Oral Cavity and Esophageal Carcinogenesis Modeled in Carcinogen-Treated Mice

Tang, Xiao‐Han; Knudsen, Beatrice S.; Bemis, Debra L.; Tickoo, Satish K.; Gudas, Lorraine J.

doi:10.1158/1078-0432.ccr-0999-3

Cited by 329 publications

(413 citation statements)

References 65 publications

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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%

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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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Section: Discussionmentioning

confidence: 99%

“…Therefore, this model is suitable for the analysis of the OCC development in various mutant and transgenic strains. 47 However, changes in the host immune system and oral microbiota induced by 4-NQO in mice have not been extensively characterized until now.…”

Section: Discussionmentioning

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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“…MDSCs constitute an immature population of myeloid cells thought to be an important subset of cells that contribute to an immunosuppressive tumor microenvironment (43,44) and are significantly increased in number in cancer patients. Therefore, to further investigate the link between calcitriol supplementation, MDSC recruitment, and esophageal tumor promotion in immunocompetent host, we induced esophageal tumors (24) and examined the effect of calcitriol on tumor progression in 4-NQO-treated mice. The model mimics many features observed in human esophageal SCC development; therefore, this model should be advantageous for studies of esophageal tumor development.…”

Section: Discussionmentioning

confidence: 99%

“…Six-week-old male C57BL/6J mice and IL6 knockout mice on a C57BL/6J background (B6.129S2-Il6tm1Kopf/J; IL6KO) were used for the 4-NQO-induced esophageal tumor model (21,24). Briefly, the mice were allowed access to drinking water containing 100 mg/mL 4-NQO (tumor-induced group) or solvent only (control group) at all times during the treatment period.…”

Section: Induction Of Esophageal Tumors In Micementioning

confidence: 99%

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling

Chen

Hsieh

et al. 2015

Molecular Cancer Therapeutics

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The aim of this study was to highlight the role of 1a,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQOinduced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO-induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D 3 may be a promising strategy for the prevention and treatment of esophageal SCC.

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“…To induce premalignant oral lesions that progress to oral cancer, female C57BL/6 mice (Charles Rivers Laboratory, Wilmington, MA) were treated with 50 μg/mL 4‐nitroquinoline 1‐oxide (4NQO) in their drinking water starting at 2 month of age 38, 39. After approximately 8 weeks of 4NQO treatment, mice developed endoscopically visible premalignant lesions on the tongue.…”

Section: Methodsmentioning

confidence: 99%

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

Levingston

Young

2017

Intl Journal of Cancer

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A carcinogen‐induced premalignant oral lesion model that progresses to oral cancer was used to examine the impact of blocking PD‐1 on cytokine expression and on progression of lesions to cancer. The results of this study show increased production of IL‐2 and the inflammatory cytokines IL‐6, IL‐17 and TNF‐α by spleen cells of lesion‐bearing mice that were treated with PD‐1 antibody for 1 week compared to cytokine production by spleen cells of lesion‐bearing mice treated with control antibody. Production of IFN‐γ increased at 3 weeks of PD‐1 antibody treatment, although production of the other Th1 and inflammatory mediators declined. By 5 weeks, levels of these cytokines declined for both control and PD‐1 antibody‐treated mice. Flow cytometric analysis for IFN‐γ‐expressing cells showed shifts in CD4+ cells expressing IFN‐γ consistent with the changes in cytokine secretion. Whether or not treatment generated reactivity to lesions or HNSCC was determined. Spleen cells from PD‐1 antibody‐treated mice were stimulated by lysates of premalignant lesion and HNSCC tongue tissues to produce increased levels of Th1 and select inflammatory cytokines early in the course of PD‐1 antibody treatment. However, with continued treatment, reactivity to lesion and HNSCC lysates declined. Analysis of clinical response to treatment suggested an early delay in lesion progression but, with continued treatment, lesions in PD‐1 antibody‐treated mice progressed to the same degree as in control antibody‐treated mice. Overall, these results show an early beneficial response to PD‐1 antibody treatment, which then fails with continued treatment and lesion progression.

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Oral Cavity and Esophageal Carcinogenesis Modeled in Carcinogen-Treated Mice

Cited by 329 publications

References 65 publications

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

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

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

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