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Expression of the Tumor-specific and Calcium-binding Protein Oncomodulin during Chemical Transformation of Rat Fibroblasts¹

Institute of Toxicology, ETH and University of Zürich [E. W. S.], CH-8603 Schwerzenbach/Zürich, and Department of Pediatrics, Division of Clinical Chemistry, University of Zürich, CH-8032 Zürich [C. W. H.], Switzerland

An in vivo-in vitro approach to studying neoplastic development in carcinogen-exposed rat fibroblasts was evaluated. In the model described, oncomodulin (M_r 12,000; pI 3.9), a tumor-associated and Ca²⁺-binding protein, was used as a specific marker of malignant transformation. A rapidly proliferating granulation tissue was exposed in vivo or in vitro to potent carcinogens like N-methyl-N'-nitro-N-nitrosoguanidine and procarbazine. As an endpoint of transformation anchorage independent (AI) colony formation in the soft agar assay was chosen. Exposure to various doses of N-methyl-N'-nitro-N-nitrosoguanidine in vivo or in vitro, or to procarbazine in vivo, led to induction of AI, transformed cells. Exposure of the cells to various doses of procarbazine in vitro produced neither formation of AI cells in the agar nor expression of oncomodulin in extracts of the exposed cell population. Almost all of the chemically induced AI cell lines tested have been found to be tumorigenic in athymic mice. In contrast, a very low rate (zero to two colonies per 10⁶ cells tested) of spontaneous AI populations derived from untreated cells. None of these control AI colonies yielded tumors.

In our transformation assay the appearance of neoplastic phenotypes seems very rapid, probably due to the increased cell division at the time of carcinogen-exposure.

Expression of oncomodulin was found in extracts of transformed cells harvested from agar colonies, derived from carcinogen-exposed granulation tissue, but not from normal, untreated fibroblasts, as shown by two-dimensional polyacrylamide gel electrophoresis and high-performance liquid chromatographic analysis, as well as ⁴⁵Ca²⁺-transblot electrophoresis. The presence of oncomodulin in extracts of transformed cells correlates well with the chemically induced colony formation in the soft agar assay.

Oncomodulin might be a suitable neoplastic marker to study chemical carcinogenesis.

¹ This work was supported by grant AFOSR-82-0338, by the Swiss National Science Foundation (3.083–0.087; 3.139–0.88), by the Swiss Cancer League (FOR 337.87.2), EMDO-Stiftung Zürich, Jubiläumsspende für die Universität Zürich, and by the League against Cancer of the Kanton Zürich.

² To whom requests for reprints should be addressed.

Received 2/25/88. Revised 9/13/88. Revised 11/11/88. Accepted 11/16/88.