Cancer Invasion And Metastasis

Cancer is a chronic and progressive disease characterized by growth deregulation, cellular dedifferentiation and invasion. Cancer is the result of an accumulation of genetic alterations leading to tumour progression (1, 2, 3) (Figure 1). Oncogenes and tumour-suppressor genes have been associated mainly with the regulation of growth. Activation of oncogenes and inactivation of tumour-suppressor genes lead to the transformation of a normal tissue into a benign tumour. Invasion-promoter and invasion-suppressor genes were distinguished from oncogenes and

Cancer Metastasis, Molecular and Cellular Mechanisms and Clinical Intervention, 73-119. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.

tumour-suppressor genes (4, 5, 6, 7). However, the distinction between both categories of genes implicated in tumour development has vanished (8, 9, 10). Although there is little doubt that these genetic alterations are the momentum of cancer development, it is our opinion that host cells are crucial for invasion and metastasis (Figure 2). Therefore, we consider invasion within a micro-ecosystem in which there is continuous molecular cross-talk between cancer cells and host elements, together establishing the tumour. Host elements implicated are : inflammatory cells, immunocytes, endothelial cells, fibroblasts, and extracellular matrix produced by them. Invasion permits the cancer cells to leave the tissue from which they originated, to enter into the circulation, to home at distant organs, to extravasate and to establish a new micro-ecosystem. There, cancer cells create a new invasive tumour, called metastasis from which a new multistep process of invasion may start (Figure 3). Each step of the invasion process is characterized by a micro-environment containing the cancer cell and elements of the host, the latter differing from organ to organ. Several cellular activities are implicated in invasion : cell-cell adhesion, cell-matrix adhesion, motility and proteolysis. All the cells participating at these activities exhibit considerable flexibility in their interactions with other cells or with components of the extracellular matrix. Most molecules of interest, such as cadherins, integrins, proteinases, motility factors and their receptors form complexes that are sensitive to modulation at multiple levels. This is in line with the opinion that invasion is a temporary and repetitive phenomenon (11, 12, 13). Our laboratory has paid major efforts to the invasion-suppressor complex formed by E-cadherin and its associated cytoplasmic proteins, the catenins. This complex is, indeed, modulated at various levels, namely gene mutation, hypermethylation of the promoter, protein phosphorylation and protein-protein association (14, 15, 16, 17, 18). We have investigated a novel way in which the E-cadherin/catenin complex is downregulated, namely ectodomain shedding of E-cadherin leading to invasion.

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