Abstract
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-β 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-β 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-κB 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.
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Acknowledgements
We would like to thank Dr Stefan Karlsson for providing us with the Tgfbr1 flox mice, Drs Raj Puri and Lalage Wakefield for critical reading of the manuscript, Drs Juan Du, Ping Zhang, Zhong Chen and Anita Terse for technical help, and Shelagh Johnson for the expert editorial assistance. This work was supported by the Divisions of Intramural Research, National Institute of Dental and Craniofacial Research (Z01-DE-000698), and National Institute on Deafness and Communication Disorders (ZIA-DC-000073), NIH.
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Bian, Y., Hall, B., Sun, ZJ. et al. Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. Oncogene 31, 3322–3332 (2012). https://doi.org/10.1038/onc.2011.494
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DOI: https://doi.org/10.1038/onc.2011.494
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