Akt activation synergizes with Trp53 loss in oral epithelium to produce a novel mouse model for head and neck squamous cell carcinoma.
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.
Moral
Marta
M
Division of Biomedicine, Molecular Oncology Unit, CIEMAT, Madrid, Spain.
Segrelles
Carmen
C
Lara
M Fernanda
MF
Martínez-Cruz
Ana Belén
AB
Lorz
Corina
C
Santos
Mirentxu
M
García-Escudero
Ramón
R
Lu
Jerry
J
Kiguchi
Kaoru
K
Buitrago
Agueda
A
Costa
Clotilde
C
Saiz
Cristina
C
Rodriguez-Peralto
Jose L
JL
Martinez-Tello
Francisco J
FJ
Rodriguez-Pinilla
Maria
M
Sanchez-Cespedes
Montserrat
M
Garín
Marina
M
Grande
Teresa
T
Bravo
Ana
A
DiGiovanni
John
J
Paramio
Jesús M
JM
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009061:Mouth Mucosa / Q000201:enzymology / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt