Muriel Hourseau

Prognostic value of the chemokine receptor CXCR4 and epithelial-to-mesenchymal transition in patients with squamous cell carcinoma of the mobile tongue

OBJECTIVE The aim of this study was to evaluate the expression and the prognostic value of chemokine receptor 4 (CXCR4), its cognate ligand the CXCL12, and markers of epithelial-to-mesenchymal transition (EMT) in squamous cell carcinoma (SCC) of the mobile tongue. PATIENTS AND METHODS Patients with primary SCC of the mobile tongue who underwent surgery in our center were screened retrospectively. Patients without prior treatment, who had pre-surgery TNM staging and available tumor samples, were eligible. Protein expression of CXCL12, CXCR4, CA9, E-cadherin, and vimentin was determined by immunohistochemical staining, scored, and correlated with clinical and pathological parameters and overall survival. Multivariate and Cox proportional hazards analyses were performed. RESULTS Among 160 patients treated and screened, 47 were analyzed. CXCR4 and CXCL12 expression was high in tumor cells. CXCR4 expression in primary tumor samples was significantly higher in patients with high-grade tumors, lymph node metastases, and microscopic nerve invasion (p ≤ 0.05). There was a non-significant trend towards a correlation between high CXCL12 expression and pathologic tumor stage (p=0.07). Tumors with high CXCR4 expression correlated with poor overall survival (hazard ratio=3.6, 95% confidence interval 1.3-9.7; p=0.011), notably in the CXCR4(high)/vimentin-positive subgroup. Vimentin-positive tumors, characterizing EMT, were associated with lower survival (hazard ratio=4.5, 95% confidence interval 1.6-12.3; p=0.0086). Multivariate analysis confirmed vimentin (but not CXCR4) expression as an independent prognostic factor of poor overall survival (p=0.016). CONCLUSION Our results suggest that CXCR4 is a marker of tumor aggressiveness and vimentin is an important and independent prognostic factor in patients with SCC of the mobile tongue.

Focus on the role of the CXCL12/CXCR4 chemokine axis in head and neck squamous cell carcinoma.

The human chemokine system includes approximately 48 chemokines and 19 chemokine receptors. The CXCL12/CXCR4 system is one of the most frequently studied that is also found overexpressed in a large variety of tumors. The CXCL12/CXCR4 axis has been increasingly identified as an important target in cancer growth, metastasis, relapse, and resistance to therapy. In this review, we highlight current knowledge of the molecular mechanisms involving chemokines CXCL12/CXCR4 and their consequences in head and neck squamous cell carcinoma (HNSCC). Overexpression of CXCL12/CXCR4 in HNSCC appears to activate cellular functions, including motility, invasion, and metastatic processes. Current findings suggest that CXCR4 and epithelial–mesenchymal transition markers are associated with tumor aggressiveness and a poor prognosis, and may be suitable biomarkers for head and neck tumors with high metastatic potential. Furthermore, knowledge of the role of CXCR4 in HNSCC could influence the development of new targeted therapies for treatment, aimed at improving the prognosis of this disease.

Remodeling of the Residual Gastric Mucosa after Roux-En-Y Gastric Bypass or Vertical Sleeve Gastrectomy in Diet-Induced Obese Rats

Whereas the remodeling of intestinal mucosa after bariatric surgeries has been the matter of numerous studies to our knowledge, very few reported on the remodeling of the residual gastric mucosa. In this study, we analyzed remodeling of gastric mucosa after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) in rats. Diet-induced obese rats were subjected to RYGB, VSG or sham surgical procedures. All animals were assessed for food intake, body-weight, fasting blood, metabolites and hormones profiling, as well as insulin and glucose tolerance tests before and up to 5 weeks post-surgery. Remodeling of gastric tissues was analyzed by routine histology and immunohistochemistry studies, and qRT-PCR analyses of ghrelin and gastrin mRNA levels. In obese rats with impaired glucose tolerance, VSG and RYGB caused substantial weight loss and rats greatly improved their oral glucose tolerance. The remaining gastric mucosa after VSG and gastric pouch (GP) after RYGB revealed a hyperplasia of the mucous neck cells that displayed a strong immunoreactivity for parietal cell H+/K+-ATPase. Ghrelin mRNA levels were reduced by 2-fold in remaining fundic mucosa after VSG and 10-fold in GP after RYGB. In the antrum, gastrin mRNA levels were reduced after VSG in line with the reduced number of gastrin positive cells. This study reports novel and important observations dealing with the remaining gastric mucosa after RYGB and VSG. The data demonstrate, for the first time, a hyperplasia of the mucous neck cells, a transit cell population of the stomach bearing differentiating capacities into zymogenic and peptic cells.

