STAT3-mediated IGF-2 secretion in the tumour microenvironment elicits innate resistance to anti-IGF-1R antibody.

ABSTRACT: Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumour microenvironment (TME) to innate resistance, to molecularly targeted therapies. In this study, we investigate the role of TME in resistance to cixutumumab, an anti-IGF-1R monoclonal antibody that has shown limited clinical efficacy. We show that treatment with cixutumumab accelerates tumour infiltration of stromal cells and metastatic tumour growth, and decreases overall survival of mice. Cixutumumab treatment stimulates STAT3-dependent transcriptional upregulation of IGF-2 in cancer cells and recruitment of macrophages and fibroblasts via paracrine IGF-2/IGF-2R activation, resulting in the stroma-derived CXCL8 production, and thus angiogenic and metastatic environment. Si

SUBMITTER: Lee JS 

PROVIDER: S-EPMC4608384 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature