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Altered expression of the epidermal growth factor receptor and transforming growth factor-alpha during multistage
O Rho1, L M Beltrán, I B Gimenez-Conti
1Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville 78957.
Abstract:
In the study presented here, we examined the possible role of the transforming growth factor-alpha (TGF alpha)/epidermal growth factor receptor (EGFR) system during multistage carcinogenesis in mouse skin. In this regard, the expression (mRNA and protein) of both TGF alpha and EGFR was examined in primary papillomas and squamous cell carcinomas (SCCs) obtained from SENCAR mice treated with standard initiation-promotion regimens and compared with the levels of expression in normal epidermis. The level of a 4.8-kb TGF alpha transcript was elevated in 100% of the skin tumors examined (both papillomas and SCCs), including papillomas obtained 13 wk after the start of promotion, compared with normal epidermis. Immunohistochemical analyses detected elevated levels of TGF alpha protein in these skin tumors and in papillomas as early as 10 wk after the start of promotion. The levels of EGFR transcripts were also significantly elevated in most (90%) of the skin tumors examined, including again those harvested after 13 wk of promotion. Interestingly, multiple EGFR transcripts (10.5, 5.8, 2.8, and 1.8 kb) were detected in both papillomas and SCCs. The two smaller transcripts appeared to encode truncated versions of the EGFR, and the 1.8-kb transcript appeared to be unique to RNA samples isolated from skin tumors, based on comparative analyses of several normal tissues. As with TGF alpha, immunohistochemical analyses detected elevated levels of EGFR protein in these skin tumors (both papillomas and SCCs), including papillomas harvested as early as 10 wk after the start of promotion. Southern analyses of genomic DNAs for TGF alpha and EGFR failed to detect any cases of gene rearrangements or amplification as a possible explanation for the elevated levels of the transcripts of these two genes. These results support the hypothesis that a key step in the development of autonomous growth in mouse skin papillomas generated in SENCAR mice by an initiation-promotion regimen may involve alterations in the synthesis of TGF alpha and its cognate receptor.
Insights
Transforming growth factor-alpha (TGF alpha) and epidermal growth factor receptor (EGFR) are elevated in mouse skin tumors, suggesting their role in carcinogenesis. These findings highlight the TGF alpha/EGFR system
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- The transforming growth factor-alpha (TGF alpha)/epidermal growth factor receptor (EGFR) system plays a role in cell growth and differentiation.
- Dysregulation of this system is implicated in various cancers.
Purpose of the Study:
- To investigate the role of the TGF alpha/EGFR system in multistage mouse skin carcinogenesis.
- To examine the expression of TGF alpha and EGFR in skin tumors and normal epidermis.
Main Methods:
- SENCAR mice were subjected to a standard initiation-promotion regimen to induce skin tumors.
- Expression levels of TGF alpha and EGFR (mRNA and protein) were analyzed in papillomas and squamous cell carcinomas (SCCs) using techniques including Northern and immunohistochemical analyses.
- Genomic DNA was analyzed by Southern blot to detect gene rearrangements or amplification.
Main Results:
- Elevated TGF alpha transcript (4.8 kb) and protein levels were observed in 100% of skin tumors, appearing as early as 10 weeks of promotion.
- Elevated EGFR transcripts (including novel truncated forms) and protein levels were detected in 90% of skin tumors.
- No gene rearrangements or amplification of TGF alpha or EGFR were found in the tumors.
Conclusions:
- The study supports the hypothesis that alterations in TGF alpha and EGFR synthesis are crucial for the development of autonomous growth in mouse skin papillomas.
- The TGF alpha/EGFR signaling pathway is a key factor in mouse skin carcinogenesis.