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A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas
J C Pena1, C M Rudin, C B Thompson
1Gwen Knapp Center for Lupus and Immunology Research, Committee on Immunology, University of Chicago, Illinois 60637, USA.
Abstract:
The role of apoptosis in the pathogenesis of skin cancer was analyzed in mice bearing a Bcl-xL transgene expressed under the control of the keratin 14 promoter. No spontaneous tumors developed in the skin of these transgenic mice. Bcl-xL transgenics also failed to develop skin lesions following treatment with the chemical mutagen 9,10-dimethyl-1,2-benzanthracene, or the tumor promoter O-tetradecanoylphorbol-13-acetate. However, Bcl-xL transgenics developed a two-fold greater number of benign papillomas than control littermates following treatment with the combination of 9,10-dimethyl-1,2-benzanthracene and O-tetradecanoylphorbol-13-acetate. More significantly, Bcl-xL transgenic mice developed invasive squamous cell carcinoma earlier and more frequently than wild-type controls in response to the chemical agents. These data suggest that Bcl-xL cannot functionally substitute for a mutagenic initiator or mitogenic promoter in tumorigenesis. In contrast, Bcl-xL overexpression can dramatically increase the malignant conversion rate of benign tumors, suggesting that inhibition of apoptosis can contribute to tumor progression.
Insights
Overexpression of Bcl-xL in mice inhibits apoptosis, but does not initiate skin cancer alone. However, it significantly accelerates malignant conversion of benign tumors, highlighting apoptosis inhibition
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Apoptosis, or programmed cell death, plays a critical role in preventing cancer development.
- Bcl-xL is a key regulator of apoptosis, and its overexpression can confer resistance to cell death.
Purpose of the Study:
- To investigate the role of Bcl-xL-mediated apoptosis inhibition in skin cancer pathogenesis.
- To determine if Bcl-xL overexpression can initiate or promote skin tumor development.
Main Methods:
- Generation of transgenic mice with keratin 14 promoter-driven Bcl-xL expression.
- Treatment of mice with chemical carcinogens (9,10-dimethyl-1,2-benzanthracene) and tumor promoters (O-tetradecanoylphorbol-13-acetate).
- Assessment of tumor development, including benign papillomas and invasive squamous cell carcinoma.
Main Results:
- Bcl-xL transgenic mice did not develop spontaneous skin tumors.
- Bcl-xL transgenics showed no increased susceptibility to chemical mutagens or tumor promoters alone.
- Combined carcinogen and promoter treatment led to a two-fold increase in benign papillomas in Bcl-xL transgenics.
- Bcl-xL transgenic mice developed invasive squamous cell carcinoma earlier and more frequently than controls.
Conclusions:
- Bcl-xL overexpression alone does not initiate skin tumorigenesis.
- Inhibition of apoptosis by Bcl-xL significantly enhances the malignant conversion of benign skin tumors.
- Apoptosis inhibition is a critical factor in promoting tumor progression in skin cancer.