Progress in molecular mechanisms of tumor metastasis and angiogenesis.

The development of metastases is the major cause of death for cancer patients, however, the mechanisms of tumor invasion and acquisition of capability to metastasize remain unclear. During the past decade, knowledge regarding the molecular and cellular processes involved in the regulation of tumor metastases has dramatically increased and has been focussed on cross-talk between selected cancer cells and the specific organ microenvironment. The three-step development of the invasive phenotype of cancer cells is described: cell attachment, local proteolysis and cell migration. The molecular analysis of invasion-associated cellular activities, mainly the role of homotypic and heterotypic cell-cell adhesions, cell-matrix interactions, proteolysis mechanisms and migration properties of cancer cells, are also discussed. The role of tumor phenotype and microenvironment in the metastatic predilection for a specific organ site is pointed out, considering the recent reports which indicate that the capacity to metastasize might be acquired early during multistep tumorigenesis, thereby also predicting the site of metastasis. In addition, this review summarizes the current knowledge regarding angiogenesis regulation in progressive tumor growth and in the complex, multistep nature of tumor cell dissemination. A better understanding of the linkage between genetic and epigenetic events in metastases development may result in new anticancer treatment strategies.