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

• Type of Material: Article
• Authors: Brian Grindel, Rice University; Quanlin Li, Cedars Sinai Medical Center; Rebecca Arnold, Emory University; John Petros, Emory University; Majd Zayzafoon, University of Alabama Birmingham; Mark Muldoon, Strateg Diagnost Inc; James Stave, Strateg Diagnost Inc; Leland W. K. Chung, Cedars Sinai Medical Center; Mary C. Farach-Carson, Rice University
• Language: English
• Date: 2016-03-01
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Grindel et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.7197
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 7
• Issue: 9
• Start Page: 10433
• End Page: 10447
• Keywords: Life Sciences & Biomedicine; BONE METASTASIS; matrilysin; Oncology; Science & Technology; invasion; MATRIX-METALLOPROTEINASE 7; prostate cancer; metastasis; CANCER; EXPRESSION; BASEMENT-MEMBRANE; IN-SITU; HEPARAN-SULFATE PROTEOGLYCAN; Cell Biology; perlecan; TUMOR MICROENVIRONMENT; GROWTH-FACTOR; CELL-ADHESION
• Research Categories: Health Sciences, General; Health Sciences, Medicine and Surgery

Abstract

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 proteasesubstrate 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.