Matrix metalloproteinases: Biologic activity and clinical implications

Tumor progression is a compiler, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acq uisition of the ability to spread and colonize distant sites in the body. A lthough many factors regulate malignant tumor growth and spread, interactio ns between a tumor and its surrounding microenvironment result in the produ ction of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradati ve enzymes with clear links to malignancy. These enzymes are associated wit h tumor cell invasion of the basement membrane and stroma, brood vessel pen etration, and metastasis. They have more recently been implicated In primar y and metastatic tumor growth and angiogenesis, and they may even have a ro le in tumor promotion. This review outlines our current understanding of th e MMP family, including the association of particular MMPs with malignant p henotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategi es that capitalize on blocking the enzymes have rapidly developed. The prec linical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is a lso examined, with the discussion encompassing important methodologic issue s associated with determining clinical efficacy of MMPIs and other novel th erapeutic agents. J Clin Oncol 18:1135-1149, (C) 2000 by American Society o f Clinical Oncology.