Akt activation synergizes with Trp53 loss in oral epithelium to produce a novel mouse model for head and neck squamous cell carcinoma.

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-kappaB and signal transducer and activator of transcription-3 pathways and decreased transforming growth factor-beta 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.

• Authors: Marta Moral, Carmen Segrelles, M Fernanda Lara, Ana Belén Martínez-Cruz, Corina Lorz, Mirentxu Santos, Ramón García-Escudero, Jerry Lu, Kaoru Kiguchi, Agueda Buitrago, Clotilde Costa, Cristina Saiz, Jose L Rodriguez-Peralto, Francisco J Martinez-Tello, Maria Rodriguez-Pinilla, Montserrat Sanchez-Cespedes, Marina Garín, Teresa Grande, Ana Bravo, John DiGiovanni, Jesús M Paramio
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 3 Pg. 1099-108 (Feb 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19176372 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Suppressor Protein p53
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Carcinoma, Squamous Cell (enzymology, genetics)
• Cell Transformation, Neoplastic (genetics, metabolism)
• Disease Models, Animal
• Enzyme Activation
• Head and Neck Neoplasms (enzymology, genetics)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Transgenic
• Mouth Mucosa (enzymology, physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Tumor Suppressor Protein p53 (genetics)