Molecular Cross Talk in Malignant Progression

As previously mentioned, although adhesion, proteolysis, and migration can be considered individually, the three are actually inseparable events in the process of invasion. Likewise, research has shed light on a myriad of interlink-ages between the processes of cancer growth, survival, invasion, and angiogenesis. What follows is a brief discussion of molecular cross-talk between these systems, with particular reference to the adhesion molecules and proteases mentioned previously.

Angiogenesis, a process central to tumor growth and survival, is an MMP-dependent process. As cancer cells employ MMPs to invade into adjacent normal tissues, endothelial cells stimulated by proangiogenic tumor signals require MMP activity to invade into the tumor substance. Both endogenous and synthetic MMP inhibitors have been shown to block angiogenesis by interfering with endothelial cell attachment, proliferation, migration, and growth. Small molecules released by proteolysis of the extracellular matrix, including growth factors and angiostatin, act as both positive and negative regulators of angiogenesis.80

The activation of pro-MMPs is a critical step in the regulation of extracellular matrix proteolysis. MMP-2 activation is known to take place on the cell surface, where MT1-MMP cleaves pro-MMP-2 into its active form in the presence of permissive concentrations of TIMP-2. Studies of cancer cells and angiogenic endothelial cells suggest that avp3 inte-grin binds the carboxyterminal PEX domain of MMP-2 and that this interaction may localize proteolytic activity to the invasive front of cells.81'82 Treatment of cancer cells with anti-integrin antibodies has been shown to increase MMP-2 secretion as well as cell invasiveness, and other studies suggest that signaling through FAK upregulates MMP-9.83'84 Integrins and the uPA/uPAR system are known to interact and exert reciprocal regulatory actions on one another, but these processes are just beginning to be understood. As mentioned before, avP3 integrin is expressed on activated endothelial cells. Antagonists of avp3 integrin are known to disrupt blood vessel formation in the chick allantoic membrane and other bioassay systems. In vivo, OvP3 integrin antagonists block tumor angiogenesis and, in some cases, can cause tumor regression.85

The role of cadherin-catenin signaling in promoting tumor growth and MMP-7 expression has already been mentioned. E-cadherin is also a substrate for MMP-3 and MMP-7. Cleavage of E-cadherin results in release of the soluble extracellular E-cadherin fragment, which has been found to promote tumor cell invasion by acting in a paracrine manner.86 The soluble E-cadherin fragment is thought to interfere with normal E-cadherin function in nearby cells and possibly to activate other signaling pathways that remain to be identified.

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