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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 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.
Insights
Growth factors like epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) can interfere with the anti-tumor effects of tumor necrosis factors (TNFs). This interference suggests growth factors may promote tumor growth by aiding cell proliferation and hindering immune defense mechanisms.
Area of Science:
- Immunology
- Cell Biology
- Oncology
Background:
- Tumor necrosis factors (TNFs) are cytokines crucial for host defense against tumor progression.
- Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are known to influence cell proliferation.
- The interaction between growth factors and TNF-mediated anti-tumor effects requires further investigation.
Purpose of the Study:
- To investigate the in vitro effects of EGF and TGF-alpha on the antiproliferative and cytotoxic actions of tumor necrosis factors (TNFs).
- To determine if growth factors interfere with TNF-alpha and TNF-beta mediated inhibition of tumor cell growth.
- To explore the mechanisms by which growth factors might influence TNF-alpha's efficacy against tumor cells.
Main Methods:
- Utilized human cervical carcinoma cell line (ME-180) and NIH 3T3 fibroblasts for in vitro experiments.
- Assessed the antiproliferative effects of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) and -beta in the presence of EGF and rHuTGF-alpha.
- Evaluated the impact of growth factors on TNF-alpha's cytotoxic effects and receptor binding affinity.
Main Results:
- EGF and rHuTGF-alpha inhibited the antiproliferative effects of rHuTNF-alpha and -beta on ME-180 cells, with effects observed at 100 pg/ml and maximal between 1-10 ng/ml.
- The observed inhibition was specific to TNFs and not due to changes in TNF receptor downregulation or affinity.
- TGF-beta also antagonized rHuTNF-alpha's cytotoxic effects on NIH 3T3 fibroblasts, independent of enhanced cell proliferation.
Conclusions:
- Growth factors like EGF and TGF-alpha can interfere with the anti-tumor activity of TNFs in vitro.
- These findings suggest that growth factors may contribute to tumor progression in vivo.
- Potential mechanisms include autocrine stimulation of tumor cell growth and interference with host defense mechanisms.