Nonpolarized secretion of human meprin alpha in colorectal cancer generates an increased proteolytic potential in the stroma.

Epithelial cells of the normal human colonic mucosa secrete an astacin-type metalloprotease, meprin a (E. C. 3.4.24.18, N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase), into the intestinal lumen. We found that Caco-2 cells, a colon carcinoma cell line, expressed endogenous meprin alpha, which was secreted at both the basolateral and apical plasma membrane. The expression of meprin alpha in colorectal cancer was confirmed using Northern blot analysis. On tissue sections, a diversity of carcinoma cells with varying immunoreactivity for meprin alpha was observed. Western blots of a series of 11 paired samples of carcinomas and normal control colon tissue revealed that meprin alpha protein accumulated at significant levels in 6 carcinomas at Union International Contre le Cancer tumor stages I-IV. In contrast, the protease was never detected in normal control tissue samples. Meprin alpha zymogen was activated in the tumor tissue, as shown by a 3-fold increase in enzymatic activity. In conclusion, we describe a cancer-specific sorting of meprin alpha, leading to a redistribution with consecutively increased proteolytic activity in the tumor stroma. Because the protease is known to cleave extracellular matrix components in vitro, meprin a may contribute to tumor progression by facilitating migration, intravasation, and metastasis of carcinoma cells.