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Characterization of Intestinal Alkaline Phosphatase Expression and the Tumorigenic Potential of -irradiated HeLa x Fibroblast Cell Hybrids¹

Division of Radiation Oncology, Department of Radiological Sciences [M. S. M., R. J. A., J. L. R.], and Department of Microbiology and Molecular Genetics [K. M. L., E. J. S.], University of California, Irvine, Irvine, California 92717

Fusion of tumorigenic HeLa cells with human skin fibroblasts results in genetically stable hybrids which are nontumorigenic and no longer express the HeLa tumor-associated antigen, intestinal alkaline phosphatase (IAP). Previous analysis of spontaneous segregants of the nontumorigenic hybrid have implicated the loss of one copy of human fibroblast chromosome 11 with reexpression of IAP and tumorigenicity. This observation suggests that a putative HeLa tumor suppressor gene(s) is located on chromosome 11 and that this gene may be a negative regulator of the IAP gene. We have isolated several -ray-induced mutants (GIMs) of the nontumorigenic HeLa x skin fibroblast hybrid CGL1 that were specifically selected for reexpression of IAP to further investigate the potential linkage between IAP regulation and the putative tumor suppressor locus. The GIMs have a wide range of cell morphology and level of IAP expression (nearly a factor of 40). The tumorigenicity of the GIMs was examined by s.c. injection into nude mice and all were found to be tumorigenic. The tumor volume-doubling time is in the range of 4 to 8 days for all the cell lines; however, the lag time to reach 500 mm³ tumor volume was significantly longer when the GIM IAP activity was low (<20% relative activity), suggesting perhaps that there is a threshold level of IAP expression required for tumor formation and selection for high IAP expression in vivo. However, studies with tumor reconstitutes of the GIMs and transfection studies with an IAP complementary DNA expression vector indicate that high IAP expression alone is not sufficient to confer rapid tumor growth. Therefore, while the data lend strong support to the continued tight correlation between IAP reexpression and tumorigenicity and to our proposal that the tumor suppressor may negatively regulate the IAP gene, it suggests that selection for other gene activities may be responsible for aggressive tumor growth in this cell hybrid system.

¹ Supported by NIH Grants CA 39312 (J. L. R., E. J. S.) and CA 19401 (E. J. S.) and the Phi Beta Psi Sorority.

² To whom requests for reprints should be addressed.

Received 2/11/91. Accepted 6/ 7/91.

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