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. Silencing IGF-2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibits the cancer-stroma communication and vascular endothelial cells' angiogenic activities. These findings suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signalling loop may overcome the adverse consequences of anti-IGF-1R monoclonal antibody-based therapies.
Subject(s)
Drug Resistance, Neoplasm , Insulin-Like Growth Factor II/metabolism , Neoplasms, Experimental/metabolism , Receptor, IGF Type 1/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , Tumor Microenvironment , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Cell Line, Tumor , Cellular Reprogramming , Human Umbilical Vein Endothelial Cells , Humans , Interleukin-8/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Neoplasm Invasiveness , Neoplasms, Experimental/drug therapy , Neovascularization, Pathologic , Paracrine Communication , Receptor, IGF Type 2/metabolismABSTRACT
The parafibromin/hCdc73 is a component of the PAFc, which controls RNA polymerase II-mediated general transcription. In parathyroid carcinoma and familial autosomal dominant hyperparathyroidism-jaw tumour (HPT-JT), hCdc73 mutations are heavily implicated, yet the underlying mechanism of its carcinogenic action is poorly understood. Here we demonstrate that hCdc73 specifically controls messenger RNA stability of p53 and p53-mediated apoptosis. hCdc73 is associated with mature p53 mRNA in the cytoplasm and facilitates its degradation. Cytoplasmic hCdc73 physically interacts with eEF1Bγ and hSki8, and this interaction is required to bind and destabilize p53 mRNA. Furthermore, enhanced association of p53 mRNA with a cancer-driven hCdc73(K34Q) mutant was also observed. As a result, reduced p53 expression as well as enhanced cell proliferation was acquired in the hCdc73 (K34Q)-overexpressed cells. Altogether, our findings indicate that hCdc73 directly targets p53 mRNA to repress p53 expression, and aberrant regulation of this interaction may lead to tumour progression.
