Learning therapeutic lessons from metastasis suppressor proteins

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Abstract
Metastasis accounts for the preponderance of morbidity and mortality in cancer, and accumulating evidence suggests that dissemination of tumour cells may occur earlier in the development of cancer than previously appreciated. Metastasis is regulated either positively or negatively by proteins that promote steps in the metastatic cascade or those that suppress them. Metastasis suppressor genes encode proteins that prevent or reduce the development of metastases in vivo, without simultaneously affecting primary tumour growth. This is in contrast to tumour suppressors, which affect primary tumorigenesis. Metastasis suppressor proteins are lost primarily during cancer progression and not during transformation. Until recently, relatively few metastasis suppressor genes had been characterized. However, expanding genomic technology has made possible in recent years the description of many metastasis suppressor genes impinging on a wide variety of cellular processes. Although metastasis suppressor genes have been shown to work at multiple steps in the process of metastasis, several have been recently demonstrated to specifically suppress the colonization step of metastasis, the process by which solitary or small clusters of tumour cells living in a second organ site (micrometastases) grow to form clinically apparent and lethal macrometastases. Recent work has shown techniques that restore metastasis suppressor function. These include re-expression of the gene from the endogenous locus or by exogenous gene therapy, direct administration of the protein itself and targeting important metastasis mediators downstream of the suppressor that are reciprocally induced with metastasis suppressor protein losses.

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