Effects of growth factors on the antiproliferative activity of tumor necrosis factors

• Published in: Cancer research (Chicago, Ill.) Ill.), 1987-02, Vol.47 (3), p.780-786
• Main Authors: SUGARMAN, B. J, LEWIS, G. D, EESSALU, T. E, AGGARWAL, B. B, SHEPARD, H. M
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Breast Neoplasms; Carcinoma, Squamous Cell; Cell Division - drug effects; Cell Line; Cell Survival - drug effects; Female; Glycoproteins - pharmacology; Growth Substances - pharmacology; Humans; Kinetics; L Cells (Cell Line) - cytology; L Cells (Cell Line) - drug effects; Medical sciences; Mice; Other treatments; Structure-Activity Relationship; Treatment. General aspects; Tumor Necrosis Factor-alpha; Tumors; Uterine Cervical Neoplasms
• ISSN: 0008-5472; 1538-7445

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 interfere 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 rHuTNF-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 tumor cell growth; and/or (b) by interfering with normal effector mechanisms of host defense.