Cancer Research AACR Conference on Molecular Diagnostics - 2008 Cancer Health Disparities Conference 2009
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Trudel, D.
Right arrow Articles by Têtu, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Trudel, D.
Right arrow Articles by Têtu, B.
[Cancer Research 63, 8511-8515, December 1, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Significance of MMP-2 Expression in Prostate Cancer

an Immunohistochemical Study

Dominique Trudel1, Yves Fradet2, François Meyer3, François Harel3 and Bernard Têtu2

1 Departments of Pathology,
2 Urology, and
3 Social and Preventive Medicine, Laval University, Centre Hospitalier Universitaire de Québec, l’Hôtel-Dieu de Québec, Québec, Canada


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prostate cancer is the most common cancer in North American men. Currently available prognostic factors inadequately predict which cancers will be aggressive and which will lead an indolent course. This study was aimed at investigating the role of matrix metalloproteinase (MMP)-2 in prostate cancer disease-free survival. We correlated MMP-2 expression by malignant prostatic epithelium and stromal cells with prostate cancer disease-free survival in 187 stage pT3NxM0 prostate carcinomas using immunohistochemistry. MMP-2 was expressed by cancer cells in 131 cases (70.0%) and by stromal cells in 142 cases (75.9%). MMP-2 expression by stromal cells was not associated with progression (P = 0.7270). However, in multivariate analyses, adjusting for the Gleason score, tumor-node-metastasis stage, and initial serum prostate-specific antigen, MMP-2 expression by >50% of malignant epithelial cells was associated with decreased disease-free survival (hazard ratio, 4.267; P = 0.0012). Increased MMP-2 expression by malignant prostatic epithelia is an independent predictor of decreased prostate cancer disease-free survival.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prostate cancer is the most common cancer in North American men. Although it is the second leading cause of death in men older than 60 years (1) , only 2.9% of the new patients will die of prostate cancer (1 , 2) . In 1999, the prostate cancer-specific 15-year survival rate after prostatectomy was 91% (3) . These data suggest that some patients would benefit from a more conservative therapy instead of the standard treatments currently available (radiotherapy and radical prostatectomy). However, our current prognostic markers are not sufficiently precise to allow us to accurately and reliably predict which patients will have aggressive tumors and which will not. The identification of new prognostic factors that better predict cancer behavior might benefit a substantial number of men with prostate cancer.

A group of endopeptidases known as MMPs4 are a potential target for cancer therapy. The MMP family includes >20 zinc-dependent proteinases that degrade various components of the extracellular matrix such as fibrillar and nonfibrillar collagen, proteoglycans, glycoproteins, and denatured collagen (4 , 5) . Because they are the only enzymes known to degrade the extracellular matrix and the basement membrane, they are thought to play a major role in tumor cell metastasis. Moreover, MMPs have been shown to be involved in the release of growth factors that enhance tumor growth and aggressiveness (4, 5, 6, 7) . MMPs are inhibited by four endogenous TIMPs (4 , 5 , 8) as well as by a number of synthetic inhibitors (9) . These inhibitors might prove useful as therapeutic agents in the treatment of cancer.

MMP-2 belongs to the gelatinase subfamily of the MMPs (10) . Gelatinases are distinguished by their fibronectin-like gelatin-binding domain, which allows them to degrade nonfibrillar and denatured collagen (5 , 6) . MMP-2 overexpression has been reported in many neoplasms (4) including ovarian (11, 12, 13) , urothelial (14, 15, 16) , cutaneous (17 , 18) , gastric (19) , breast (20 , 21) , and cervical (22) cancers. Besides its direct proteolytic actions, MMP-2 activates another major gelatinase called MMP-9 (23) . In a knockout mouse model, MMP-9 has been shown to be involved in prostate cancer pathogenesis (24) and has been associated with vascular endothelial growth factor release in pancreatic cancer (25) . These data suggest that MMP-2 may not only be an independent predictor of increased tumor aggressiveness but also be important in the activation of other proteases that are directly involved in tumor angiogenesis (26) .

