It has been suggested that both these mechanisms operate in vivo in some tumors, but the relative contribution of each to cell migration is not known.The expression of both uPA and its receptor is increased by growth factors VEGF and bFGF, and this induction is regulated independently of their effects on cell proliferation. Note that although VEGF has a net effect to increase endothelial cell proteolytic activity, in some cell types it induces both uPA and PAI; evidence also indicates that bFGF and TGF may induce coexpression of uPA and PAI. However, the magnitude of uPA and PAI induction by these growth factors is markedly different.For example, in response to VEGF or bFGF, the uPA:PAI ratio is significantly increased in favour of uPA, and so the net balance of proteolytic activity is positive, whereas TGF has a net antiproteolytic effect.The coinduction of uPA and PAI is likely to provide a mechanism for preserving the integrity within the ECM by limiting matrix degradation to the pericellular environment.For example, in wound healing one of the roles for PAI is to prevent premature dissolution of the brin clot, which provides a temporary scaffold for invading inammatory cells. There are MMP family members with enzymatic activity against virtually all components of the ECM and basement membranes.Most importantly, the MMP family includes the only enzymes capable of cleaving brillar collagens.Cellmediated activation mechanisms are also possible.Recent studies showed that when membrane type MMP was overexpressed in a human melanoma cell line, the cells made contact with the ECM, activated soluble and ECM bound MMP, and degraded and invaded the ECM. In this study the membranebound protease was predominantly localized at surface extensions called invadopodia.However, not only is TIMP an inhibitor, but in complex with MTMMP, it is also an activator and receptor for progelatinase A, which suggests a dual role for TIMP in extracellular proteolysis.In early stages of outgrowth the vessel wall and perhaps circulating EC precursors supply the necessary cells, but in later stages cell proliferation is essential; without it sprouts eventually regress. Effective chemotaxis is a complex and as yet poorlyunderstood process that hinges on extracting directional information from an extracellular scalar eld and organizing the intracellular motile machinery so as to exert force in the proper direction.We begin this section by describing some of the forces that act on a motile cell as it migrates through the ECM.The role of adhesive cellcell and cellECM interactions in lumen formation is also discussed.Whereas the level of extracellular noise is not controllable, the intracellular noise level of the transduced signal may be far less, and small differences in extracellular signal may be amplied within the cell.The forces needed for cell migration are generated by the actin cytoskeleton and by myosin.Motion is generally described as a multistep process involving actin polymerization at the leading edge, which leads to extension of a Heptaminol hydrochloride pseudopod or lamellipodia, attachment of the pseudopod or lamellipod to the substrate or ECM via integrinmediated adhesion sites, release of adhesion sites at the rear, and recycling of adhesion receptors and other membrane components to the front of the cell via D-Cycloserine endocytosis and vesicular transport.