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Prognostic Significance of Matrix Metalloproteinase 2 and Tissue Inhibitor of Metalloproteinase 2 Expression in Prostate Cancer Jeffrey S

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Prognostic Significance of Matrix Metalloproteinase 2 and Tissue Inhibitor of Metalloproteinase 2 Expression in Prostate Cancer Jeffrey S Prognostic Significance of Matrix Metalloproteinase 2 and Tissue Inhibitor of Metalloproteinase 2 Expression in Prostate Cancer Jeffrey S. Ross, M.D., Prabhjot Kaur, M.D., Christine E. Sheehan, B.S, Hugh A.G . Fisher, M.D., Ronald A. Kaufman, Jr, M.D., Bhaskar V. S. Kallakury, M.D. Departments of Pathology and Laboratory Medicine (JSR, PK, CES, BVSK) and Surgery (Urology; HAGF, RAK Jr), Albany Medical College, Albany, New York the previously documented anti-tumor effects of Matrix metalloproteinases (MMPs) are proteolytic TIMPs, TIMP2 expression appears to have a tumor- enzymes capable of degrading the structural sup- promoting role in PACs and warrants further port network for normal and malignant cells, pro- investigation. moting neoplastic cell invasion and metastasis. Tis- sue inhibitors of metalloproteinases (TIMPs) KEY WORDS: Immunohistochemistry, MMP, Prog- maintain connective tissue integrity by modulating nosis, Prostate cancer, TIMP. MMP activity. Formalin-fixed paraffin-embedded Mod Pathol 2003;16(3):198–205 tissue sections from 138 prostatic adenocarcinomas (PACs) were immunostained by a combined auto- Matrix metalloproteinases (MMPs), a family of mated/manual method using monoclonal antibod- zinc-dependent endopeptidases, degrade the base- ies against MMP2 and TIMP2. Immunoreactivity ment membrane and extracellular matrix, facilitat- was semiquantitatively scored based on stain inten- ing cell migration, tumor invasion, and metastasis sity and distribution, and results were correlated (1–5). There are at least 20 human MMPs, divided with Gleason grade, pathologic stage, ploidy status, into the collagenases, gelatinases, stromelysins, and and disease recurrence. One hundred five of 138 membrane-type MMPs (MT-MMPs; 1–5). Tissue in- (76%) and 113/138 (82%) PACs expressed MMP2 hibitors of metalloproteinases (TIMPs) are the ma- and TIMP2, respectively. Co-expression was ob- jor endogenous regulators of MMPs and consist of correlated ,(01. ؍ served in 94/138 (68%) of PACs (P four homologous members (TIMP1–4; 6–8). TIMPs and tended to ,(05. ؍ with advanced tumor stage (P are multifunctional proteins that inhibit cell inva- .(07. ؍ be associated with disease recurrent cases (P sion in vitro and tumorigenesis and metastasis in TIMP2 expression individually correlated with ad- vivo (6). Although each TIMP appears capable of and reached near (04. ؍ vanced tumor stage (P inhibiting several MMPs, these proteins exhibit .(06. ؍ significance with disease recurrence (P preferential inhibitory capacity; for example, MMP2 expression was also more frequent in recur- TIMPs1 and 2 selectively inhibit MMP9 and 2, re- rent PACs, although this value did not reach statis- spectively (9). -However, on multivari .(07. ؍ tical significance (P Increased expression of MMPs has been associ- and (009. ؍ ate analysis, only pathologic stage (P ated with poor prognosis and shortened patient -independently predicted dis (03. ؍ ploidy status (P survival in a variety of malignancies including car- ease recurrence. In conclusion, MMP2 and TIMP2 are co-expressed in a majority of PACs and correlate cinomas of the esophagus (10), stomach (11), colon with prognostic variables. Interestingly, contrary to (12), breast (13), pancreas (14), lung (15), kidney (16), and ovary (17). TIMP expression has been associated with both tumor suppressor or anti- Copyright © 2003 by The United States and Canadian Academy of metastatic effects and tumor-promoting effects in Pathology, Inc. selected cancers (18–20). MMP and TIMP expres- VOL. 16, NO. 3, P. 198, 2003 Printed in the U.S.A. Date of acceptance: January 6, 2002. sion in prostate cancer has been recently reviewed Presented in part at the 90th annual meeting of the United States and (21). Both MMPs and TIMPs have been character- Canadian Academy of Pathology, March 2001, Atlanta, Georgia. Address reprint requests to: Jeffrey S. Ross, M.D., Department of Pathol- ized in prostate cancer cell lines (22–25) and clinical ogy and Laboratory Medicine, Albany Medical College, Mail Code 81, 47 samples from prostate cancer patients (26–33), New Scotland Avenue, Albany, NY 12208; fax: (518) 262-3663; e-mail: [email protected]. with conflicting results. Similarly, serum levels of DOI: 10.1097/01.MP.0000056984.62360.6C circulating MMPs and TIMPs have shown variable 198 capability of predicting disease progression (34– performed on the Ventana ES automated immuno- 37). The aim of the current study was to evaluate histochemistry system. Negative-control slides the immunohistochemical expression of MMP2 were incubated with isotype-matched immuno- and TIMP2 