An increased expression of MMP-2 has been reported in prostate cancer (27, 28, 29, 30, 31, 32, 33, 34, 35) . Four groups have investigated the relationship between MMP-2 expression and prostate cancer progression (31 , 33, 34, 35) . Relationships between MMP-2 expression and the GS and the pathological TNM stage have been described (31 , 34) . Similarly, Ross et al. (35) found a relationship among MMP-2, TIMP-2, and advanced cancer stage in 138 prostate cancers of all stages. Using an in situ hybridization approach on 41 patients, Wood et al. (33) found that TIMP-1 and MMP-2 expression are independent predictors of poor post-radical prostatectomy outcome. These data prompted us to investigate the role of MMP-2 in prostate cancer progression using a large and uniform cohort of prostate cancer patients having undergone radical prostatectomy and having a long term follow-up.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Population.
The patient cohort included all patients who underwent radical prostatectomy at l’Hôtel-Dieu de Québec Hospital between 1991 and 1997 having pT3NxM0 disease and follow-up PSA measurements. Patients were excluded from the study if they had received neoadjuvant hormonal therapy. Patients’ charts were scanned by experienced research nurses to retrieve clinical information (age, tumor stage, initial and follow-up serum PSA level, status at last follow-up). Investigations were performed after approval by the Laval University Institutional Review Board.

Disease Recurrence and Survival.
Prostate cancer disease-free survival was the primary end point used in our study. Prostate cancer was considered to have recurred in the following circumstances: (a) two consecutive PSA measurements above 0.3 ng/ml; (b) a last recorded PSA value >0.3 ng/ml; (c) radiological evidence of local recurrence or metastases; or (d) the initiation of adjuvant hormonal or radiation therapy.

Histology.
All of the radical prostatectomies were performed by one surgeon (Y. F.). The excised prostates were handled and sectioned following a standardized method described by Vaillancourt et al. (36) . GS, TNM stage, and surgical margin status were recorded for every patient. Slides not showing evidence of prostate cancer were eliminated from the study.

IHC.
IHC was performed using the avidin-biotin complex method previously described by Hsu et al. (37) . Briefly, one representative 5-µm tissue section was cut from a paraffin-embedded sample of the radical prostatectomy specimen. Sections were deparaffinized and rehydrated in graded alcohols and then incubated with normal goat serum for 20 min. Sections were incubated at room temperature for 1 h with a mouse monoclonal antibody to MMP-2 (MMP-2 VC2; Neomarkers, Fremont, CA; dilution 1/50). Afterward, sections were incubated with a biotinylated secondary antibody (Dako, Carpinteria, CA) and then exposed to a streptavidin complex (Dako). Complete reaction was revealed by 3,3'-diaminobenzidine, and the slide was counterstained with hematoxylin. Breast cancer specimens known for their high expression of MMP-2 were used as positive controls. Negative controls consisted of tissue sections incubated with PBS (0.16 M, pH ~7.5) instead of the primary antibody.

Each case was evaluated blindly by two independent readers (D. T. and B. T.). The immunolabeling of cancer cells and stromal cells was evaluated separately. The number of cells expressing the marker was assessed using a semiquantitative four-grade scale (0%, <10%, 10–50%, or >50%). The immunolabeling of normal or hyperplastic prostate glands, prostatic intraepithelial neoplasia, basal cells, vessel walls, and endothelial cells was also noted. The intensity of labeling was evaluated using a four-grade scale (0, +, ++, or +++). The localization of labeling relative to the tumor front, defined as the border between malignant and nonmalignant cells, was also recorded. Labeling patterns were defined as either homogeneous or heterogeneous according to the amount of consistency of labeling within the tumor specimen. Cases in which the two observers had obtained different results were collectively reviewed, and a consensus was obtained.

Statistical Analyses.
The relationships between the IHC data and traditional prostate cancer prognostic factors (age, initial PSA serum level, GS, pathological TNM stage, margin status) were evaluated by Pearson’s {chi}2 test or Fisher’s exact test. Kaplan-Meier curves were developed to compare prostate cancer disease-free survival between the various groups of immunohistochemical MMP-2 labeling. These curves were compared for statistical significance using the log rank test. P < 0.05 was considered statistically significant. A Cox proportional hazards model was developed to assess whether the amount of MMP-2 immunolabeling was a significant prognostic marker independent of other traditional predictors of prostate cancer disease-free survival. A trend test was used to test whether the different labeling categories were distributed along a progressive order. The analyses were performed with SAS statistical software version 8.2 (SAS, Cary, NC).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Population and Tumor Characteristics.
The initial study population consisted of 207 cases of stage pT3NxM0 prostate cancer. Of these, 20 cases were excluded because adequate follow-up was lacking or because the paraffin-embedded specimen was inadequate for analysis, leaving 187 patients for the present analysis. Characteristics of the patient population are shown in Table 1Citation . Median patient age was 64 years (range, 44–74), and the mean serum PSA level was 14.5 ng/ml (range, 1.7–126). Thirty-four patients had initial serum PSA value >20 ng/ml and 65 patients (34.8%) experienced disease recurrence. Median follow-up time was 4.61 years.


