Inflammation and Hras signaling control epithelial-mesenchymal transition during skin tumor progression

Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94158, USA
Genes & development (Impact Factor: 10.8). 03/2013; 27(6):670-82. DOI: 10.1101/gad.210427.112
Source: PubMed


Epithelial-mesenchymal transition (EMT) is thought to be an important, possibly essential, component of the process of tumor dissemination and metastasis. About 20%-30% of Hras mutant mouse skin carcinomas induced by chemical initiation/promotion protocols have undergone EMT. Reduced exposure to TPA-induced chronic inflammation causes a dramatic reduction in classical papillomas and squamous cell carcinomas (SCCs), but the mice still develop highly invasive carcinomas with EMT properties, reduced levels of Hras and Egfr signaling, and frequent Ink4/Arf deletions. Deletion of Hras from the mouse germline also leads to a strong reduction in squamous tumor development, but tumors now acquire activating Kras mutations and exhibit more aggressive metastatic properties. We propose that invasive carcinomas can arise by different genetic and biological routes dependent on exposure to chronic inflammation and possibly from different target cell populations within the skin. Our data have implications for the use of inhibitors of inflammation or of Ras/Egfr pathway signaling for prevention or treatment of invasive cancers.

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    • "The generally assumed route of skin carcinogenesis is from benign papilloma, to malignant squamous cell carcinoma (SCC), with some tumors undergoing EMT to progress to spindle cell carcinomas [104]. Interestingly, upon reduction of TPA-induced chronic inflammation fewer papillomas and squamous cell carcinomas (SCC) were observed, yet mice still developed aggressive spindle cell carcinomas [105]. This suggests that inflammation levels may result in a potential network rewiring, and these highly invasive tumors may arise from a different target cell population from papillomas and SCC [105]. "
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