Perlecan/HSPG2 and matrilysin/MMP-7 as indices of tissue invasion: tissue localization and circulating perlecan fragments in a cohort of 288 radical prostatectomy patients
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Brian Grindel1, Quanlin Li2, Rebecca Arnold3, John Petros3,4, Majd Zayzafoon5, Mark Muldoon6,9, James Stave6,10, Leland W. K. Chung7, Mary C. Farach-Carson1,8
1Department of BioSciences, Rice University, Houston, TX 77005, USA
2Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
3Emory University Departments of Urology, Pathology and Laboratory Medicine and Hematology and Medical Oncology, Atlanta, GA 30322, USA
4The Atlanta Veteran Affairs Medical Center, Decatur, GA 30033, USA
5Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
6Strategic Diagnostics Inc., Newark, DE 19702, USA
7Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
8Department of Bioengineering, Rice University, Houston, TX 77005, USA
9Romer Labs Technology, Inc., Newark, DE 19713, USA
10CD Diagnostics, Claymont, DE 19703, USA
Mary C. Farach-Carson, e-mail: firstname.lastname@example.org
Keywords: perlecan, matrilysin, prostate cancer, metastasis, invasion
Received: July 09, 2015 Accepted: January 01, 2016 Published: February 04, 2016
Prostate cancer (PCa) cells use matrix metalloproteinases (MMPs) to degrade tissue during invasion. Perlecan/HSPG2 is degraded at basement membranes, in reactive stroma and in bone marrow during metastasis. We previously showed MMP-7 efficiently degrades perlecan. We now analyzed PCa tissue and serum from 288 prostatectomy patients of various Gleason grades to decipher the relationship between perlecan and MMP-7 in invasive PCa. In 157 prostatectomy specimens examined by tissue microarray, perlecan levels were 18% higher than their normal counterparts. In Gleason grade 4 tissues, MMP-7 and perlecan immunostaining levels were highly correlated with each other (average correlation coefficient of 0.52) in PCa tissue, regardless of grade. Serial sections showed intense, but non-overlapping, immunostaining for MMP-7 and perlecan at adjacent borders, reflecting the protease-substrate relationship. Using a capture assay, analysis of 288 PCa sera collected at prostatectomy showed elevated levels of perlecan fragments, with most derived from domain IV. Perlecan fragments in PCa sera were associated with overall MMP-7 staining levels in PCa tissues. Domain IV perlecan fragments were present in stage IV, but absent in normal, sera, suggesting perlecan degradation during metastasis. Together, perlecan fragments in sera and MMP-7 in tissues of PCa patients are measures of invasive PCa.
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