View this table:
[in this window]
[in a new window]
  		Table 1 Prevalence of tumor pathological substages and GSs

 
Immunohistochemistry.
A summary of MMP-2 labeling results is shown in Table 2Citation . Stromal cells expressed MMP-2 in 142 cases (75.9%; Fig. 1Citation ), and prostate cancer cells expressed MMP-2 in 131 cases (70.0%; Fig. 2Citation ). No specific pattern of labeling or localization along the tumor front was found. The intensity of labeling was variable. Immunolabeling of MMP-2 was also present in benign prostatic epithelial glandular cells in 169 cases (90.3%) and was generally limited to either the basal cells (Fig. 3)Citation or the secretory cells but, in some cases, both secretory and basal cells expressed the marker. MMP-2 labeling of endothelial cells and of smooth muscle cells in either vessel walls or prostatic stroma was also found.


View this table:
[in this window]
[in a new window]
  		Table 2 Cohort immunolabeling description

 


View larger version (170K):
[in this window]
[in a new window]
  		Fig. 1. MMP-2 expression by stromal cells (IHC).

 


View larger version (144K):
[in this window]
[in a new window]
  		Fig. 2. MMP-2 expression by cancer cells (IHC).

 


View larger version (155K):
[in this window]
[in a new window]
  		Fig. 3. MMP-2 expression by basal cells only (IHC).

 
Statistical Analyses.
Kaplan-Meier curves showed no significant association between the amount of MMP-2 labeling by stromal cells and prostate cancer disease-free survival (Fig. 4A)Citation . However, a trend to lower disease-free survival was noted when MMP-2 expression levels by cancer cells increased (P = 0.0679; Fig. 4BCitation ).



View larger version (26K):
[in this window]
[in a new window]
  		Fig. 4. Kaplan-Meier disease-free survival curves. A, MMP-2 expression by stromal cells; B, MMP-2 expression by cancer cells.

 
Univariate analyses showed no correlation between the amount of MMP-2 labeling by stromal cells and disease-free survival, but the hazard ratio of developing recurrent prostate cancer was significantly higher in cases in which prostate cancer cells expressed increasingly higher amounts of MMP-2 (Table 3)Citation . This relationship remained significant in multivariate analyses (Table 3)Citation adjusting for other prognostic factors that were found prognostically significant (TNM stage, GS, preoperative PSA level; Table 4Citation ). No individual association was found between MMP-2 expression by prostate cancer cells and other prognostic factors (Table 5)Citation . MMP-2 expression by >50% of the cancer cells was a significant predictor of prostate cancer recurrence (hazard ratio, 4.267; P = 0.0012; Table 3Citation ). A multivariate trend test confirmed that the risk of developing recurrent prostate cancer increases with MMP-2 expression (hazard ratio, 1.539; P = 0.0030; Table 3Citation ). MMP-2 labeling by benign prostate glands, basal cells, vessel walls, and endothelial cells provided no additional information (data not shown).


View this table:
[in this window]
[in a new window]
  		Table 3 Disease-free survival rates according to MMP-2 percentage of expression

 

View this table:
[in this window]
[in a new window]
  		Table 4 Hazard ratios of potential prognostic factors on disease-free survival

 

View this table:
[in this window]
[in a new window]
  		Table 5 Correlation of MMP-2 expression by cancer cells with recognized prognostic factors

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Evidence that matrix metalloproteinase-2 expression is important in the pathogenesis of prostate cancer is rapidly accumulating (27, 28, 29, 30, 31, 32, 33, 34, 35) . To date, four groups have evaluated the role of the MMP-2 protease as a prognostic factor in prostate cancer (31 , 33, 34, 35) . These reports have shown that MMP-2 expression is correlated with disease stage and the GS (31 , 34 , 35) . One group has shown that MMP-2 may be a prognostic factor independent of disease stage and grade (33) . In the current study, we show that in a large and uniform cohort of patients who underwent radical prostatectomy, MMP-2 expression in >50% of prostate cancer cells is a major and independent predictor of decreased prostate cancer disease-free survival.

