International Journal of Molecular Sciences Review The Many Facets of Metzincins and Their Endogenous Inhibitors: Perspectives on Ovarian Cancer Progression Ruth M. Escalona 1,2,3 , Emily Chan 1 , George Kannourakis 3,4 , Jock K. Findlay 1,2 and Nuzhat Ahmed 1,2,3,4, * 1 Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia; ruthescalona74@gmail.com (R.M.E.); epchan@student.unimelb.edu.au (E.C.); jock.findlay@hudson.org.au (J.K.F.) 2 The Hudson Institute of Medical Research, Clayton, VIC 3168, Australia 3 Fiona Elsey Cancer Research Institute, Ballarat, VIC 3353, Australia; George@fecri.org.au 4 Federation University Australia, Ballarat, VIC 3010, Australia * Correspondence: nuzhata@unimelb.edu.au; Tel.: +61-403038387 Received: 19 December 2017; Accepted: 24 January 2018; Published: 2 February 2018 Abstract: Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication and signaling regulating key biological processes in cancer progression. This review investigates the role of metzincins and their inhibitors in ovarian cancer. We propose that understanding the metzincins and TIMP biology in ovarian cancer may provide valuable insights in combating ovarian cancer progression and chemoresistance-mediated recurrence in patients. Keywords: metzincins; ovarian cancer; metastasis; matrix metalloproteinases (MMPs); disintegrin and metalloproteinases (ADAMs); ADAM proteases with thrombospondin motifs (ADAMTS); TIMPs 1. What Are Metzincins? Metzincins are one of the five members of zinc endopeptidases (serine, metallo, threonine, aspartic, cysteine) that belong to the metalloproteinase family and are named metzincins due to their conserved Met residue at the active site and the use of a zinc ion in the enzymatic reaction. This family is comprised of Matrixin (MMPs), Adamalysin (ADAMs and ADAMTS), Astacin (Meprin and BMP1/Tolloids), Pappalysins and Serralysin [1,2]. Matrixin and Adamalysin are mostly soluble proteins that are secreted or sequestered by direct binding through the transmembrane domain of many cell types. They play a role in normal tissue remodeling, and are up-regulated in diverse human diseases and cancer [2]. In this review, we will focus on the roles of Matrixin, Adamalysin and their endogenous inhibitors in ovarian cancer. 2. The Origin of Epithelial Ovarian Cancer Ovarian cancer is the eighth most common cancer among women, but is the fifth leading cause of cancer-related death, and is the deadliest of gynecologic cancers [3]. Ovarian cancer was diagnosed in nearly 225,000 women world-wide, and was responsible for estimated 140,100 deaths in 2017 [4]. Nine out of ten women with ovarian cancer have an epithelial ovarian cancer and approximately 70% of these are serous carcinomas. Until recently, the vast majority of epithelial ovarian cancer was Int. J. Mol. Sci. 2018, 19, 450; doi:10.3390/ijms19020450 www.mdpi.com/journal/ijms