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c-Ha-ras-I Oncogene-induced Differentiation and Natural Killer Cell Resistance in a Human Colorectal Carcinoma Cell Line¹

Laboratory of Cancer Biology, Department of Surgery, New England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 02115

Natural killer (NK) activity is primariliy a peripheral blood function of a lymphocyte population capable of spontaneous lysis of many transformed and metastatic targets. However, NK-susceptible targets tend to be relatively poorly differentiated. We have previously shown that poorly differentiated human colorectal carcinoma are lysed by NK cells. Well-differentiated and chemically differentiated colorectal carcinomas are insensitive to NK lysis. The present study demonstrates that transfection of the c-Ha-ras-I oncogene into a poorly differentiated colorectal carcinoma cell line also renders it NK resistant. This resistance is accompanied by a more differentiated colorectal carcinoma phenotype. Two ras-transfected lines (Clone-A-5 and Clone-A-4) showed a 30-66% decrease in susceptibility to NK lysis as compared to the parental line in standard cytotoxicity assays. The resistance of these transfectants was strictly dependent on expression of the activated p21, the H-ras protein product. Studies to assess the integrity of the initial binding step in NK lysis showed a significant decrease in the ability of these transfectants to form conjugates with fresh NK cells. It is likely that transfection with c-Ha-ras-I has selectively modulated critical NK target recognition structures.

¹ This work was supported by NIH grants CA-44852, CA-44704, and BRSG grant RR-09551-24. Dr. Bagli was supported by NIH Training Grant CA-09580-01.

² To whom requests for reprints should be addressed, at: BASF Bioresearch Corporation, 195 Albany Street, Cambridge, MA 02139.

Received 7/17/89. Revised 11/13/89.