This study uses PSA failure as a surrogate end point for disease recurrence because it is currently recognized as the most sensitive indicator of residual or recurrent disease after radical prostatectomy (3 , 38) . In fact, clinically detectable recurrent prostate cancer occurring in the absence of a detectable serum PSA is a rare event (3 , 39) . With a median follow-up of 4.62 years, we found that 65 of 187 patients (34.8%) with pT3NxM0 disease treated by radical prostatectomy had experienced either a clinical or biochemical treatment failure.

The pattern of MMP-2 expression in prostate cancer cells and stromal cells observed in the current study is consistent with that previously reported by other groups (27 , 40) . As shown in Table 2Citation , we observed the highest levels of MMP-2 expression in malignant prostate glands and in stromal fibroblasts. However, MMP-2 expression was also noted in normal prostatic epithelial cells as well as in prostatic and vascular smooth muscle, albeit at a much lower level. This tends to support the concept of constitutive but differentially regulated MMP-2 expression (41) .

The association of increased MMP-2 expression by malignant epithelial cells but not by stromal cells with disease recurrence is intriguing. One group has found that MMP-2 mRNA levels were increased in stromal prostatic cells only (33) , thus suggesting that MMP-2 is produced by stromal cells and not by malignant epithelium. However, our group and others have found increased MMP-2 expression in both prostatic cell types (27 , 31 , 32 , 35) . One potential explanation for the apparent discordance between the ISH and IHC findings may be the particular mechanism of MMP-2 activation. Stetler-Stevenson et al. (42) were the first to propose that MMP-2 activation was a stromal event. Others have since demonstrated that MMP-14, a protein anchored to the cell membrane of stromal cells, binds to TIMP-2 through its catalytic domain and then uses it as a receptor for pro-MMP-2, a protein also initially produced by the stromal cells. Free adjacent MMP-14 can then cleave the Asn37-Leu38 bond of pro-MMP-2 leading to MMP-2 intermolecular autocatalytic cleavage of the Asn80-Tyr81 bond. This process leads to an active and soluble form of MMP-2 called MMP-2a. MMP-2a can then bind to cancer cells via an {alpha}vß3 integrin (7 , 26 , 43) . By IHC, using a monoclonal antibody directed against MMP-2a, Stearns and Stearns (31) found that MMP-2a was expressed only in malignant epithelium. They also showed a correlation between increased MMP-2a expression and high Gleason scores. Although the antibody used in our study cannot differentiate pro-MMP-2 from MMP-2a, our results and those of Stearns and Stearns (31) are consistent with current knowledge of the molecular biology of MMP-2 (7) . Our results showing that increased MMP-2 expression in cancerous prostate cells is associated with decreased disease-free survival suggest that most MMP-2a is bound to cancer cells.

Although the results of our study are quite interesting, a few points should be clarified. Our study population consisted only of pT3NxM0 cases treated by radical prostatectomy. Whether our results are generalizable to patients with different disease stages or those preferring other treatment options remain to be proved. Secondly, our IHC was conducted on radical prostatectomy specimens, not prostate biopsy cores. If MMP-2 is to be a used as part of a pretreatment decision-making tool, its predictive power on biopsy specimens must first be validated. Despite these caveats, we think that our results are important and that they support the concept of synthetic MMP inhibitors as potential novel antineoplastic agents. Studies are currently evaluating prinomastat (AG-3340; Agouron/Pfizer) and neovastat (AE-941; Aeterna) as treatment options in prostate cancer and other neoplasms (10 , 44) . Murine studies report a reduction in tumor burden when these drugs are administered at an earlier stage (44 , 45) . Whether or not these agents ultimately have a role in the treatment of prostate cancer remains to be determined.

In conclusion, our study suggests that increased MMP-2 expression by malignant prostate glands may be a predictor of prostate cancer disease-free survival independent of disease stage, PSA, and GS.


   ACKNOWLEDGMENTS
 
We thank Dr. Brant Inman for careful reading and reviewing of this article.


