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Purpose: Increasing evidence indicates that the microbiome may influence tumor growth and modulate the tumor microenvironment of gastrointestinal cancers. However, the role of oral bacteria in the development of esophageal squamous cell carcinoma (EsoSCC) has remained unclear. Herein, we investigated the relationship between the periodontal pathogen Porphyromonas gingivalis and EsoSCC. Methods: To identify bacterial biomarkers associated with EsoSCC, we analyzed microbiomes in oral biofilms. The presence of P. gingivalis in esophageal tissues and relationships of P. gingivalis infection with clinicopathologic characteristics in 156 patients with EsoSCC were assessed using immunohistochemistry. The role of P. gingivalis infection in in vitro and in vivo EsoSCC progression was also assessed. Results: Microbiota profiles in oral biofilms revealed that P. gingivalis abundance was associated with an increased risk of EsoSCC development. In total, 57% of patients with EsoSCC were found to be infected with P. gingivalis. The presence of P. gingivalis was found to be associated with advanced clinical stages and a poor prognosis. It was also found to be associated with an elevated esophageal cancer incidence in a 4-nitroquinoline 1-oxide-induced mouse model and with an increased xenograft tumor growth. P. gingivalis infection increased interleukin (IL)‐6 production and it promoted epithelial-mesenchymal transition and the recruitment of myeloid-derived suppressor cells. Furthermore, inhibited IL‐6 signaling attenuated the tumor-promoting effects of P. gingivalis in 4-nitroquinoline 1-oxide-treated mice and xenograft mouse models. Conclusions: Our data indicate that P. gingivalis may promote esophageal cancer development and progression. Direct targeting of P. gingivalis or concomitant IL-6 signaling may be a promising strategy to prevent and/or treat EsoSCC associated with P. gingivalis infection. [ABSTRACT FROM AUTHOR]

ABSTRACT Background The purpose of this study was to present our assessment of the significance of myeloid-derived suppressor cells (MDSCs) in head and neck squamous cell carcinoma (HNSCC). Methods We examined the percentage of MDSCs in the peripheral blood of patients with HNSCC. The relationship among MDSC recruitment, tumor progression, and cyclooxygenase (COX)-2 inhibition was also evaluated by animal models. Results Circulating MDSCs were significantly increased in patients with HNSCC compared with healthy people, and this was associated with the clinical tumor burden. In immunocompetent 4-nitroquinoline-1-oxide (4-NQO)-induced oral tumor and immunocompromised tumor implantation animal models, MDSC recruitment was associated with the duration of 4-NQO treatment and tumor progression. The responsible mechanisms included the suppressive ability of T-cell proliferation and augmenting angiogenesis by MDSC. Blockade of COX-2 attenuated the induction and function of MDSCs and subsequently inhibited tumor growth. Conclusion The levels of MDSC are linked with tumor progression in HNSCC. Moreover, targeting COX-2 could be a promising strategy for the treatment of HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 39: 347-355, 2017 [ABSTRACT FROM AUTHOR]

