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.