   FOOTNOTES
 
Grant support: Medical Research Council of Canada Grant MOP-36447.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Bernard Têtu, Department of Pathology, Centre Hospitalier Universitaire de Québec, l’Hôtel-Dieu de Québec, 11, Côte du Palais, Québec, Canada, G1R 2J6. Phone: 418-691-5233; Fax 418-691-5226; E-mail: Bernard.Tetu{at}chuq.qc.ca

4 The abbreviations used are: MMP, matrix metalloproteinase; PSA, prostate-specific antigen; IHC, immunohistochemistry; GS, Gleason score; MMP-2a, activated MMP-2; TIMP, tissue inhibitor of metalloproteinase; TNM, tumor-node-metastasis. Back

Received 9/30/02. Revised 8/22/03. Accepted 9/30/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Neal D. E., Leung H. Y., Powell P. H., Hamdy F. C., Donovan J. L. Unanswered questions in screening for prostate cancer. Eur. J. Cancer, 36: 1316-1321, 2000.
  2. Hsing A. W., Tsao L., Devesa S. S. International trends and patterns of prostate cancer incidence and mortality. Int. J. Cancer, 85: 60-67, 2000.[Medline]
  3. Pound C. R., Partin A. W., Eisenberger M. A., Chan D. W., Pearson J. D., Walsh P. C. Natural history of progression after PSA elevation following radical prostatectomy. J. Am. Med. Assoc., 281: 1591-1597, 1999.[Abstract/Free Full Text]
  4. Nelson A. R., Fingleton B., Rothenberg M. L., Matrisian L. M. Matrix metalloproteinases: biologic activity and clinical implications. J. Clin. Oncol., 18: 1135-1149, 2000.[Abstract/Free Full Text]
  5. Chambers A. F., Matrisian L. M. Changing views of the role of matrix metalloproteinases in metastasis. J. Natl. Cancer Inst., 89: 1260-1270, 1997.[Abstract/Free Full Text]
  6. DeClerck Y. A., Imren S., Montgomery A. M., Mueller B. M., Reisfeld R. A., Laug W. E. Proteases and protease inhibitors in tumor progression. Adv. Exp. Med. Biol., 425: 89-97, 1997.[Medline]
  7. Noel A., Albert V., Bajou K., Bisson C., Devy L., Frankenne F., Maquoi E., Masson V., Sounni N. E., Foidart J. M. New functions of stromal proteases and their inhibitors in tumor progression. Surg. Oncol. Clin. North Am., 10: 417-432, 2001.[Medline]
  8. Brew K., Dinakarpandian D., Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim. Biophys. Acta, 1477: 267-283, 2000.[Medline]
  9. Hidalgo M., Eckhardt S. G. Matrix metalloproteinase inhibitors: how can we optimize their development?. Ann. Oncol., 12: 285-287, 2001.[Free Full Text]
  10. Vihinen P., Kahari V. M. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int. J. Cancer, 99: 157-166, 2002.[Medline]
  11. Afzal S., Lalani E. N., Poulsom R., Stubbs A., Rowlinson G., Sato H., Seiki M., Stamp G. W. MT1-MMP and MMP-2 mRNA expression in human ovarian tumors: possible implications for the role of desmoplastic fibroblasts. Hum. Pathol., 29: 155-165, 1998.[Medline]
  12. Davidson B., Goldberg I., Gotlieb W. H., Kopolovic J., Ben Baruch G., Nesland J. M., Berner A., Bryne M., Reich R. High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma. Clin. Exp. Metastasis, 17: 799-808, 1999.[Medline]
  13. Sakata K., Shigemasa K., Nagai N., Ohama K. Expression of matrix metalloproteinases (MMP-2, MMP-9, MT1-MMP) and their inhibitors (TIMP-1, TIMP-2) in common epithelial tumors of the ovary. Int. J. Oncol., 17: 673-681, 2000.[Medline]
  14. Davies B., Waxman J., Wasan H., Abel P., Williams G., Krausz T., Neal D., Thomas D., Hanby A., Balkwill F. Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. Cancer Res., 53: 5365-5369, 1993.[Abstract/Free Full Text]
  15. Gohji K., Fujimoto N., Fujii A., Komiyama T., Okawa J., Nakajima M. Prognostic significance of circulating matrix metalloproteinase-2 to tissue inhibitor of metalloproteinases-2 ratio in recurrence of urothelial cancer after complete resection. Cancer Res., 56: 3196-3198, 1996.[Abstract/Free Full Text]