BACKGROUND: The identification of potential tumor markers can improve therapeutic planning and patient management. The objective of this study was to highlight the role of DNA methyltransferase 3b (DNMT3b) in esophageal squamous cell carcinoma (SCC). METHODS: One hundred seventy-three esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of DNMT3b with clinical outcome. Furthermore, a human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after the manipulation of DNMT3b expression. RESULTS: The incidence of nuclear DNMT3b immunoreactivity in esophageal cancer specimens was significantly higher than in nonmalignant epithelium, and this incidence was linked positively to developing distant metastasis (56% in localized disease vs 80% in distant metastasis; P = .002). Furthermore, increased expression of DNMT3b was linked significantly to lower treatment response rates ( P = .002) and reduced survival rates ( P = .000). Inhibition of DNMT3b expression resulted in slower cellular proliferation, increased cell death, a less invasive capacity, and less epithelial-mesenchymal-transition changes. Moreover, DNMT3b silencing vectors sensitized esophageal cancer cells to irradiation and cisplatin treatment. The current results also indicated that constitutional activation of signal transducer and activator of transcription 3 (STAT3) signaling associated with inhibited expression of suppressor of cytokine signaling 3 (SOCS3) may be the mechanism underlying more aggressive tumor growth in DNMT3b-positive esophageal cancer. CONCLUSIONS: DNMT3b was linked significantly to a poor prognosis for patients with esophageal cancer. Moreover, the current results indicated that targeting this enzyme may be a promising strategy for treating esophageal cancer, as evidenced by inhibited aggressive tumor behavior and treatment resistance. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-1 beta has been reported to be a marker of shorter survival in gastric and colorectal adenocarcinoma. In the present study, we examined the potential role and prognostic value of IL-1 beta in esophageal squamous cell carcinoma (SCC). Human esophageal SCC cell line, CE81T, was selected for cellular and animal experiments, in which biological changes after experimental manipulation of IL-1 beta signaling were explored, including tumor growth, invasion capacity, and the sensitivity to treatment. Moreover, 147 esophageal SCC samples were analyzed using immunohistochemical staining to correlate the expression of IL-1 beta with clinical outcome. Our data revealed that IL-1 beta was significantly overexpressed both at mRNA and protein levels in cancer specimens compared to nonmalignant tissues. When IL-1 beta signaling was blocked, tumor growth, invasion ability, and treatment resistance were attenuated. Activation of NF-kappa B, increase of E2-EPF ubiquitin carrier protein and subsequent epithelial-mesenchymal transition might be the underlying mechanisms of the more aggressive tumor growth in IL-1 beta-positive esophageal cancer. The immunochemistry findings indicate that positivity staining of IL-1 beta correlated significantly with higher clinical stage, lower response rate to concurrent chemoradiotherapy (CCRT), and higher recurrence rate after curative treatment. Moreover, IL-1 beta was a significant predictor of survival in patients undergoing surgical intervention or definite CCRT. In conclusion, IL-1 beta is significantly linked to poor prognosis for patients with esophageal cancer and may be a promising molecular target for therapeutic intervention for esophageal SCC. [ABSTRACT FROM AUTHOR]

The ubiquitin proteasome pathway has been implicated in carcinogenesis. However, the role of E2-EPF ubiquitin carrier protein (UCP) in esophageal cancer remains relatively unstudied. In the study, we examined the mRNA level of circulating tumor cells from 60 esophageal cancer patients by membrane arrays consisting of a panel of potential markers including UCP, compared to 40 normal populations. The predictive capacity of UCP was also assessed by immunohistochemical staining of a retrospective series of 84 biopsied esophageal squamous cell carcinomas in relation to clinical outcome. In addition, we studied in vitro biological changes including tumor growth, metastatic capacity, and the sensitivity to irradiation and cisplatin, after experimental manipulation of UCP expression in esophageal cancer cells. By the data of 25-gene membrane array analysis, UCP was the only factor significantly associated with the extent of tumor burden in esophageal cancer patients. Our immunochemistry findings further indicate that UCP positivity was linked to poor response to neoadjuvant therapy and worse survival. In cell culture, inhibited UCP significantly decrease tumor growth and the capacity for metastasis. The epithelial–mesenchymal transition (EMT) induced by VHL/HIF-1α-TGF-β1 pathway might be the underlying mechanism responsible to the more aggressive tumor growth in UCP-positive esophageal cancer. Our results suggest that UCP was significantly associated with poor prognosis of esophageal cancer and may be a new molecular target for therapeutic intervention for esophageal squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the value of Foxo3a in predicting the response to neoadjuvant treatment of, and prognosis for, esophageal squamous cell carcinoma. Methods and Materials: Immunohistochemical staining was performed in a retrospective series of 60 biopsied esophageal squamous cell carcinomas, and the correlation between nuclear accumulation of Foxo3a and clinicopathologic features was analyzed, including patient survival. In addition, in vitro biologic changes, radiosensitivity, and in vivo tumorigenicity of esophageal carcinoma cells after experimental manipulation of Foxo3a expression levels were determined. Results: Clinical findings point to a significant correlation between the nuclear accumulation of Foxo3a and the survival rate of esophageal cancer patients. In addition, Foxo3a is a significant predictor for the response to neoadjuvant therapy. In cell culture, irradiation and oxidative stress seemed to result in nuclear accumulation of Foxo3a. Down-regulation of Foxo3a significantly decreased radiosensitivity but had no obvious effect on tumor growth, as measured by a clonogenic assay in vitro and growth delay in vivo. Conclusions: Nuclear accumulation of Foxo3a in tumor cells was correlated with increased radiosensitivity and with improved patient survival. Thus, it is suggested that Foxo3a may be a potential marker for esophageal cancer. [Copyright &y& Elsevier]

