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Published on: June 30, 2023
Inactivation of Autophagy in Keratinocytes Reduces Tumor Growth in Mouse Models of Epithelial Skin Cancer
Caterina Barresi1, Heidemarie Rossiter1, Maria Buchberger1
1Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria.
Abstract:
Autophagy is a ubiquitous degradation mechanism, which plays a critical role in cellular homeostasis. To test whether autophagy suppresses or supports the growth of tumors in the epidermis of the skin, we inactivated the essential autophagy gene Atg7 specifically in the epidermal keratinocytes of mice (Atg7) and subjected such mutant mice and fully autophagy-competent mice to tumorigenesis. The lack of epithelial Atg7 did not prevent tumor formation in response to 7, 12-dimethylbenz(a)anthracene (DMBA) as the initiator and 12-O tetradecanoylphorbol-13-acetate (TPA) as the promoter of tumor growth. However, the number of tumors per mouse was reduced in mice with epithelial Atg7 deficiency. In the K5-SOS EGFR mouse model, epithelial tumors were initiated by Son of sevenless (SOS) in response to wounding. Within 12 weeks after tumor initiation, 60% of the autophagy-competent K5-SOS EGFR mice had tumors of 1 cm diameter and had to be sacrificed, whereas none of the Atg7 mice formed tumors of this size. In summary, the deletion of Atg7 reduced the growth of epithelial tumors in these two mouse models of skin cancer. Thus, our data show that the inhibition of autophagy limits the growth of epithelial skin tumors.
Insights
Inhibiting autophagy, a cellular process, by deleting the Atg7 gene in skin cells reduced tumor growth in mouse models of skin cancer. This suggests autophagy supports, rather than suppresses, epidermal tumor development.
Area of Science:
- Cell Biology
- Cancer Research
- Dermatology
Background:
- Autophagy is a fundamental cellular degradation process crucial for maintaining homeostasis.
- Its role in cancer, specifically whether it suppresses or supports tumor growth, remains a key question in oncology.
Purpose of the Study:
- To investigate the role of autophagy in epidermal skin tumor development.
- To determine if inhibiting autophagy affects tumor initiation and progression in the skin.
Main Methods:
- Inactivated the essential autophagy gene *Atg7* in epidermal keratinocytes of mice.
- Induced skin tumorigenesis using chemical carcinogens (DMBA/TPA) and a genetic model (K5-SOS EGFR).
- Compared tumor formation and growth rates between autophagy-deficient (*Atg7* mutant) and autophagy-competent mice.
Main Results:
- Epithelial *Atg7* deficiency did not prevent tumor formation but significantly reduced the number of tumors per mouse.
- In the K5-SOS EGFR model, *Atg7* deficient mice showed no tumors of 1 cm diameter, unlike control mice.
- The deletion of *Atg7* demonstrably reduced the growth of epithelial skin tumors in both models.
Conclusions:
- Inhibition of autophagy limits the growth of epithelial skin tumors.
- Autophagy appears to support, rather than suppress, the progression of epidermal tumors.
- Targeting autophagy could be a potential therapeutic strategy for skin cancer.
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