  16. Kanayama H., Yokota K., Kurokawa Y., Murakami Y., Nishitani M., Kagawa S. Prognostic values of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in bladder cancer. Cancer (Phila.), 82: 1359-1366, 1998.
  17. Dumas V., Kanitakis J., Charvat S., Euvrard S., Faure M., Claudy A. Expression of basement membrane antigens and matrix metalloproteinases 2 and 9 in cutaneous basal and squamous cell carcinomas. Anticancer Res., 19: 2929-2938, 1999.[Medline]
  18. Ikebe T., Shinohara M., Takeuchi H., Beppu M., Kurahara S., Nakamura S., Shirasuna K. Gelatinolytic activity of matrix metalloproteinase in tumor tissues correlates with the invasiveness of oral cancer. Clin. Exp. Metastasis, 17: 315-323, 1999.[Medline]
  19. Mori M., Mimori K., Shiraishi T., Fujie T., Baba K., Kusumoto H., Haraguchi M., Ueo H., Akiyoshi T. Analysis of MT1-MMP and MMP2 expression in human gastric cancers. Int. J. Cancer, 74: 316-321, 1997.[Medline]
  20. Pacheco M. M., Mourao M., Mantovani E. B., Nishimoto I. N., Brentani M. M. Expression of gelatinases A and B, stromelysin-3 and matrilysin genes in breast carcinomas: clinico-pathological correlations. Clin. Exp. Metastasis, 16: 577-585, 1998.[Medline]
  21. Talvensaari-Mattila A., Paakko P., Blanco-Sequeiros G., Turpeenniemi-Hujanen T. Matrix metalloproteinase-2 (MMP-2) is associated with the risk for a relapse in postmenopausal patients with node-positive breast carcinoma treated with antiestrogen adjuvant therapy. Breast Cancer Res. Treat., 65: 55-61, 2001.[Medline]
  22. Nuovo G. J., MacConnell P. B., Simsir A., Valea F., French D. L. Correlation of the in situ detection of polymerase chain reaction-amplified metalloproteinase complementary DNAs and their inhibitors with prognosis in cervical carcinoma. Cancer Res., 55: 267-275, 1995.[Abstract/Free Full Text]
  23. Fridman R., Toth M., Pena D., Mobashery S. Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res., 55: 2548-2555, 1995.[Abstract/Free Full Text]
  24. Itoh T., Tanioka M., Matsuda H., Nishimoto H., Yoshioka T., Suzuki R., Uehira M. Experimental metastasis is suppressed in MMP-9-deficient mice. Clin. Exp. Metastasis, 17: 177-181, 1999.[Medline]
  25. Bergers G., Brekken R., McMahon G., Vu T. H., Itoh T., Tamaki K., Tanzawa K., Thorpe P., Itohara S., Werb Z., Hanahan D. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol., 2: 737-744, 2000.[Medline]
  26. Silletti S., Kessler T., Goldberg J., Boger D. L., Cheresh D. A. Disruption of matrix metalloproteinase 2 binding to integrin {alpha}vß3 by an organic molecule inhibits angiogenesis and tumor growth in vivo. Proc. Natl. Acad. Sci. USA, 98: 119-124, 2001.[Abstract/Free Full Text]
  27. Boag A. H., Young I. D. Increased expression of the 72-kd type IV collagenase in prostatic adenocarcinoma. Demonstration by immunohistochemistry and in situ hybridization. Am. J. Pathol., 144: 585-591, 1994.[Abstract]
  28. Still K., Robson C. N., Autzen P., Robinson M. C., Hamdy F. C. Localization and quantification of mRNA for matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in human benign and malignant prostatic tissue. Prostate, 42: 18-25, 2000.[Medline]
  29. Pajouh M. S., Nagle R. B., Breathnach R., Finch J. S., Brawer M. K., Bowden G. T. Expression of metalloproteinase genes in human prostate cancer. J Cancer Res. Clin. Oncol., 117: 144-150, 1991.[Medline]
  30. Stearns M., Stearns M. E. Evidence for increased activated metalloproteinase 2 (MMP-2a) expression associated with human prostate cancer progression. Oncol. Res., 8: 69-75, 1996.[Medline]
  31. Stearns M. E., Stearns M. Immunohistochemical studies of activated matrix metalloproteinase-2 (MMP-2a) expression in human prostate cancer. Oncol. Res., 8: 63-67, 1996.[Medline]
  32. Stearns M. E., Wang M. Type IV collagenase (Mr 72,000) expression in human prostate: benign and malignant tissue. Cancer Res., 53: 878-883, 1993.[Abstract/Free Full Text]
