Heterogeneity in responses of human and rodent respiratory epithelial cells to tumor promoters in culture.

Phorbol ester tumor promoters enhance the ability of primary normal rat tracheal epithelial cells to form colonies in a time-dependent fashion. The potency of phorbol derivatives in inducing this effect is relative to their potency as tumor promoters in mouse epidermis. Agents which do not interact with the putative TPA receptor are not effective. In contrast, both hamster tracheal and human bronchial epithelial cells are inhibited from forming colonies by phorbol esters. The sensitivity of human cells varied among individuals but could not be related to age, smoking history, or presence of a cancerous condition. These results bear some similarity to those of Harris et al. where levels of BP-DNA binding were measured in organ cultures of human bronchus. An interindividual variation of 120-fold was observed in 37 specimens of human bronchus, however, no correlation was apparent between levels of binding and whether the specimens were from patients with cancer. It would be of interest to determine if there is a relationship between carcinogen metabolism or binding and the ability to respond to promoters in specimens from normal and lung cancer patients. It is conceivable that lung cancer arises in individuals that have rare peculiarities in carcinogen metabolism combined with peculiarities in their responses to promoters present in cigarette smoke. Several conclusions can be drawn from these data. Species vary in response to tumor promoting agents, and the type of response may be a result of the biochemical events which are triggered by interaction with protein kinase C or another cellular receptor. Both responses, that of enhanced growth of epithelial cells observed in the rat, or that of inhibition of growth (induction of terminal differentiation) seen in human and hamster epithelial cells are consistent with proposed mechanisms by which tumor promoters may function. A general enhancement of cell proliferation may lead to fixation or expansion of genetic damage in initiated cells, while induction of terminal differentiation in normal cells could lead to expanded cell proliferation in initiated cells resistant to differentiation controls. This indicates that both responses may be useful in detecting environmental promoting agents. In light of these studies perhaps the hamster trachea may more closely mimic the responses of the human bronchus than does the rat. This is consistent with observations of the difficulty in transforming hamster tracheal epithelium (Dr. Brooke Mossman, personal communication) and human bronchial epithelium compared with rat tissue.(ABSTRACT TRUNCATED AT 400 WORDS)