Human papilloma virus prevalence in HIV patients with head and neck squamous cell carcinoma.

Objective:The implication of human papilloma virus (HPV) in head and neck squamous cell carcinoma (HNSCC) is well established, especially in oropharyngeal SCC. HIV patients have a higher risk of persistent HPV infection. We investigated the role of HPV in HNSCC carcinogenesis in HIV population. Design:Retrospective monocentric study. Methods:We studied HIV patients who presented with HNSCC between 1994 and 2014. For each patient, tumor characteristics, HIV disease, and survival information were collected. Tumor HPV testing was performed using p16 immunohistochemistry (IHC), in-situ hybridization and PCR. We assessed the percentage of HPV in this population of HIV patients with HNSCC and compared HIV disease characteristics based on HPV status. Results:Forty-seven patients were included: 11 women/36 men, the median age was 50 years. Tumor HPV testing was performed in 40 patients. Tumors were located in oropharynx (32%), oral cavity (32%), larynx (21%), and hypopharynx (11%). At the time of diagnosis, median CD4+ level was 385 cells/&mgr;l, 31% of the patients were stage (Centers for Disease Control, stage C). The percentage of HPV linked to HNSCC for all locations in HIV patients was 30% (n = 12). HPV16 accounted for 50% of all HPV genotypes. HPV positive status was associated with a CD4+ nadir of less than 200 (P = 0.026), but not with CD4+ level at time of diagnosis (P = 0.414). HPV-negative tumors tend to be associated with poorer 5-year overall survival (hazard ratio = 2.9, P = 0.0711). Conclusion:HPV plays a critical role in HNSCC development in HIV population. HIV immunodeficiency may increase HPV persistence and progression of HNSCC.

Abstract 728: CXCL12 (SDF-1) chemokine expression as a baseline factor associated with resistance to induction chemotherapy in head and neck squamous cell carcinoma

Background. SDF-1, and its cognate receptor CXCR4, are recognized as major factors in tumor progression and metastasis. Recent data also suggest that chemokines may play a role in resistance to chemotherapy. In this study, we investigated the expression of SDF-1 and CXCR4 in initial tumor biopsies prior to treatment in patients treated by induction chemotherapy for organ preservation and correlated this expression with response to chemotherapy. Material and Methods. Patients with locally advanced pharyngo-laryngeal carcinomas, candidates for neoadjuvant platinum-based chemotherapy as part of an organ preservation program, were considered for this study. Objective response in organ preservation accounted for more than 50% reduction in tumor size on CT-scan or MRI. Tissue biopsies were scored for SDF-1, CXCR4, Vimentin and E-cadherin staining by immunohistochemistry. Staining was measured according to a specific scoring scale. Biopsies were all read by three different observers for scoring adjudication and quantification was performed using the Histolab Software (Microvision). Results. Among the 42 patients who entered in this study, 23 had primary site in the hypopharynx and 19 in the larynx. Twenty-two patients experienced objective response and 20 patients were non-responders to induction chemotherapy. SDF-1 staining score was higher in cancer cells than that in normal epithelial cells located in the close vicinity of the tumor. SDF-1 staining was predominantly located in the cytoplasm of cancer cells. The level of SDF-1 expression was significantly higher in tumors from non-responders compared to responders (score: 155 vs 110, p=0.01). CXCR4 expression was similar between responders and non-responders, and predominantly located in the cytoplasm and the nucleus of cancer cells. Vimentin and E-cadherin were evaluated as potential differentiation markers. Few tumor cells expressed Vimentin in our biopsies. Interestingly lower E-cadherin expression was observed in non-responders compared to responders (score: 110 vs 170, p=0.01) suggesting that loss in epithelial differentiation may facilitate resistance to chemotherapy in this population. Conclusion. High expression levels of SDF-1 cytokine and the loss of E-cadherin as a marker of epithelial differentiation in cancer cells were shown to correlate with the lack of response to induction chemotherapy in hypopharyngeal and laryngeal squamous cell carcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 728. doi:1538-7445.AM2012-728