This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grignon, D. J. Articles by Fridman, R. Search for Related Content PubMed PubMed Citation Articles by Grignon, D. J. Articles by Fridman, R.

High Levels of Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) Expression Are Associated with Poor Outcome in Invasive Bladder Cancer¹

Departments of Pathology [D. J. G., W. S., M. T., J. C. C. R. F.], Radiation Oncology [F. S.], and Urology [V. R., J. A., J. E. P.], Wayne State University, Detroit, Michigan 48201

The matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinase (TIMPs) have been associated with tumor invasion and metastasis in many human cancers. Immunohistochemical studies were performed on frozen tumor samples from 42 patients with invasive bladder cancer treated by cystectomy with monoclonal antibodies against the M_r 72,000 gelatinase A (MMP-2), M_r 92,000 gelatinase B (MMP-9), and TIMP-2 to evaluate their significance in bladder cancer. Immunoreactivity for the gelatinases was predominantly tumor cell-associated, whereas strong TIMP-2 staining was mostly detected in the stroma. Tumor cells demonstrated moderate to strong reactivity for MMP-2 and MMP-9 in 71 and 71% of cases, respectively, which did not correlate with stage, grade, or outcome. Tumor cells were positive for TIMP-2 in 26 (62%) of 42 cases, and this correlated with a worse outcome (69 versus 25% died of disease; P < 0.05). In 31 (74%) of 42, there was moderate to strong stromal staining for TIMP-2; this also was associated with a poor outcome (65 versus 25% died of cancer; P < 0.05). Tumor basement membrane (BM) status was investigated using an antibody to type IV collagen. In 9 cases, the invasive tumor nests were surrounded by an intact BM; in 7 of these, stromal staining for TIMP-2 was absent. None of these 9 patients (0%) died of tumors compared with 7 (100%) of 7 with complete loss of BM staining (P < 0.001). These results suggest a potential role for TIMP-2 and BM staining as prognostic indicators in invasive bladder cancer.

¹ Supported in part by NIH Grant CA61986 (R. F.).

² To whom requests for reprints should be addressed, at Department of Pathology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201.

Received 10/10/95. Accepted 2/ 1/96.

This article has been cited by other articles:

				A. K. Kader, J. Liu, L. Shao, C. P. Dinney, J. Lin, Y. Wang, J. Gu, H. B. Grossman, and X. Wu Matrix Metalloproteinase Polymorphisms Are Associated with Bladder Cancer Invasiveness Clin. Cancer Res., May 1, 2007; 13(9): 2614 - 2620. [Abstract] [Full Text] [PDF]

				B. E. Nicholson, H. F. Frierson, M. R. Conaway, J. M. Seraj, M. A. Harding, G. M. Hampton, and D. Theodorescu Profiling the Evolution of Human Metastatic Bladder Cancer Cancer Res., November 1, 2004; 64(21): 7813 - 7821. [Abstract] [Full Text] [PDF]

				R. Aalinkeel, M. P. N. Nair, G. Sufrin, S. D. Mahajan, K. C. Chadha, R. P. Chawda, and S. A. Schwartz Gene Expression of Angiogenic Factors Correlates with Metastatic Potential of Prostate Cancer Cells Cancer Res., August 1, 2004; 64(15): 5311 - 5321. [Abstract] [Full Text] [PDF]

				A Noel, C Maillard, N Rocks, M Jost, V Chabottaux, N E Sounni, E Maquoi, D Cataldo, and J M Foidart Membrane associated proteases and their inhibitors in tumour angiogenesis J. Clin. Pathol., June 1, 2004; 57(6): 577 - 584. [Abstract] [Full Text] [PDF]

				T. Okamoto, R. Niu, and S. Yamada Increased expression of tissue inhibitor of metalloproteinase-2 in clear cell carcinoma of the ovary Mol. Hum. Reprod., October 1, 2003; 9(10): 569 - 575. [Abstract] [Full Text] [PDF]

