Induction of stable p53 oncoprotein and of c-myc overexpression in cultured normal human uroepithelium by radiation and N-nitrosodiethanolamine.

Uroepithelium cultured from normal patients without cancer (60 individuals) was found to segregate into four subtypes based on the level of carcinogen treatment needed to induce abnormal p53 and c-myc. Twenty-two percent of patient cultures never showed abnormal p53 expression, even after chronic exposure to nitrosamines, in addition to irradiation. In these cultures, c-myc expression was confined to viable, normal-appearing cells at the growing edge of the culture and to apoptotic bodies. Twenty-eight percent of cultures were negative for abnormal p53 unless challenged with both radiation and chronic administration of nitrosamines, while a further 26% required only a single dose of radiation to induce the abnormal protein. The remaining patients had tissue which, while initially negative for stable p53, became positive when put into culture and stimulated to grow. The c-myc protein was overexpressed in all cultures with abnormal p53. It would appear that elevated expression of conformationally inactive p53 and of high levels of c-myc represents an early response of normal uroepithelial cells to carcinogen challenge. It also appears that a relatively high number of patients without cancer express these proteins when their cells are challenged to grow; a pre-exposure to environmental carcinogens such as nitrosamines in cigarette smoke is likely to be involved.