The invasive phenotypes

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Abstract
The expression of the invasive (I+ or I-) phenotypes determines cancer metastasis (M+ or M- phenotype). The invasive (I+ or I-) phenotypes can be divided according to time and site of expression into subphenotypes, which can be assessed separately. At various sites along the metastatic pathway the expression of the I phenotypes can be accompanined by the presence of uncontrolled growth (G+ phenotype) or its absence (G- phenotype). Various combinations of the I and G phenotypes determine the behaviour of metazoan or parasitic cells under normal, pathological non-neoplastic and neoplastic conditions. Although the G+I+M+ combination correlates with full malignancy, the sequence of events leading to the acquisition of these phenotypes during tumor development is not clear. Conditional invasion in experimental systems indicates that a tumor may be invasive and metastatic when part of its population temporarily expresses the I+ phenotype. These experiments further stress the importance of the tumor-host ecosystem for the regulation of the I phenotypes. As distinct from some parasites, the invasive morphotype of vertebrate cells cannot be simply identified. Nevertheless, within the tumor-host ecosystem morphological correlates of the activities of invasive cells may be recognized. They reflect one or more of the I+ functions, namely: motility; loss of homotypic cell-cell adhesion; establishment of alternative cell-substrate and heterotypic cell-cell adhesion; breakdown of extracellular matrices. These functions are not exclusive for I+ tumor cells, and neither are the molecular markers investigated so far. Oncogene activation leads mainly to G+ expression, and in this way serves as a signal amplifier for the I and M phenotypes. Attractive candidate molecular markers of I phenotypes are: regulators of hydrolase activities; cell-cell adhesion molecules; cell surface receptors. From data presently available, we hypothesize that invasion depends upon the balance between an I+ and an I- pathway, with both pathways being sensitive to stimulation and inhibition.