EXPRESSION OF TRANSFORMING GROWTH-FACTOR-ALPHA AND EPIDERMAL GROWTH-FACTOR RECEPTOR IN RAT LUNG NEOPLASMS INDUCED BY PU-239

Ninety-two rat lung proliferative lesions and neoplasms induced by inh aled (PuO2)-Pu-239 were evaluated for aberrant expression of transform ing growth factor alpha (TGF-alpha) and epidermal growth factor recept or (EGFR). Expression of TGF-alpha protein, measured by immunohistoche mistry, was higher in 94% of the squamous cell carcinomas and 87% of t he foci of alveolar epithelial squamous metaplasia than that exhibited by the normal appearing, adjacent lung parenchyma. In contrast, only 20% of adenocarcinomas and foci of epithelial hyperplasia expressed el evated levels of TGF-alpha. Many neoplasms expressing TGF-alpha alsb e xpressed excessive levels of EGFR mRNA. Southern and DNA slot blot ana lyses showed that the elevated EGFR expression was not due to amplific ation of the EGFR gene. These data suggest that increased amounts of T GF-alpha were early alterations in the progression of plutonium-induce d squamous cell carcinoma, and these increases may occur in parallel w ith overexpression of the receptor for this growth factor. Together, t hese alterations create a potential autocrine loop for sustaining clon al expansion of cells initiated by high-LET radiation.