Inhibition of carcinogen-altered rat tracheal epithelial cell proliferation by normal epithelial cells in vivo.

Abstract

The experiments described investigate the potential influence of surrounding normal tracheal epithelial cells on the survival and growth of carcinogen-exposed epithelial cells in tracheal mucosa reconstructed from known cell mixtures. Cell mixtures containing preneoplastic or neoplastic rat tracheal epithelial cells and a small fraction of normal tracheal or esophageal epithelial cells were inoculated into the lumen of previously frozen-thawed tracheas which were then transplanted s.c. into syngeneic hosts. Within 2-3 weeks an intact tracheal mucosa was regenerated from the inoculated cells. At various times after cell inoculation and transplantation, cells were harvested from the repopulated trachea and the number of diploid normal and/or aneuploid carcinogen-exposed tracheal epithelial cells determined by flow cytometry (DNA content) and the frequency of cells with altered in vitro growth capacity determined. The data suggest that normal tracheal epithelial cells have an enhanced 'survival' capacity relative to carcinogen-exposed cell lines in the regenerated tracheal mucosa. When greater than 10(4) normal cells were inoculated with a 2- to 100-fold excess of carcinogen-exposed cell lines the regenerated epithelium was comprised almost entirely of normal-diploid-epithelial cells. Independent of the ratio of normal to altered cells, when less than 10(4) normal epithelial cells were inoculated in the mixture some carcinogen-altered cells and some normal cells were present in the regenerated epithelium. When established repopulated tracheas containing mixtures of normal and neoplastic epithelial cells were left in the animal no tumors developed. In contrast tracheas containing neoplastic cells alone or partially scraped tracheas containing comparable numbers of neoplastic cells covering a contiguous area of the submucosa, tumors developed within 2-5 weeks of cell inoculation and transplantation. These data suggest that normal tracheal epithelial cells have the capacity to modulate expression of the neoplastic phenotype (tumor development) in neoplastic populations. This effect appears to require close contact with the normal cells as inhibition is not observed when the neoplastic cells occupy a single contiguous area of the trachea.