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Connective Tissue Degradation by Invasive Rat Bladder Carcinomas: Action of Nonspecific Proteinases on Collagenous Matrices¹

Departments of Pathology [B. U. P., L. H. H.] and Biochemistry [B. U. P., C. A., L. H. H., D. E. S.], Rush Medical College, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612

The invasive RBTCC-8 rat bladder carcinoma cell line (passage number, >100) and its derivates, the RBTCC-8 tumor isografts and the 1-RBTCC-8 daughter cell line (fourth passage), express proteolytic activities of broad substrate specificity, which allow them to efficiently degrade extracellular (collagenous) matrices. Cell-associated, collagenolytic activity is evidenced by the release of hydroxyproline from collagen substrates of types I and IV, by visualizing the low-molecular-weight collagen breakdown products on sodium dodecyl sulfate-polyacrylamide gels, and by the depth of invasion into extracellular matrices in our bone invasion assays. Fractionated by diethylaminoethyl column chromatography, the major collagenolytic activities against collagens of types I and IV coelute in a relatively narrow peak within a NaCl gradient. The pooled collagenolytic diethylaminoethyl fractions contain: (a) two chymotrypsin-like, catheptic activities; (b) activity against a synthetic elastase substrate; (c) gelatinase activity; and (d) caseinolytic activity. Despite efficient collagenolysis, a vertebrate-type collagenase cannot be detected in any of our tumor samples, even after trypsin activation of the tumor cell extracts. The mechanism of action of these nonspecific proteinases is thought to be that of collagen "crosslinkases." The neutral proteinase activities are highest in RBTCC-8 tumor isografts, intermediate in the fourth passage 1-RBTCC-8 carcinoma cell line, and lowest in the RBTCC-8 carcinoma cell line of high passage number. The levels of these nonspecific enzyme activities are well correlated with the depth of invasion into bony matrices, as shown by our invasion assays.

¹ Supported by USPHS Grants CA25034 and CA21566 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at the Department of Pathology, Rush-Presbyterian-St. Luke's Medical Center, 1753 West Congress Parkway, Chicago, IL 60612.

Received 10/ 4/85. Revised 1/ 6/86. Accepted 1/ 7/86.