Akt Activation Synergizes with Trp53 Loss in Oral Epithelium to Produce a Novel Mouse Model for Head and Neck Squamous Cell Carcinoma

¹Molecular Oncology Unit, Division of Biomedicine, ²Division of Hematopoiesis and Gene Therapy, and ³Unit of Medical Applications, CIEMAT; ⁴Pathology Department, Hospital Universitario 12 de Octubre; ⁵Centro Nacional de Investigaciones Oncológicas, Madrid, Spain; ⁶Department of Carcinogenesis, Science Park-Research Division, University of Texas M. D. Anderson Cancer Center, Smithville, Texas; and ⁷Department of Veterinary Clinical Sciences, Veterinary Pathology Unit, Veterinary Faculty, University of Santiago de Compostela, Lugo, Spain

^* To whom correspondence should be addressed. E-mail: jesusm.paramio{at}ciemat.es.

	Abstract

Head and neck squamous cell carcinoma (HNSCC) is a common human neoplasia with poor prognosis and survival that frequently displays Akt overactivation. Here we show that mice displaying constitutive Akt activity (myrAkt) in combination with Trp53 loss in stratified epithelia develop oral cavity tumors that phenocopy human HNSCC. The myrAkt mice develop oral lesions, making it a possible model of human oral dysplasia. The malignant conversion of these lesions, which is hampered due to the induction of premature senescence, is achieved by the subsequent ablation of Trp53 gene in the same cells in vivo. Importantly, mouse oral tumors can be followed by in vivo imaging, show metastatic spreading to regional lymph nodes, and display activation of nuclear factor-B and signal transducer and activator of transcription-3 pathways and decreased transforming growth factor- type II receptor expression, thus resembling human counterparts. In addition, malignant conversion is associated with increased number of putative tumor stem cells. These data identify activation of Akt and p53 loss as a major mechanism of oral tumorigenesis in vivo and suggest that blocking these signaling pathways could have therapeutic implications for the management of HNSCC. [Cancer Res 2009;69(3):1099–108]

Key Words: Akt, head and neck squamous cell carcinoma, p53

This article has been cited by other articles:

				M. MORAL, C. SEGRELLES, A. B. MARTINEZ-CRUZ, C. LORZ, M. SANTOS, R. GARCIA-ESCUDERO, J. LU, A. BUITRAGO, C. COSTA, C. SAIZ, et al. Transgenic Mice Expressing Constitutively Active Akt in Oral Epithelium Validate KLFA as a Potential Biomarker of Head and Neck Squamous Cell Carcinoma In Vivo, September 1, 2009; 23(5): 653 - 660. [Abstract] [Full Text] [PDF]