4NQO carcinogenesis: A mouse model of oral cavity squamous cell carcinoma

Hawkins, Brian L.; Heniford, B. W.; Ackermann, D. Michael; Leonberger, M.; Martinez, Serge A.; Hendler, F. J.

doi:10.1002/hed.2880160506

Cited by 123 publications

(110 citation statements)

References 14 publications

(1 reference statement)

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“…Treatment of mouse oral epithelia with 4-nitroquinoline-1-oxide (4NQO) is a well-established model for human head and neck SCCs (20,21). The developing tumors are moderate to welldifferentiated SCCs that morphologically resemble human tumors (19). We found that p53 transgenic mice are highly susceptible to 4NQO-induced oral cancer and that the resulting tumors are more likely to progress.…”

Section: Introductionmentioning

confidence: 74%

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p53 Transgenic Mice Are Highly Susceptible to 4-Nitroquinoline-1-Oxide-Induced Oral Cancer

Zhang

Wang

Yao

et al. 2006

Molecular Cancer Research

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In this study, we did a bioassay employing mice with a dominant-negative p53 mutation (p53 Val135/WT ) to assess whether a germ-line p53 mutation predisposed mice toward the development of squamous cell carcinomas (SCC) in the oral cavity. Treatment of the mouse oral cavity with 4-nitroquinoline-1-oxide produced a 66%, 91%, and 20% tumor incidence in the oral cavity, esophagus, and forestomach/stomach, respectively, in p53 Val135/WT mice. In contrast, only a 25%, 58%, and 4% tumor incidence was observed in oral cavity, esophagus, and forestomach/stomach, respectively, in wild-type littermates (p53 WT/WT ). The most striking difference between p53 Val135/WT and p53 WT/WT mice following the carcinogen treatment was the higher prevalence and more rapid development of SSC in p53 Val135/WT mice than in wild-type mice. To identify the precise genes or pathways involved in these differences during tumor development, we examined gene expression profiles of 4-nitroquinoline-1-oxide-treated normal tongues as well as tongue SCC in p53 Val135/WT and p53 WT/WT mice. Microarray and GenMAPP analysis revealed that dominant-negative p53 ( 135 Valp53) affects several cellular processes involved in SCC development. Affected processes included apoptosis and cell cycle arrest pathways, which were modulated in both tumor and normal epithelium. These results showed that reduction of p53-dependent apoptosis and increases in cell proliferation might contribute to the observed increase in oral cavity and gastroesophageal malignancies in p53 Val135/WT mice as well as to the more rapid growth and progression of tumors.

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Section: Introductionmentioning

confidence: 74%

“…Mutation in the p53 gene is also commonly seen in SCCs of oral mucosa (13)(14)(15)(16). Abnormal staining of p53 protein is a frequent finding (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

p53 Transgenic Mice Are Highly Susceptible to 4-Nitroquinoline-1-Oxide-Induced Oral Cancer

Zhang

Wang

Yao

et al. 2006

Molecular Cancer Research

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“…47 Among them, the 4-NQO-induced oral cancer mouse model is one of the most widely used, 24,25,47,48 as it recapitulates many features observed in human OSCC development including molecular expression of keratin, p16, and epidermal growth factor receptor (EGFR) which are associated with human oral carcinogenesis. Therefore, this model is suitable for the analysis of the OCC development in various mutant and transgenic strains.…”

Section: Discussionmentioning

confidence: 99%

“…24,25 This model was selected because of the in situ development and similarities to carcinogenesis induction in humans. In this model, CD24 C/¡ and CD24 ¡/¡ mice were treated with 4-NQO (50 mg/mL) in the drinking water for 16 weeks and then changed to regular water for the remainder of the experiment.…”

