EFFECTS OF GROWTH-FACTORS ON THE ANTIPROLIFERATIVE ACTIVITY OF TUMOR NECROSIS FACTORS

Abstract

Tumor necrosis factors (TNFs) are a class of cytokines secreted by activated effector cells involved in host defense against tumor progression. Epidermal growth factor (EGF) and recombinant human transforming growth factor-.alpha. (rHuTGF-.alpha.) were shown to interfere with the in vitro antiproliferative effects of recombinant human tumor necrosis factor-.alpha. (rHuTNF-.alpha.) and -.beta. on a human cervical carcinoma cell line, ME-180. The inhibitory effect could be observed at EGF or rHuTGF-.alpha. concentrations of 100 pg/ml, and was maximal between 1 and 10 ng/ml. This response was not due to down regulation of the TNF receptor or to alteration of the affinity of TNF-.alpha. for its receptor. Since the antiproliferative effect of recombinant human interferon-.gamma. was not significantly affected by the presence of EGF or rHuTGF-.alpha., the inhibition was specific for recombinant TNFs and was not due solely to enhanced proliferation induced by the growth factors. Neither growth factor had a substantial protective effect on the synergistic cytotoxicity observed when tumor cells were exposed simultaneously to rHuTNF-.alpha. and recombinant human interferon-.gamma.. TGF-.beta. can also interfer with the antiproliferative effects of rHuTNF-.alpha. in vitro. At concentrations of less than 1 ng/ml, TGF-.beta. significantly antagonized the cytotoxic effects of rHuTNF-.alpha. on NIH 3T3 fibroblasts. Since EGF, platelet-derived growth factor, and TGF-.beta. all enhanced NIH 3T3 cell proliferation, but only TGF-.beta. interfered with rHuTNF-.alpha. cytotoxicity, the protective effects of TGF-.beta. were not related in a simple manner to enhanced cell proliferation. rHuTGF-.alpha. and TGF-.beta. did not have a significant protective effect against rHuTGF-.alpha.-mediated cytotoxicity on two other tumor cell lines, BT-20 and L-929 cells. Based upon these observations we suggest that growth factors might enhance tumor growth in vivo by a combination of distinct mechanisms: (a) by autocrine stimulation of tumor cell growth; and/or (b) by interfering with normal effector mechanisms of host defense.