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Natural Killer Cell Regulation of Implantation and Early Lung Growth of H-ras-transformed 10T Fibroblasts in Mice¹

Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada R3E 0V9

We examined the relative role of the natural killer (NK) cell and H-ras gene in controlling metastasis formation using a novel assay for quantitating viable tumor cells entering and surviving in the lung for up to 13 days following i.v. tumor inoculation. This assay utilized the resistance to G418 sulfate conferred by transfection of the neo^R gene into 10T fibroblasts along with activated H-ras. We had previously shown that the metastatic efficiency of T-24-H-ras-transformed 10T fibroblasts correlated with H-ras expression at the RNA level. In this paper we show that the NK cell could recognize H-ras-transformed fibroblasts in vivo and control experimental metastasis formation using NK-suppressed and -activated syngeneic C3H recipients. Evaluation of NK sensitivity in vitro of individual lines did not predict metastatic ability. However, NK susceptibility in vitro did inversely correlate with the ability of tumor cells to arrest and survive in the lung for the first 48 h after i.v. inoculation. Although the level of H-ras RNA correlated with the ultimate metastatic potential, it did not correlate with the initial rate of tumor cell pulmonary retention or clearing. Over the next 10 to 12 days, however, we detected a preferential survival and outgrowth of high H-ras-expressing variants, which correlated well with the ultimate metastatic ability but not NK susceptibility. These observations argue that the NK cell has its major effect early in the course of the disease, while subsequent tumor growth occurs preferentially in high H-ras-expressing cell lines.

¹ This work was supported by the National Cancer Institute of Canada.

² Terry Fox Scientist. To whom requests for reprints should be addressed, at Manitoba Institute of Cell Biology, 100 Olivia Street, Winnipeg, Manitoba, Canada R3E 0V9.

³ Recipient of a Steve Fonyo Studentship.

⁴ Terry Fox Scientist.

Received 2/16/87. Revised 5/14/87. Accepted 6/19/87.