Matrix-directed regulation of pericellular proteolysis and tumor progression.
The microenvironment of cancer cells, composed of extracellular matrix (ECM) macromolecules, plays a pivotal function in tumor progression. ECM preexisting modules or cryptic sites revealed by partial enzymatic hydrolysis positively or negatively regulate matrix metalloproteinase (MMP) expression and activation, further influencing matrix invasion by cancer cells. Pericellular activation of gelatinase A (MMP-2) proceeds via the formation of a complex involving its inhibitor, TIMP-2, its activator(s), MT-MMPs and alphavbeta3 integrin forming a docking system. This proteinase has been invariably linked to cancer cell invasive potential and is often predictive of a poor survival. MMP-2 degrades most ECM macromolecules and appears to act as a main 'decryptase'. ECM modulation of MMP-2 activation pathway thus influences angiogenesis and tumor growth. For instance the noncollagenous domain of alpha3 chain of type IV collagen, through alphavbeta3 integrin binding, inhibits both MT1-MMP and alphavbeta3 integrin expression from melanoma cells and empedes cell migration and proliferation. At the opposite, a particular module in elastin (VGVAPG) with type VIII beta turn conformation stimulates MT1-MMP and proMMP-2 activation through binding to S-gal elastin receptor, and increases the matrix invasive capacity of several cancer cell lines and endothelial cells. Endocytosis emerges as a main mechanism controlling MMP-2, and also other MMPs; it proceeds via the formation of a MMP-thrombospondin(s) complex further recognized by the LRP scavenger receptor. ECM undergoes conspicuous variations with aging linked to alterations of tissue organization and post-translational modifications of matrix constituents that modify cell-matrix interactions and MMP-2 activation pathway.
Hornebeck
William
W
Institut Fédératif de Recherche Biomolécules (IFR 53), Centre National de la Recherche Scientifique (CNRS, FRE 2534), Faculté de Médecine, Université de Reims-Champagne Ardenne, France. william.hornebeck@univ-reims.fr
Emonard
Hervé
H
Monboisse
Jean-Claude
JC
Bellon
Georges
G
D000818:Animals; D018450:Disease Progression; D005109:Extracellular Matrix / Q000201:enzymology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism
D010447:Peptide Hydrolases; D020778:Matrix Metalloproteinase 2