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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)
Published on: December 19, 2019
Is the loss of pRb essential for the mouse skin carcinogenesis?
Sergio Ruiz1, Mirentxu Santos, Jesús M Paramio
1Molecular Oncology Unit, Biomedicine Division, CIEMAT, Madrid, Spain.
Abstract:
The pRb pathway is inactivated in most, if not all, human and mouse tumors, including skin tumors. However, a relatively low frequency of Rb gene alterations is found. The embryonic lethality of pRb-deficient animals restricts the analysis of these mice to midgestation and precludes the analysis of the roles of pRb in mouse cancer models. To solve this problem, we used the Cre/LoxP technology to induce the tissue-specific deletion of pRb. In epidermis, pRb deletion leads to altered proliferation and differentiation but these alterations do not induce the development of spontaneous skin tumors. To gain insight in the possible roles of pRb in mouse skin carcinogenesis, we have performed chemical tumorigenesis experiments in mice bearing epidermal-specific inactivation of Rb gene. Unexpectedly, these mice develop fewer and smaller tumors than control animals, but showing increased malignant conversion to squamous cell carcinomas. Detailed biochemical analysis demonstrates that, in the absence of pRb, multiple pathways are activated leading to increased tumor apoptosis. In particular, we characterized the aberrant p53 activation mediated by E2F/p19(ARF) and other transduction pathways. This may generate a selective pressure in the tumor leading to premature p53 loss of function, which ultimately results in increased malignancy. Overall, these data highlights the role of pRb during the malignant conversion in the mouse skin carcinogenesis, and the intimate relationships between pRb and multiple tumor suppressor networks in this system.
Insights
The retinoblastoma protein (pRb) pathway is crucial in preventing skin cancer. Its absence unexpectedly reduces tumor size but increases malignant conversion, highlighting pRb
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The retinoblastoma protein (pRb) pathway is frequently inactivated in various cancers, including skin tumors.
- Embryonic lethality of pRb-deficient mice limits studying its role in cancer development.
- Understanding pRb's function in skin carcinogenesis is crucial due to its tumor suppressor role.
Purpose of the Study:
- To investigate the role of pRb in mouse skin carcinogenesis using tissue-specific gene deletion.
- To elucidate the molecular mechanisms underlying skin tumor development in the absence of pRb.
- To explore the relationship between pRb and other tumor suppressor networks in skin cancer.
Main Methods:
- Utilized Cre/LoxP technology for inducible, epidermis-specific deletion of the Rb gene in mice.
- Performed chemical carcinogenesis experiments on mice with epidermal pRb inactivation.
- Conducted detailed biochemical analyses to study pathway activation and tumor apoptosis.
Main Results:
- Epidermal pRb deletion did not induce spontaneous skin tumors but altered proliferation and differentiation.
- Chemical carcinogenesis in pRb-deficient mice resulted in fewer, smaller tumors with increased malignant conversion to squamous cell carcinomas.
- Absence of pRb led to aberrant p53 activation via E2F/p19(ARF) and other pathways, promoting tumor apoptosis and selective pressure for p53 loss.
Conclusions:
- pRb plays a critical role in regulating malignant conversion during mouse skin carcinogenesis.
- The loss of pRb function creates a complex cellular environment favoring tumor progression and malignancy.
- pRb interacts intimately with multiple tumor suppressor networks, influencing skin cancer development and progression.
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