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

Purpose: Matrix metalloproteinases (MMPs) degrade components of the extrace llular matrix and are implicated in tissue remodeling and tumor infiltratio n. Tissue inhibitor of metalloproteinases (TIMPs) inhibit enzymes of the MM P family and preserve stromal integrity, thus inhibiting tumor migration. A lthough numerous studies on several human carcinomas have demonstrated a ro le for MMPs in tumor metastasis and patient survival, their prognostic role in patients with renal cell carcinoma (RCC) has not been well defined. Mor e importantly, the recently documented paradoxical functions of TIMI's have not been characterized in these neoplasms. Experimental Design: Five-mum, formalin-fixed, paraffin-embedded tissue sec tions from 153 RCCs were immunostained using specific antibodies against MM P2, MMP9, (Novocastra, Burlingame, CA) TIMP1, and TIMP2 (Neo-Markers, Fremo nt, CA) proteins. Immunostaining was semiquantitatively scored based on int ensity and distribution, and results were correlated with histological and prognostic variables. Results: The rates of increased expression of MMPs and TIMI's in RCC were a s follows: MMP2, 67 %; MMP9, 43 %; TIMP1, 46 %; and TIMP2,73 %. Each of the se 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 coe xpression of MMPs and TIMI's was observed (P = 0.0001). Increased immunorea ctivity for each of these proteins correlated with high tumor grade (P rang e, 0.0001-0.01). On univariate analysis, expression of each of these marker s correlated with shortened survival (P range, 0.004-0.05). On multivariate analysis, including tumor grade, stage, and all four markers, only advance d stage (P = 0.047) and increased TIMP1 expression (P = 0.007) independentl y predicted shortened survival. Conclusion: Increased expression of MMP2, MMP9, TIMP1, and TIMP2 proteins i n RCCs correlate with poor prognostic variables including shortened patient survival. The paradoxical poor prognostic implication of TIMP overexpressi on complements the recently documented dual function of TIMPs and warrants further investigation.