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Growth regulation of human renal carcinoma cells: role of transforming growth factor alpha
I Atlas1, J Mendelsohn, J Baselga
1Laboratory of Receptor Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Abstract:
Findings of increased numbers of epidermal growth factor receptors (EGF-R) and increased expression of transforming growth factor alpha (TGF-alpha) in surgical specimens of human renal cell carcinoma have led to the proposal that growth of these tumors may be regulated by TGF-alpha in an autocrine manner. In the studies presented here, we have examined this hypothesis using two human renal carcinoma cell lines, SKRC-4 and SKRC-29. We demonstrated that both SKRC-4 and SKRC-29 cells were growth stimulated by greater than 35% when cultured in the presence of TGF-alpha or EGF and were inhibited by 29% to 46% if cultured in the presence of anti-EGF-R monoclonal antibody 225. Treatment of cells with TGF-alpha enhanced the levels of expression of EGF-R mRNA and TGF-alpha mRNA. In addition, incubation of cells with monoclonal antibody 225 significantly elevated the levels of excreted TGF-alpha species in the culture medium. Our findings suggest that proliferation of human renal carcinoma cells may be regulated by endogenously produced TGF-alpha and that this regulatory pathway can be interrupted using antibody to its receptor, EGF-R.
Insights
Transforming growth factor alpha (TGF-alpha) may drive renal cell carcinoma growth. Blocking the epidermal growth factor receptor (EGF-R) with an antibody inhibited tumor cell proliferation, suggesting a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Human renal cell carcinoma (RCC) exhibits increased epidermal growth factor receptor (EGF-R) and transforming growth factor alpha (TGF-alpha).
- A hypothesis suggests TGF-alpha autocrine signaling regulates RCC tumor growth.
Purpose of the Study:
- To investigate the role of TGF-alpha in the autocrine regulation of human renal cell carcinoma (RCC) cell lines.
- To determine if blocking the epidermal growth factor receptor (EGF-R) pathway impacts RCC proliferation.
Main Methods:
- Utilized two human RCC cell lines (SKRC-4 and SKRC-29).
- Assessed cell growth stimulation with TGF-alpha and epidermal growth factor (EGF).
- Evaluated growth inhibition using anti-EGF-R monoclonal antibody 225.
- Measured EGF-R mRNA and TGF-alpha mRNA expression levels.
- Quantified excreted TGF-alpha in culture medium after antibody treatment.
Main Results:
- TGF-alpha and EGF significantly stimulated SKRC-4 and SKRC-29 cell growth by over 35%.
- Anti-EGF-R monoclonal antibody 225 inhibited cell proliferation by 29% to 46%.
- TGF-alpha treatment increased EGF-R mRNA and TGF-alpha mRNA expression.
- Monoclonal antibody 225 treatment elevated TGF-alpha levels in the culture medium.
Conclusions:
- Endogenously produced TGF-alpha appears to regulate human renal cell carcinoma cell proliferation.
- The EGF-R pathway is a viable target for interrupting TGF-alpha-mediated RCC growth.
- Monoclonal antibody targeting EGF-R offers a potential therapeutic strategy for RCC.