PROGELATINASE-A MESSENGER-RNA EXPRESSION IN CELL-LINES DERIVED FROM TUMORS IN PATIENTS WITH METASTATIC RENAL-CELL CARCINOMA CORRELATES INVERSELY WITH SURVIVAL

Objectives. Tumors are thought to metastasize by a process involving t umor cell attachment to extracellular matrix, degradation of matrix co mponents by tumor-associated proteases, and cellular movement into the area modified by protease activity. Type IV collagen comprises the ma jor element tumor cells must degrade to gain access to the rest of the body. Renal cancer cell line progelatinase A (E.C. 3.4.24.24; 72-kDa type IV collagenase; MMP-2) mRNA expression was correlated with patien t survival. Methods. Total cellular mRNA was extracted from tumor cell lines derived from patients with metastatic renal cell carcinoma. The results of the densitometric analysis of Northern blots were correlat ed with patient survival. Formalin-fixed, paraffin-embedded tissue sec tions of primary renal cancers were examined for immunohistochemical e xpression of MMP-2. Results. Cell lines established from 23 primary re nal tumors and six metastatic sites in 26 patients with metastatic ren al carcinoma were studied. Variable expression of progelatinase A, rel ative to A2058 melanoma cells (mean +/- SEM, 0.60 +/- 0.21; median, 0. 082; range, 0 to 4.78), was found. There was a significant inverse ass ociation between patient survival and the log of the MMP-2 expression (P = 0.045 by the Cox proportional-hazards model). Using a cutoff valu e of 0.10, the closest round number to the median expression of MMP-2, a significant difference between survival of patients with lower and higher MMP-2 expression in their primary renal cell line was found (P = 0.0054). Cell lines with low, intermediate, and high expression of M MP-2 mRNA all had primary tumors with high tissue immunohistochemical expression of MMP-2. Conclusions. These studies demonstrate an inverse relationship between renal cancer cell line MMP-2 mRNA expression and patient survival. Immunohistochemical studies of the primary tumors f rom which the cell lines were derived uniformly showed high MMP-2 expr ession. Previous work suggests local renal factors upregulate cellular expression of MMP-2 in the primary tumor, and are not active at extra renal sites.