Metastasis suppressor genes: from gene identification to protein function and regulation.

In the past decade, findings from various disciplines of research have stimulated a reevaluation of fundamental concepts of the biology of metastasis. The convergence of two avenues of research has largely been responsible for this shift. First, clinical and experimental studies of specific steps of the metastatic cascade have shown that cancer cells often disseminate early in the natural history of disease and can persist at secondary sites for extended periods of time. These findings suggest that disseminated cells remain subject to growth regulation at distant sites as "dormant" single cells or microscopic metastases consisting of small numbers of cells. Second, complementary functional, biochemical, and signal transduction studies have identified a specific class of proteins that suppress the formation of overt metastases. These proteins are encoded by metastasis suppressor genes, which are operationally defined as genes that suppress in vivo metastasis without inhibiting primary tumor growth when expressed ectopically in metastatic cell lines. While metastasis suppressor proteins may affect many steps in metastatic development, recent evidence specifically implicates several of these proteins in the regulation of growth of disseminated cells at secondary sites. This review describes the evolving understanding of rate-limiting steps of metastatic growth, and the role of metastasis suppressor proteins in the regulation of these processes. We will give an overview of the studies of metastasis suppressor protein function, which have shifted our attention toward mechanisms of growth control at the secondary site (i.e., "metastatic colonization"). Emphasis is placed upon the complimentary research in the fields of metastasis and signal transduction that has identified signaling pathways controlling metastatic colonization. We also discuss the regulation of metastasis suppressor proteins and the potential biological and biochemical mechanisms responsible for their organ-type specificity. Finally, the implication of these emerging concepts on the development of therapeutic strategies will be presented.