Tumor necrosis factor alpha-induced stimulation of neoplastic progression of preneoplastic, hyperplastic alveolar nodule line C4

Abstract

Lymphocytic infiltrates of the mouse mammary preneoplastic, hyperplastic alveolar nodule (HAN) line C4 have elevated reactivity which correlates positively with the progression of HAN to mammary adenocarcinoma. In this study we investigated the hypothesis that the immunoregulatory mechanisms of HAN infiltrating lymphocytes (HILs) on mammary neoplastic progression are mediated, at least in part, by tumor necrosis factor alpha (TNF alpha). C4 HAN epithelial cells express mRNA for both the p55-60 receptor and the p75-80 TNF alpha receptors. High levels of both TNF alpha and TNF beta are expressed by HILs, whereas only TNF alpha is expressed by the C4 HAN epithelial cells. Treatment of C4 HAN bearers 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. Growth of normal mammary cells in 3-dimensional collagen cultures is also significantly stimulated by TNF alpha. Our results suggest that stimulation of epithelial cell proliferation by HIL-produced TNF alpha is one mechanism responsible for the 'immune stimulation' of neoplastic progression in the HAN model.