  33. Wood M., Fudge K., Mohler J. L., Frost A. R., Garcia F., Wang M., Stearns M. E. In situ hybridization studies of metalloproteinases 2 and 9 and TIMP-1 and TIMP-2 expression in human prostate cancer. Clin. Exp. Metastasis, 15: 246-258, 1997.[Medline]
  34. Kuniyasu H., Troncoso P., Johnston D., Bucana C. D., Tahara E., Fidler I. J., Pettaway C. A. Relative expression of type IV collagenase, E-cadherin, and vascular endothelial growth factor/vascular permeability factor in prostatectomy specimens distinguishes organ-confined from pathologically advanced prostate cancers. Clin. Cancer Res., 6: 2295-2308, 2000.[Abstract/Free Full Text]
  35. Ross J. S., Kaur P., Sheehan C. E., Fisher H. A., Kaufman R. A., Jr., Kallakury B. V. Prognostic significance of matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression in prostate cancer. Mod. Pathol., 16: 198-205, 2003.[Medline]
  36. Vaillancourt L., Têtu B., Fradet Y., Dupont A., Gomez J., Cusan L., Suburu E. R., Diamond P., Candas B., Labrie F. Effect of neoadjuvant endocrine therapy (combined androgen blockade) on normal prostate and prostatic carcinoma. A randomized study. Am. J. Surg. Pathol., 20: 86-93, 1996.[Medline]
  37. Hsu S. M., Raine L., Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J. Histochem. Cytochem., 29: 577-580, 1981.[Abstract]
  38. Austin JC, Williams RD. Staging failures of initial therapy Resnick M. I. Thompson I. M. eds. . Advanced Therapy of Prostate Disease, 340-352, B. C. Decker London 2000.
  39. Partin A. W., Pound C. R., Clemens J. Q., Epstein J. I., Walsh P. C. Serum PSA after anatomic radical prostatectomy. The Johns Hopkins experience after 10 years. Urol. Clin. North Am., 20: 713-725, 1993.[Medline]
  40. Montironi R., Fabris G., Lucarini G., Biagini G. Location of 72-kd metalloproteinase (type IV collagenase) in untreated prostatic adenocarcinoma. Pathol. Res. Pract., 191: 1140-1146, 1995.[Medline]
  41. Sternlicht M. D., Werb Z. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol., 17: 463-516, 2001.[Medline]
  42. Stetler-Stevenson W. G., Aznavoorian S., Liotta L. A. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu. Rev. Cell Biol., 9: 541-573, 1993.[Medline]
  43. Nagase H. Cell surface activation of progelatinase A (proMMP-2) and cell migration. Cell Res., 8: 179-186, 1998.[Medline]
  44. Coussens L. M., Fingleton B., Matrisian L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science (Wash. DC), 295: 2387-2392, 2002.[Abstract/Free Full Text]
  45. Zucker S., Cao J., Chen W. T. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene, 19: 6642-6650, 2000.[Medline]



This article has been cited by other articles:


Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
E. J. Jacobs, A. W. Hsing, E. B. Bain, V. L. Stevens, Y. Wang, J. Chen, S. J. Chanock, S. L. Zheng, J. Xu, M. J. Thun, et al.
Polymorphisms in Angiogenesis-Related Genes and Prostate Cancer
Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 972 - 977.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. Hara, H. Miyazaki, A. Lee, C. P. Tran, and R. E. Reiter
Androgen Receptor and Invasion in Prostate Cancer
Cancer Res., February 15, 2008; 68(4): 1128 - 1135.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
I. S. Aljada, N. Ramnath, K. Donohue, S. Harvey, J. J. Brooks, S. M. Wiseman, T. Khoury, G. Loewen, H. K. Slocum, T. M. Anderson, et al.
Upregulation of the Tissue Inhibitor of Metalloproteinase-1 Protein Is Associated With Progression of Human Non-Small-Cell Lung Cancer
J. Clin. Oncol., August 15, 2004; 22(16): 3218 - 3229.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Trudel, D.
Right arrow Articles by Têtu, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Trudel, D.
Right arrow Articles by Têtu, B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online