Section: Low Cd24 Expression In Oral Cancer Is Associated With Poor Pmentioning

confidence: 99%

CD24 blunts oral squamous cancer development and dampens the functional expansion of myeloid-derived suppressor cells

et al. 2016

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CD24 expression has been implicated in the oncogenesis of multiple types of cancer and high tumor expression is considered a poor prognosis factor; however, the role of CD24 in oral cancer progression is unknown. Unlike other cancer types, we found that higher CD24 levels in human oral cancers are correlated to lower clinical stage and better overall survival. We then dissected the role of CD24 and mechanisms in oral cancer pathogenesis in mice using a genetic strategy and demonstrated that CD24 deficiency increased the oral cavity tumor burden in response to the carcinogen 4-nitroquioline 1-oxide (4-NQO). Immune profile analysis showed a significant expansion as well as increased suppressive function of myeloid-derived suppressor cells (MDSCs) in CD24 ¡/¡ mice, but no apparent impairment in T cells, B cells, or dendritic cells. Further, studies with an orthotopically transplanted syngeneic squamous carcinoma model in the tongue of CD24 ¡/¡ and CD24 C/¡ mice confirmed the protective roles of CD24 against cancer. Moreover, the difference in tumor growth between CD24 ¡/¡ and CD24 C/¡ mice was blunted by immunodepletion of MDSCs. We conclude that CD24 expression impedes MDSC expansion and function, and thus slows oral cancer oncogenesis. This study is the first to examine the role of CD24 in a de novo oral cancer model, and it highlights the need to consider the immune regulatory roles of CD24 in the development of CD24-targeted therapy for cancer.

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“…Twenty-four 4-to-6-week-old CBA/CaJ mice received a low-dose (5 mg/mL) tobacco-derivative 4-nitroquinoline 1-oxide (4NQO) painted in their oral cavity (100 mL) 3 times per week for 20 weeks that mimics tobacco-induced carcinogenesis in humans (25), and followed up to 50 weeks. During the same period of carcinogen exposure, mice were also painted 5 times per week with 0, 5, 10, or 15 mg curcumin (in 100 mL of corn oil) to determine if curcumin prevents carcinogenesis.…”

Section: Oral Carcinogen-induced Modelmentioning

confidence: 99%

Curcumin Inhibits Carcinogen and Nicotine-Induced Mammalian Target of Rapamycin Pathway Activation in Head and Neck Squamous Cell Carcinoma

Clark

McEachern

Shah

et al. 2010

Cancer Prevention Research

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Curcumin appears to be a safe, bioactive food compound that is a potential chemopreventive for patients at a high risk for head and neck squamous cell carcinoma (HNSCC). Identification and validation of intermediate endpoints is an important step in evaluating chemopreventive agents. AKT/ MTOR pathway biomarkers are intrinsic to the carcinogenic process as well as the mechanism of intervention with curcumin. Antiproliferative effects of curcumin were assayed in 9 HNSCC and a keratinocyte cell line. Nicotine, a genotoxic alkaloid involved in tobacco addiction, forms DNA adducts and has been implicated in upper aerodigestive tract cancer promotion. The antiproliferative effects of curcumin were associated with inhibition of the AKT/MTOR pathway in presence and absence of nicotine, which also induced this pathway. Curcumin was highly effective at suppressing growth of SCC40 xenografts and its activity is associated with modulation of MTOR's downstream target pS6. Curcumin at 15 mg significantly increased survival (286 AE 37 vs. 350 days) in the 4NQO carcinogenic model survival study. A major cause of lethal progression of HNSCC is local regional migration and invasion of malignant cells, and curcumin significantly inhibited cancer cell migration and invasion in vitro and in vivo where downregulation of pS6 was associated with a significant decrease in MMP-9. This is the first study to demonstrate that curcumin inhibits the adverse effects of nicotine by blocking nicotine-induced activation of the AKT/MTOR pathway in HNSCC, which retards cell migration. These studies indicate that inhibiting the AKT/MTOR pathway with curcumin may be useful as an oral chemopreventive agent. Cancer Prev Res; 3(12); 1586-95. Ó2010 AACR.

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4NQO carcinogenesis: A mouse model of oral cavity squamous cell carcinoma

Cited by 123 publications

References 14 publications

p53 Transgenic Mice Are Highly Susceptible to 4-Nitroquinoline-1-Oxide-Induced Oral Cancer

p53 Transgenic Mice Are Highly Susceptible to 4-Nitroquinoline-1-Oxide-Induced Oral Cancer

CD24 blunts oral squamous cancer development and dampens the functional expansion of myeloid-derived suppressor cells

Curcumin Inhibits Carcinogen and Nicotine-Induced Mammalian Target of Rapamycin Pathway Activation in Head and Neck Squamous Cell Carcinoma

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