[Proteases by reactive stromal cells in cancer: an attractive therapeutic target]

Cancer-associated or reactive stromal cells are composed of endothelial and inflammatory cells as well as of spindle cells such as fibroblasts and myofibroblasts. In addition to participating to the tumor tissue frame, these cells contribute actively to tumor nutrition and progression through neo-angiogenesis and production of a variety of molecules including numerous proteases, of which a number (MMP14, MMP11, FAP and uPA) are almost exclusively produced by reactive stromal cells. Cancer cells interact with reactive stromal cells which involves a large number of proteases. Several molecules (TGFbeta, PDGF, EMMPRIN) produced by cancer cells induce the production of stromal proteases which in turn stimulate cancer cells through binding to a receptor (for example, MMP-2 and integrin alpha v beta 3). Our experience shows that protease overexpression by reactive stromal cells (cathepsin D, MMP-11, MMP-14) leads to an adverse clinical course in breast cancer. Phenotypic and genotypic differences were found between reactive stromal cells and fibroblasts of normal tissue and our research team found that reactive stromal cells also respond differently to similar stimulations in different individuals. These results support the hypothesis that the biologic behaviour of cancer is not only dependent on tumour characteristics but also on those of patients'stromal cells and that comparable tumours in two individuals may follow different clinical courses. These studies and our experience underscores the importance of characterising cancer-associated reactive stromal cells because of the therapeutic potential of this approach. Furthermore, reactive stromal cells should be genetically more stable that cancer cells and, in theory, should less likely develop mutations and treatment resistance.