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THE PAPER EXPLAINED
PROBLEM:
While the tumour microenvironment is known to contribute to tumour progression, the role of carcinoma‐associated fibroblasts (CAFs) remains controversial and their origin unclear. This study addresses the hypothesis that chronic oxidative stress can modulate tumour growth and spread by modulating surrounding tumour fibroblasts.
RESULTS:
We took advantage of the chronic oxidative stress resulting from junD deletion to examine the role of reactive oxygen species (ROS) in tumour development. In this model, CAFs derive from stress‐exposed fibroblasts and promote metastatic dissemination of neoplastic cells. Pro‐invasive myofibroblast properties resulted from ROS‐mediated accumulation of the pro‐angiogenic HIF‐1α and the pro‐inflammatory chemokine CXCL12 that activated the RhoA‐GTPase. Invasive HER2‐human breast adenocarcinomas, characterized by high rate of lymph node metastases, exhibit a correlated stromal accumulation of both CXCL12 and myofibroblasts and display an associated oxido‐reduction signature, indicating the relevance of our findings in human cancers.
IMPACT:
HER2‐amplifying human breast adenocarcinomas, a breast cancer molecular subtype associated with a very poor prognosis and lymph node metastases, express high levels of CXCL12 in the stroma. Our study raises the intriguing possibility that, in addition to current treatments, CXCR4‐blocking antibodies may be effective in combating tumour metastasis in lymph node‐positive HER2 patients.
INTRODUCTION
Carcinomas are highly complex tissues composed of neoplastic and stromal cells, including mesenchymal cells, fibroblasts or myofibroblasts, endothelial cells, pericytes and inflammatory cells (Bissell & Radisky, 2001; Mueller & Fusenig, 2004). In past decades, the major focus of cancer research has been the transformed cell itself. However, new clinical data have shown that the stroma contributes significantly to the development of a wide variety of tumours. Tissues exhibiting chronically inflamed stroma or those suffering from repetitive wound healings display a higher incidence of tumour formation (Joyce & Pollard, 2009; Tlsty & Coussens, 2006). Fibroblasts are the most common type of stromal cells in various human carcinomas, yet their specific contributions to tumour growth have only recently been clarified (Erez et al, 2010; Orimo et al, 2005). Stromal fibroblasts, named carcinoma‐associated fibroblasts (CAFs), have been extracted from a number of invasive human breast carcinomas. CAFs are more competent in promoting growth of mammary carcinoma cells and enhancing tumour angiogenesis than fibroblasts derived from outside tumour masses (Olumi et al, 1999;...