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Neoplastic Progression by EJ/ras at Different Steps of Transformation in Vitro of Human Uroepithelial Cells¹

Cellular and Molecular Biology Program [C. I. P., C. A. R.], Department of Pathology [K. G.], Department of Biochemistry [C. K.], and Department of Human Oncology [C. A. R., S-Q. W.], University of Wisconsin, Madison, Wisconsin 53792, and orthwestern University Medical School [R. O.], Chicago, Illinois 60611

The biological effects of expression of mutant ras at different stages of human uroepithelial cell (HUC) tumorigenesis were tested after transfection of EJ/ras into nonestablished HUC and three isogeneic cell lines representing different steps in HUC transformation in vitro. Transfection with EJ/ras failed to immortalize diploid HUC and also failed to cause tumorigenic conversion of a near-diploid SV40-immortalized HUC line (SV-HUC) except at one of six nude mouse inoculation sites. In contrast, EJ/ras-transfected aneuploid low-grade squamous cell carcinoma cells formed undifferentiated, invasive carcinomas at four of six inoculation sites. Furthermore, EJ/ras accelerated tumor growth in MC-ppT11-HA2, an aneuploid high-grade transitional cell carcinoma line, as determined by decreased tumor latent periods and doubling times. These results suggest that EJ/ras contributes to progression, possibly by accelerating tumor growth, but does not in itself cause tumorigenic transformation of uroepithelial cells. To test whether chromosome losses accompanied EJ/ras transformation of SV-HUC, the karyotype of the one SV-HUC tumorigenic transformant obtained (above) was examined. This tumor cell line showed losses of chromosome arms 3p, 10p, 11p, and 18, all of which have been hypothesized to contain genes that suppress cancer development. Therefore, these results also provide new evidence suggesting that genetic losses may be required for mutant ras to contribute to HUC tumorigenic progression.

¹ This work was supported by NC1-R01-CA29525-12 and P01-BM144-CA13-1 to C. A. R., C. I. P. was supported in part by NIH Training Grant 5 T32 GM07215, and C. K. was supported in part by a predoctoral fellowship from the Haertle Foundation.

² To whom requests for reprints should be addressed.

Received 8/22/91. Accepted 11/ 6/91.

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