				G. C. Durkan, J. E. Nutt, C. Marsh, P. H. Rajjayabun, M. C. Robinson, D. E. Neal, J. Lunec, and J. K. Mellon Alteration in Urinary Matrix Metalloproteinase-9 to Tissue Inhibitor of Metalloproteinase-1 Ratio Predicts Recurrence in Nonmuscle-invasive Bladder Cancer Clin. Cancer Res., July 1, 2003; 9(7): 2576 - 2582. [Abstract] [Full Text] [PDF]

				A. H. Baker, D. R. Edwards, and G. Murphy Metalloproteinase inhibitors: biological actions and therapeutic opportunities J. Cell Sci., January 10, 2002; 115(19): 3719 - 3727. [Abstract] [Full Text] [PDF]

				G. C. Durkan, J. E. Nutt, P. H. Rajjayabun, D. E. Neal, J. Lunec, and J. K. Mellon Prognostic Significance of Matrix Metalloproteinase-1 and Tissue Inhibitor of Metalloproteinase-1 in Voided Urine Samples from Patients with Transitional Cell Carcinoma of the Bladder Clin. Cancer Res., November 1, 2001; 7(11): 3450 - 3456. [Abstract] [Full Text] [PDF]

				B. V. S. Kallakury, S. Karikehalli, A. Haholu, C. E. Sheehan, N. Azumi, and J. S. Ross Increased Expression of Matrix Metalloproteinases 2 and 9 and Tissue Inhibitors of Metalloproteinases 1 and 2 Correlate with Poor Prognostic Variables in Renal Cell Carcinoma Clin. Cancer Res., October 1, 2001; 7(10): 3113 - 3119. [Abstract] [Full Text] [PDF]

				J. W. Slaton, T. Karashima, P. Perrotte, K. Inoue, S. J. Kim, J. Izawa, D. Kedar, D. J. McConkey, R. Millikan, P. Sweeney, et al. Treatment with Low-Dose Interferon-{alpha} Restores the Balance between Matrix Metalloproteinase-9 and E-Cadherin Expression in Human Transitional Cell Carcinoma of the Bladder Clin. Cancer Res., September 1, 2001; 7(9): 2840 - 2853. [Abstract] [Full Text] [PDF]

				B. Schmalfeldt, D. Prechtel, K. Harting, K. Spathe, S. Rutke, E. Konik, R. Fridman, U. Berger, M. Schmitt, W. Kuhn, et al. Increased Expression of Matrix Metalloproteinases (MMP)-2, MMP-9, and the Urokinase-Type Plasminogen Activator Is Associated with Progression from Benign to Advanced Ovarian Cancer Clin. Cancer Res., August 1, 2001; 7(8): 2396 - 2404. [Abstract] [Full Text] [PDF]

				P. O-charoenrat, P. H. Rhys-Evans, and S. A. Eccles Expression of Matrix Metalloproteinases and Their Inhibitors Correlates With Invasion and Metastasis in Squamous Cell Carcinoma of the Head and Neck Arch Otolaryngol Head Neck Surg, July 1, 2001; 127(7): 813 - 820. [Abstract] [Full Text] [PDF]

				C. D. Hough, K. R. Cho, A. B. Zonderman, D. R. Schwartz, and P. J. Morin Coordinately Up-Regulated Genes in Ovarian Cancer Cancer Res., May 1, 2001; 61(10): 3869 - 3876. [Abstract] [Full Text]

				H. Yamamoto, F. Itoh, S. Iku, Y. Adachi, H. Fukushima, S. Sasaki, M. Mukaiya, K. Hirata, and K. Imai Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Human Pancreatic Adenocarcinomas: Clinicopathologic and Prognostic Significance of Matrilysin Expression J. Clin. Oncol., February 15, 2001; 19(4): 1118 - 1127. [Abstract] [Full Text] [PDF]

				G Cox, W P Steward, and K J O'Byrne The plasmin cascade and matrix metalloproteinases in non-small cell lung cancer Thorax, February 1, 1999; 54(2): 169 - 179. [Full Text]