Journal
ONCOGENE
Volume 31, Issue 28, Pages 3322-3332Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.494
Keywords
TGF-beta; PI3K/Akt; head and neck squamous cell carcinoma; conditional knockout; cancer mouse model
Funding
- Divisions of Intramural Research, National Institute of Dental and Craniofacial Research [Z01-DE-000698]
- National Institute on Deafness and Communication Disorders, NIH [ZIA-DC-000073]
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The molecular mechanisms that contribute to the initiation and progression of head and neck squamous cell carcinoma (HNSCC) have not been completely delineated. Our observations indicate that defects in the transforming growth factor-beta and PI3K/Akt signaling pathways are common in human HNSCCs. Conditional activation of the PI3K/Akt pathway due to Pten deletion in the mouse head and neck epithelia gives rise to hyperproliferation, but only a few lesions progress to HNSCC. However, Pten-deficient mice developed full-penetrance HNSCC in combination with type I TGF-beta receptor (Tgfbr1) deletion. Molecular analysis revealed enhanced cell proliferation, decreased apoptosis, and increased expression of CCND1 in the basal layer of the head and neck epithelia, as well as in the tumors of Tgfbr1/Pten double conditional knockout (2cKO) mice. Furthermore, neoplastic transformation involves senescence evasion, and is associated with an increased number of putative cancer stem cells. In addition, the nuclear factor-kappa B pathway activation, myeloid-derived suppressor cell infiltration, angiogenesis and immune suppression in the tumor microenvironment, all of which are characteristics of human HNSCCs, contribute significantly to head and neck carcinogenesis in 2cKO mice. These tumors display pathology and multiple molecular alterations resembling human HNSCCs. This suggests that the Tgfbr1/Pten 2cKO mouse model is suitable for preclinical intervention, and that it has significant implications in the development of diagnostic cancer biomarkers and effective strategies for prevention and treatment of HNSCCs. Oncogene (2012) 31, 3322-3332; doi: 10.1038/onc.2011.494; published online 31 October 2011
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