Matrix metalloproteinases in cancer metastasis: An unsolved mystery

Abstract

Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and acquisition of the ability to spread and colonization to distant sites in the human body. Understanding the molecular mechanisms of metastasis is crucial for developing novel therapeutic strategies to combat metastatic cancers. Early studies established the importance of the extracellular matrix on tumor cell growth and differentiation. With time, the role of the extracellular matrix and matrix metalloproteinases (MMPs), a family of degradative enzymes, in the regulation of tumor invasion, metastasis, and angiogenesis was recognized. Initially, it was believed that the major role of MMPs in metastasis was to facilitate the breakdown of physical barriers to metastasis, thus promoting invasion and entry into and out of blood or lymphatic vessels (intravasation, extravasation). However, recent evidence suggests that MMPs may have a more complex and divergent role in metastasis as well as in cancer stem cell maintenance. In the present review, the role of MMPs and their functional contribution in metastasis have been revisited and discussed. Upcoming approaches target MMPs and their inhibitors, e.g., tissue inhibitors of metalloproteinases (TIMPs), genetically or pharmacologically, suggesting that MMPs are key regulators of growth of tumors, both at primary and metastatic sites. These evidences present MMPs as the important candidates in creating and maintaining an environment that supports the initiation and maintenance of growth of primary and metastatic tumors. Future endeavors to target matrix metalloproteinases would be important in the development of novel therapeutic strategies against metastatic cancers.