromal cells, eventually leading to decreased survival of mice. The metastatic tumor formation was confirmed in the orthotopic xenograft model using humanized mice. Further studies demonstrated that cixutumumab treatment activated STAT3 and transcriptionally up-regulated IGF2 in cancer cells. IGF2 further mediated interaction with fibroblasts and monocytes via IGF2R, thereby inducing CXCL8 production in these cells and eventually leading to recruitment of vascular endothelial cells, angiogenesis, and metastasis. Silencing IGF2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibited the cancer-stroma communication and angiogenesis. These results suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signaling loop may overcome the adverse consequences of anti-IGF-1R mAb-based therapies.