in prostate cancer and determine globulin in parallel with each batch of staining to whether the expression of these markers correlates confirm the specificity of the antibodies. with prognostic variables, including patient survival. Staining Interpretation Staining results were interpreted without prior MATERIALS AND METHODS knowledge of clinical and pathologic parameters by two observers using a consensus method. For all Patients and Specimens markers, both the intensity of staining and approx- One hundred thirty-eight randomly selected imate percentage of positive tumor cells were con- prostatic adenocarcinomas (PACs) treated by radi- sidered in the semiquantitative assessment, as pre- cal retropubic prostatectomy obtained from the viously published (40, 41). Briefly, the distribution files of the Albany Medical Center Hospital between of positive staining in the tumors was graded as 1987 and 1997 were included in this study. All he- focal (Յ10%), regional (11–50%), and diffuse matoxylin and eosin–stained slides from each case (Ͼ50%). The staining intensity was subjectively were reviewed, and tumors were graded according scored as weak, moderate, or intense. Staining pat- to the Gleason system (38) and staged according to terns of moderate diffuse, moderate regional, in- TNM criteria (39). Multiple blocks were identified tense regional, and intense diffuse were considered based on the presence of adequate tumor and the as increased expression of each protein. representative nature of the overall grade. For sta- tistical evaluations, tumors with Gleason scores of 6 or lower were considered as low grade, and tumors Quantitative DNA Analysis with Gleason scores of 7 or higher were considered Quantitative analysis of DNA content was deter- as high grade. Statistical analysis was also per- mined for each case using 5-␮m tissue sections formed using a three-tier scheme isolating tumors stained by the Feulgen reaction and evaluated by with Gleason score of 7. Serum PSA levels as mea- the CAS 200 image analyzer (Tripath Corp., Burl- sured by the Hybritech Tandem method (Hy- ington, NC), as previously described (42, 43). britech) were obtained from review of the patients’ Ͼ medical records. Postoperative PSA of 0.4 ng/mL Statistical Analysis on two consecutive occasions after prostatectomy Statistical comparisons were performed using was considered as biochemical evidence of disease Stata software (Stata Corp, College Station, TX). recurrence. Correlation between protein expression and patho- logic variables was performed using the ␹2 univar- Immunohistochemistry iate analysis. Survival curves for all univariate anal- To analyze for the expression of MMP2 and of yses were assessed using the Kaplan-Meier method. TIMP2 proteins, contiguous 4-␮m sections were cut Overall survival was defined as the interval between from a single block of formalin-fixed, paraffin- surgery and postsurgical biochemical disease recur- embedded tissue randomly chosen from those ini- rence. Multivariate analyses of clinicopathologic tially identified; sections were placed on charged parameters, including survival, were performed us- slides. After deparaffinization, primary antibody in- ing the Cox proportional hazards model. The level cubation was performed by an automated system of significance was set at .05. (Ventana Medical Systems, Tucson, AZ) for MMP2 and manually for TIMP2. Pertinent details regard- RESULTS ing antibodies and staining procedure are summa- rized in Table 1. The remainder of the staining Of the 138 PACs, there were 75 (54%) low-grade procedure included incubation with a biotinylated and 63 (46%) high-grade tumors. At prostatectomy, anti-mouse secondary antibody, diaminobenzidine there were 78 (57%) organ-confined tumors (Stages substrate, and hematoxylin counterstain and was I and II) and 60 (43%) advanced-stage (Stages III TABLE 1. Antibodies and Immunohistochemical Procedure Citrate Antigen Antibody Primary Antibody Antibody Manufacturer Clone Positive Controls Retrieval (min) Dilution Incubation MMP2 Novocastra 4D3 60 1:10 32 min at 41°C Colon carcinoma TIMP2 Neomarkers 2TMP04 60 1:10 Overnight at 4°C Breast carcinoma MMP2 and TIMP2 in Prostate Cancer (J.S. Ross et al.) 199 and IV) cancers. Of the 77 cases tested for total DNA increased MMP expression also has been impli- content, 52 (68%) were diploid, and 25 (32%) were cated in the development of prostate cancer, as nondiploid. A total of 131/138 (95%) had sequential evidenced by increased levels found in carcinomas serum PSA follow-up information available. Of versus benign prostatic hypertrophy and prostatic these 131 patients, 50(38%) had biochemical post- intraepithelial neoplasia (47, 48). surgical disease recurrence. Serum measurements of MMPs in prostate can- cer have yielded conflicting correlations with dis- ease outcome. Several studies have found a corre- Immunohistochemistry and Statistical Analysis lation between
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