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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

Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208 [B. V. S. K., S. K., C. E. S., J. S. R.], and Georgetown University Medical Center, Washington, DC 20007 [A. H., N. A.]

Purpose: Matrix metalloproteinases (MMPs) degrade components of the extracellular matrix and are implicated in tissue remodeling and tumor infiltration. Tissue inhibitor of metalloproteinases (TIMPs) inhibit enzymes of the MMP family and preserve stromal integrity, thus inhibiting tumor migration. Although numerous studies on several human carcinomas have demonstrated a role for MMPs in tumor metastasis and patient survival, their prognostic role in patients with renal cell carcinoma (RCC) has not been well defined. More importantly, the recently documented paradoxical functions of TIMPs have not been characterized in these neoplasms.

Experimental Design: Five-µm, formalin-fixed, paraffin-embedded tissue sections from 153 RCCs were immunostained using specific antibodies against MMP2, MMP9, (Novocastra, Burlingame, CA) TIMP1, and TIMP2 (NeoMarkers, Fremont, CA) proteins. Immunostaining was semiquantitatively scored based on intensity and distribution, and results were correlated with histological and prognostic variables.

Results: The rates of increased expression of MMPs and TIMPs in RCC were as follows: MMP2, 67%; MMP9, 43%; TIMP1, 46%; and TIMP2, 73%. Each of these four markers individually correlated with histological tumor type with a vast majority of papillary and sarcomatoid RCCs expressing these proteins as compared with clear cell tumors (P range, 0.0001–0.003). Significant coexpression of MMPs and TIMPs was observed (P = 0.0001). Increased immunoreactivity for each of these proteins correlated with high tumor grade (P range, 0.0001–0.01). On univariate analysis, expression of each of these markers correlated with shortened survival (P range, 0.004–0.05). On multivariate analysis, including tumor grade, stage, and all four markers, only advanced stage (P = 0.047) and increased TIMP1 expression (P = 0.007) independently predicted shortened survival.

Conclusion: Increased expression of MMP2, MMP9, TIMP1, and TIMP2 proteins in RCCs correlate with poor prognostic variables including shortened patient survival. The paradoxical poor prognostic implication of TIMP overexpression complements the recently documented dual function of TIMPs and warrants further investigation.

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