Elastolysis induces collagenolysis: implication in tumor progression

H. Emonard, Ph.D., W. Hornebeck, Ph.D.

Centre National de la Recherche Scientifique CNRS, FRE 2260, Institut Biomolécules IFR 53, Université de Reims-Champagne Ardenne, Reims, France

AIM: Proteolysis or conformational alteration of extracellular matrix (ECM) macromolecules reveals cryptic sites or releases ECM-derived peptides which provide signals controlling cell phenotype, migration, proliferation or survival. Degradation of elastic fibers by elastase-type proteases belonging to the serine protease: elastase, cathepsin G, or matrix metalloproteinase (MMP) family led to the liberation of elastin-derived peptides (EDPs). EDPs behave as matricryptins modulating for instance fibroblast growth and activating leucocyte functions. Those effects are mediated through binding of EDPs to a cell plasma membrane protein characterized as S-gal, a truncated form of β-galactosidase. S-gal was identified in plasma membrane of several cell types including fibroblasts, cancer cell lines and endothelial cells. The influence of those peptides on cancer invasion is now investigated. METHODS: Effect of EDPs on proteolytic equipment of various cultured cell lines, including cancer cells, fibroblasts and endothelial cells, was analyzed at mRNA and protein levels. Effect of those peptides on tumor cell invasion and angiogenesis was also evaluated. RESULTS: S-gal occupancy by EDPs was found to stimulate MMP expression and to induce the MMP-1 and MMP-2 proteolytic cascades from fibrosarcoma and melanoma cell lines and Rous sarcoma virus-transformed lung epithelial cell line. Parallelly, the matrix (matrigel, type I collagen) invasive capability of these cells was considerably enhanced. Similarly, EDPs increased MMP-2 and MMP-1 production from fibroblasts; they also stimulated MT1-MMP expression and proMMP-2 activation from endothelial cells increasing their rate of tube formation within matrigel. Structure-function studies allowed us to demonstrate that only peptides with GXXPG consensus sequence adopting a type VIII β turn conformation, were active in promoting MMP expression, and associated events, in above-mentioned cell types. CONCLUSIONS: Such a motif, which is recovered in several other ECM macromolecules, might represent a major cryptic site favoring tumor growth and metastasis.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Metastasis.