Proteases in Cancer: Significance for Invasion and Metastasis
There is an extensive body of literature documenting the association of proteases with cancer. Indeed, a search of PubMed for the phrase “proteases in cancer” brings up a list of ~73,000 papers, including >7,200 reviews. Nonetheless, the protease commu
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Proteases in Cancer: Significance for Invasion and Metastasis Bonnie F. Sloane, Karin List, Barbara Fingleton, and Lynn Matrisian
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Introduction
There is an extensive body of literature documenting the association of proteases with cancer. Indeed, a search of PubMed for the phrase “proteases in cancer” brings up a list of ~73,000 papers, including >7,200 reviews. Nonetheless, the protease community still has not identified and validated all of the proteases and proteolytic pathways that play causal roles in neoplastic progression, nor determined which proteases would be appropriate therapeutic targets in pre-malignant lesions as compared to end-stage cancers or in any one type of cancer. Furthermore, more than one catalytic type of protease has been implicated in the progression of human tumors, as have interactions among proteases of more than one catalytic type. How vast a repertoire of proteases has been implicated in cancer is evident from a
B.F. Sloane (*) Department of Pharmacology, School of Medicine, Wayne State University, 540 E. Canfield, Detroit, MI 48201, USA e-mail: [email protected] K. List Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA e-mail: [email protected] B. Fingleton Vanderbilt University Medical Center, 771 Preston Research Building, Nashville, TN 372326840, USA e-mail: [email protected] L. Matrisian Vanderbilt University Medical Center, 23rd and Pierce Avenues, 771 Preston Research Building, Nashville, TN 37232-6840, USA Pancreatic Research Action Network, 1500 Rosecrans Ave, Manhattan Beach, CA 90266 e-mail: [email protected] K. Brix and W. Sto¨cker (eds.), Proteases: Structure and Function, DOI 10.1007/978-3-7091-0885-7_15, © Springer-Verlag Wien 2013
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comprehensive tome on the many proteases that comprise the cancer degradome (Edwards et al. 2008b). The initial working hypothesis for those studying proteases in cancer was that invasive processes (local and during metastatic spread) require degradation of extracellular matrices by proteases. The roles of proteases in cancer are now known to be much broader, as will be discussed here. Furthermore, the proteases themselves derive not only from tumor cells, but also from other cells that make up the tumor microenvironment, e.g., fibroblasts, macrophages, mast cells, neutrophils and endothelial cells. A critical factor to remember when considering whether a protease plays a causal role in malignant progression is that a purified protease capable of cleaving a protein substrate in vitro may not be the protease or the only protease responsible for degradation of that substrate in vivo. Transgenic mice deficient in specific proteases have helped elucidate the in vivo functions of proteases, but have also confirmed that there is redundancy and compensation. This along with the large number of proteases in the human genome, the interplay of proteases with one another as well as with their endogenous inhibitors an
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