TUMOR-NECROSIS-FACTOR ALPHA-INDUCED STIMULATION OF NEOPLASTIC PROGRESSION OF PRENEOPLASTIC, HYPERPLASTIC ALVEOLAR NODULE LINE C4

Lymphocytic infiltrates of the mouse mammary preneoplastic, hyperplast ic alveolar nodule (HAN) line C4 have elevated reactivity which correl ates positively with the progression of HAN to mammary adenocarcinoma. In this study we investigated the hypothesis that the immunoregulator y mechanisms of HAN infiltrating lymphocytes (HILs) on mammary neoplas tic progression are mediated, at least in part, by tumor necrosis fact or alpha (TNF alpha). C4 HAN epithelial cells express mRNA for both th e p55-60 receptor and the p75-80 TNF alpha receptors. High levels of b oth TNF alpha and TNF beta are expressed by HILs, whereas only TNF alp ha is expressed by the C4 HAN epithelial cells. Treatment of C4 HAN be arers with TNF alpha in vivo decreases the latency period and enhances the frequency of HAN progression to tumor. Proliferation of monolayer cultures of epithelial cells from mammary glands of normal and C4 HAN -bearing mice, as well as C4 tumor cells, is enhanced by TNF alpha. Gr owth of normal mammary cells in 3-dimensional collagen cultures is als o significantly stimulated by TNF alpha. Our results suggest that stim ulation of epithelial cell proliferation by HIL-produced TNF alpha is one mechanism responsible for the 'immune stimulation' of neoplastic p rogression in the HAN model.