Dataset Information

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.

SUBMITTER: Moral M

PROVIDER: S-EPMC2914485 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Moral Marta M 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

Cancer research 20090127 3

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 inducti ...[more]

PMID: 19176372

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Project description:Importance:Case-control studies show a possible relationship between oral bacteria and head and neck squamous cell cancer (HNSCC). Prospective studies are needed to examine the temporal relationship between oral microbiome and subsequent risk of HNSCC. Objective:To prospectively examine associations between the oral microbiome and incident HNSCC. Design, Setting, and Participants:This nested case-control study was carried out in 2 prospective cohort studies: the American Cancer Society Cancer Prevention Study II Nutrition Cohort (CPS-II) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Among 122?004 participants, 129 incident patient cases of HNSCC were identified during an average 3.9 years of follow-up. Two controls per patient case (n?=?254) were selected through incidence density sampling, matched on age, sex, race/ethnicity, and time since mouthwash collection. All participants provided mouthwash samples and were cancer-free at baseline. Exposures:Oral microbiome composition and specific bacterial abundances were determined through bacterial 16S rRNA gene sequencing. Overall oral microbiome composition and specific taxa abundances were compared for the case group and the control group, using PERMANOVA and negative binomial generalized linear models, respectively, controlling for age, sex, race, cohort, smoking, alcohol, and oral human papillomavirus-16 status. Taxa with a 2-sided false discovery rate (FDR)-adjusted P-value (q-value) <.10 were considered significant. Main Outcomes and Measures:Incident HNSCC. Results:The study included 58 patient cases from CPS-II (mean [SD] age, 71.0 [6.4] years; 16 [27.6%] women) and 71 patient cases from PLCO (mean [SD] age, 62.7 [4.8] years; 13 [18.3%] women). Two controls per patient case (n?=?254) were selected through incidence density sampling, matched on age, sex, race/ethnicity, and time since mouthwash collection. Head and neck squamous cell cancer cases and controls were similar with respect to age, sex, and race. Patients in the case group were more often current tobacco smokers, tended to have greater alcohol consumption (among drinkers), and to be positive for oral carriage of papillomavirus-16. Overall microbiome composition was not associated with risk of HNSCC. Greater abundance of genera Corynebacterium (fold change [FC], 0.58; 95% confidence interval [CI], 0.41-0.80; q?=?.06) and Kingella (FC, 0.63; 95% CI, 0.46-0.86; q?=?.08) were associated with decreased risk of HNSCC, potentially owing to carcinogen metabolism capacity. These findings were consistent for both cohorts and by cohort follow-up time. The observed relationships tended to be stronger for larynx cancer and for individuals with a history of tobacco use. Conclusions and Relevance:This study demonstrates that greater oral abundance of commensal Corynebacterium and Kingella is associated with decreased risk of HNSCC, with potential implications for cancer prevention.

Dataset Information

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

Publications

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

Similar Datasets

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