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Urokinase Secretion from Human Colon Carcinomas Induced by Endogenous Diglycerides¹

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [B. M., D. I., S. W., E. F.], and Department of Experimental Biology, Roswell Park Memorial Institute, Buffalo, New York 14263 [S. H., G. M.]

Colon tumor cells are more responsive to certain growth modulators in their local environment in vivo than are normal colonocytes. Examples of this class of compounds are the fecal diglycerides (DGs) (E. Friedman et al., Cancer Res., 49: 544–548, 1989), which may act as endogenous tumor promoters. At the concentration found in vivo, fecal DGs composed of oleic, myristic, and palmitic fatty acids induced mitogenesis of all classes of benign tumor cells and of half of the resected carcinomas tested in primary culture, but induced no detectable mitogenesis of normal colonocytes. Colon tumor cells also exhibit selective responses to these endogenous modulators as measured by another biological parameter, secretion of urokinase. Addition of the fecal DG dimyristin led to release of 17 times more urokinase from carcinomas than from normal colonocytes. Fecal DGs also induced a 13-fold increase in urokinase mRNA synthesis in colon carcinoma cells and induced secretion of active urokinase from each of five research carcinomas. Colon carcinomas, at both the primary site and metastatic to the liver, secreted the M_r 55,000 form of urokinase constitutively and secreted the same form upon treatment with fecal DGs. An increase in the steady-state level of urokinase secretion by saturated-chain DGs exhibited a strong dependency on the chain length of the fatty acid residues, those of 14 and 16 carbons having the greatest activity. Thus, fecal DGs composed of oleic, myristic, and palmitic acid residues induce two biological activities selectively in colon tumor cells, each of which would enhance tumor development. Selective mitogenesis would increase adenoma and carcinoma cell number relative to normal colonocyte number, and induction of the proteolytic enzyme urokinase would aid local invasion of the carcinoma within the bowel wall.

¹ Supported by American Cancer Society Grant BC613 to E. F., National Cancer Institute Grant CA41576 to S. H., and Program Project Grant CA28853 to G. M.

² To whom requests for reprints should be addressed.

Received 6/21/89. Revised 1/ 4/90.