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Tumor Invasion and Metastasis: An Imbalance of Positive and Negative Regulation¹

Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20892

A group of coordinated cellular processes, not just one gene product, is responsible for invasion and metastasis, the most life-threatening aspect of cancer. It is now recognized that negative factors may be just as important as positive elements. Genetic changes causing an imbalance of growth regulation lead to uncontrolled proliferation necessary for both primary tumor and metastasis expansion. However, unrestrained growth does not, by itself, cause invasion and metastasis. This phenotype may require additional genetic changes. Thus, tumorigenicity and metastatic potential have both overlapping and separate features. Invasion and metastasis can be facilitated by proteins which stimulate tumor cell attachment to host cellular or extracellular matrix determinants, tumor cell proteolysis of host barriers, such as the basement membrane, tumor cell locomotion, and tumor cell colony formation in the target organ for metastasis. Facilitory proteins may act at many levels both intracellularly or extracellularly but are counterbalanced by factors which can block their production, regulation, or action. A common theme has emerged. In addition to loss of growth control, an imbalanced regulation of motility and proteolysis appears to be required for invasion and metastasis.