Coordination Of The Machinery Of Invasion At The Cell Surface

Significant progress has been made in our understanding of the molecular cross-talk between tumour cells and host cells at the invasion front. A cascade of cytokines, motility factors, matrix receptors, enzymes and enzyme inhibitors simultaneously carries out the regulation, steering, pro-teolysis, traction and locomotion required for invasion

Remodelling of the extracellular matrix, within the immediate pericellular environment of the cell, appears to be a necessary step in local invasion (Liotta et al., 1991; Werb, 1997). The complement of enzyme classes is tightly and exquisitely regulated by a series of activation steps and specific inhibitors. In a striking demonstration of host-tumour interdependence, a majority of the enzymes and inhibitors complexed at the invasion front are contributed by host cells, not by the invading tumour cells (Nakahara et al., 1997; Bowden et al., 1999; Coussens et al., 2000).

The enzyme machinery is confined to the cell surface at the point of invading pseudopodia 'invadopodia' by binding the enzymes to adhesion sites, cell surface receptors and adjacent ECM molecules (Nakahara et al., 1997; Bowden et al., 1999; Hoegy et al, 2001). MT1-MMP, a membrane-anchored ECM-degrading enzyme, contains a transmembrane--cytoplasmic sequence that confines it to microinvasion sites on the tumour cell invadopodia surface (Figure 3). In complex with one of the tissue inhibitors of metalloproteinases (TIMP-2) it becomes a receptor and activator of MMP-2 (Nakahara et al., 1997), a soluble MMP produced by stromal fibroblasts and endothelial cells. The serine proteinase uPA is confined to the invading pseudopodia through a cooperation between integrins and the uPA receptor (uPA-R) (Andreasen et al., 1997). uPA-R is an adhesion receptor for vitronectin, and also interacts laterally with integrin fl chains. Proteolysis of ECM proteins modifies integrin mediated anchorage, focal adhesions and cytoskeletal architecture and triggers signalling molecules such as focal adhesion kinase (FAK) (Braga, 2000; Fashena and Thomas, 2000). Such heterotypic complexes direct and confine the enzymatic field at the forward edge of the invading cell, leaving intact the peripheral and distal attachment sites required for traction. As the invading cell moves forward through ECM barriers, the leading edge complex of enzymes, inhibitors and receptors molecules cycle through adhesion, deadhesion and pro-teolysis. The direction of tumour cell invasion and migration can be influence by chemoattractants and by marking of preferred adhesion pathways. Local attractants include (1) hepatocyte growth factor/scatter factor, which binds to the Met (c-Met) receptor (Wernert, 1997; Jo et al., 2000), (2) proteolysed matrix fragments which are recognized by integrins (Varner and Cheresh, 1996) or (3) cytokines and growth factors, such as EGF and TGF-,3 released from the degraded matrix (Roberts et al., 1992). Cryptic RGD sites exposed by proteolysis (Davis, 1992; Fukai et al., 1995; Varner et al., 1995; Varner and Cheresh, 1996) may guide the path in front of the invading tumour cells.

The combination of microdissection and protein microarrays has been successfully applied to the micro-world of early stage cancer (Clark et al., 2000; Paweletz et al., 2001). Protein lysate microarrays consist of very small mass quantities (picograms) of protein lysates from cell lines, whole lysed tissue or microdissected subpopulations of lysed tissue cells immobilized and arrayed on a solid phase. The array can be probed with antibodies recognizing phosphorylated forms of signal proteins. Detection is highly sensitive, quantitative and precise, so that the state of signal pathways may be profiled. Individual subpopulations of host and tumour tissue cells within a microscopic field of invasion or premalignant transition can be microdissected and individually studied.

In conclusion, the process of cancer invasion is a coordinated effort by tumour cells and host cells within a microinvasion field. Within this field the tumour cells exchange cytokines, enzymes, inhibitors and growth factors which promote invasion by all cells involved. Pericellular remodelling of the ECM is commensurate with invasion. The different events of the metastatic cascade of angiogenesis, adhesion, proteolysis, motility and proliferation may provide useful and novel therapeutic targets. Investigators have identified some of the critical molecules involved in the extracellular cross-talk taking place among and between cells in the invasion field. This synthesis provides strategies for a new therapy concept 'stromal therapy' which targets the tumour-host communication interface. (See the chapter Targeting the Extracellular Matrix.)

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