Evasion of immune surveillance is a significant factor in head and neck squamous cell carcinoma (HNSCC) carcinogenesis. IL-6 signaling is a critical mechanism for the induction of dysfunctional immune responses. In the present study, we examined the role of IL-6 in the prognosis of HNSCC regarding the immunosuppressive tumor microenvironment. We retrospectively analyzed the clinical outcomes of HNSCC patients and examined its correlation with the levels of IL-6 in tumors and circulating myeloid-derived suppressor cells (MDSCs) in peripheral blood. Furthermore, the relationships between IL and 6, programmed death ligand (PD-L1) expression, and immune response were examined in vitro and in vivo. Our data revealed that IL-6 overexpression was associated with the increased risk of developing disease failure and poor prognosis for HNSCC. The immunoreactivity of IL-6 in HNSCC specimens was positively linked to the staining of PD-L1 and the level of circulating MDSCs. By cellular and animal experiments, there were augmented radiation-induced increases in the expression of PD-L1 and the activation of MDSCs noted in IL-6-positive tumors. When IL-6 signaling was inhibited, the levels of PD-L1 and MDSC recruitment were significantly down-regulated. Furthermore, the neutrophil-to-lymphocyte ratio (NLR) was positively correlated with the levels of IL-6 and PD-L1 in tumor, and circulating MDSCs. In conclusion, IL-6 is a significant predictor of treatment outcome in HNSCC patients, and plays an important role in the induction of immunosuppressive tumor microenvironment mediated by increased MDSCs and PD-L1 expression. Furthermore, IL-6 combined with NLR can assist the clinician to make an informed decision regarding treatment options. [ABSTRACT FROM AUTHOR]

Objectives: Aldehyde dehydrogenase 1 (ALDH1) is associated with tumorigenesis, and shown to identify cancer stem cells (CSC)-like cells. We aimed to investigate the significance of ALDH1 in oral squamous cell carcinoma (OSCC) and its correlation with DNMT3b and immune evasion in the present study.Methods: We retrospectively analyzed the clinical outcomes of OSCC patients and examined its correlation with the levels of ALDH1 in tumors and circulating myeloid-derived suppressor cells (MDSCs) in the peripheral blood. Furthermore, the relationships between the DNMT3b, ALDH1 expression, and immune response were examined via clinical specimens and cellular and animal experiments. We also investigated the therapeutic potential of DNA hypomethylating agents in OSCC.Results: Our data revealed that the levels of ALDH1 expression were linked to treatment resistance, CSC-like properties, higher circulating MDSC and poor prognosis for OSCC. The radiation resistance noted in ALDH1-positive tumors was associated with augmented radiation-induced increases in the expression of programmed death ligand (PD-L1) and the activation of MDSCs. Furthermore, there was a positive link between ALDH1 and DNMT3b expression shown by clinical specimens and cellular experiments. DNA hypomethylating agents attenuated the radioresistance of ALDH1-positive cancer cells associated with the decreased ALDH1 and the increased DNA damages. In addition, the activation of MDSCs and the expression of PD-L1 were significantly attenuated by epigenetic therapy.Conclusions: Our findings suggested that ALDH1 played an important role in treatment response and the tumor-promoting microenvironment in OSCC. Moreover, epigenetic therapy could be a promising strategy for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Summary: The aim of this study was to assess the treatment results and toxicity profiles of post-operative conventional radiotherapy (Conv-RT) and intensity-modulated radiotherapy (IMRT) for stage III and IV oral cavity cancer. During the period from April 2002 to December 2005, a total of 49 patients with stage III and IV squamous cell carcinoma of the oral cavity were treated with radical surgery followed by post-operative RT. Twenty-seven patients received Conv-RT while 22 received IMRT. Only three patients received adjuvant chemotherapy. With a median follow-up time of 3.3years, the 3-year overall survival and disease-free survival rates for patients who received Conv-RT vs IMRT were comparable. There was no significant difference in acute toxicity between the two different RT techniques. However, in terms of late toxicity, patients receiving IMRT had significantly less moderate to severe xerostomia and dysphagia than those receiving Conv-RT (36% vs 82%, p =0.01 for xerostomia and 21% vs 59%, p =0.02 for dysphagia). Post-operative Conv-RT and IMRT are equally effective in terms of tumor control for locally advanced oral cavity cancer. Patients receiving IMRT had comparable acute and significant less late toxicity than those receiving Conv-RT. [Copyright &y& Elsevier]