Invasion And Metastasis

^ The spread of solid cancers beyond the confinements of their tissue compartment into other parts of the same tissue and successively into neighboring tissues (invasion) and distant organs (metastasis) is the defining property of malignancy. Invasion and metastasis are decisive for the clinical course of most cancers.

> Invasion and metastasis are complex processes, particularly in carcinomas, since normals epithelia are strongly adherent and are confined by a basement membrane. Before or during invasion, carcinomas activate their surrounding connective tissue, eliciting inflammation and angiogenesis. Actual invasion by carcinoma cells involves decreased cell adhesion and increased motility as well as destruction of the basement membrane and remodeling of the extracellular matrix. Metastasis, in addition, requires cancer cells to enter blood or lymph vessels, to survive there, to extravasate, reattach, and proliferate in a different tissue. Furthermore, during invasion and metastasis, cancer cells need to evade cytotoxic cells of the immune system such as cytotoxic T-cells (CTL) and natural killer (NK) cells.

> Invasion and metastasis require an extensive reorganization of carcinoma cells, particularly of their cytoskeleton and their surface. Likely, this reorganization involves coordinated changes of gene expression and cell structure that impress as 'programs' for invasion or metastasis. These 'programs' are predominantly secondary consequences of mutations in oncogenes or tumor suppressor genes, but are aided by specific mutations, e.g. in cell adhesion molecules.

> Changes in cell surface molecules accompany altered cell-cell and cell-matrix interactions during invasion and metastasis. Molecules mediating homotypic interactions such as E-cadherin and connexins are down-regulated or mutated. Expression patterns of proteins mediating interactions with the extracellular matrix, such as integrins, are changed. Various other proteins on the cell surface including adhesion molecule, antigenic glycoproteins, and recognition proteins for immune cells are expressed at altered levels, alternatively spliced or processed, or mutated.

^ Successful invasion depends crucially on interactions with non-tumor 'stromal' cells, i.e. tissue mesenchymal, endothelial and inflammatory cells, which also display changes in gene expression and behavior. The emergence of 'activated stroma' may distinguish highly malignant carcinomas.

^ The destruction of the basement membrane and other extracellular matrix components in connective tissues surrounding a carcinoma is predominantly accomplished by proteases secreted from tumor and stromal cells, notably metalloproteinases and plasmin. Various members of the matrix metalloproteinase (MMP) family are over-expressed in tumor tissues and their inhibitors (TIMP) are often down-regulated. Proteases also activate latent growth factors from their storage sites in the extracellular matrix that act on carcinoma and stromal cells.

^ Angiogenesis is a prerequisite for the progression of many solid tumors. Migration and proliferation of endothelial cells which form new blood capillaries and lymph vessels is stimulated by several factors secreted by tumor cells and reactive stroma, such as VEGFs, PDGF, and certain FGFs.

> Recent evidence indicates that the changes in gene expression during tumor invasion are contingent on an overall activation of protein synthesis in tumor as well as stromal cells evident as an increase in expression of translation initiation factors and phosphorylation of translational proteins.

> Paracrine interactions between tumor and stromal cells are copious in carcinomas. At least during early progression stages, carcinoma cells may still depend to a large extent on growth factors from the stroma for their survival and proliferation. In turn, carcinoma cells stimulate production of growth factors from the stroma acting on carcinoma cells, stromal, immune and endothelial cells. Moreover, tumor cells secrete factors like TGFB which stimulate proliferation of connective tissue cells, but inhibit lymphocytes.

> Interactions with stromal cells are probably even more crucial in the establishment of metastases. While tissues with microcapillary systems, such as liver, lung, and bone, are obviously preferred targets for metastases for mechanical reasons, the actual pattern of metastases does not only depend on mechanical and anatomical factors. Rather, to survive and expand, metastatic tumor cells need to set up mutual interactions with stromal cells in the target tissue. This is the molecular basis of the 'seed-and-soil' hypothesis.

> Primary tumors and metastasizing tumor cells are potential targets of the immune system. Multiple mechanisms limit its ability to eliminate tumor cells. Theycomprise production of inhibitory cytokines, down-regulation of recognition molecules and of death receptors used by cytotoxic immune cells and even active counterattack by expression of death receptor ligands.

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