S100A16 promotes differentiation and contributes to a less aggressive tumor phenotype in oral squamous cell carcinoma.

BACKGROUND: Altered expression of S100A16 has been reported in human cancers, but its biological role in tumorigenesis is not fully understood. This study aimed to investigate the clinical significance and functional role of S100A16 in oral squamous cell carcinoma (OSCC) suppression. METHODS: S100A16 mRNA and/or protein levels were examined by quantitative RT-PCR and immunohistochemistry in whole- and laser microdissected-specimens of normal human oral mucosa (NHOM, n = 65), oral dysplastic lesions (ODL, n = 21), OSCCs (n = 132) and positive cervical nodes (n = 17). S100A16 protein expression in OSCC was examined for correlations with clinicopathological variables and patient survival. S100A16 was over-expressed and knocked-down in OSCC-derived (CaLH3 and H357) cells by employing retroviral constructs to investigate its effects on cell proliferation, sphere formation and three dimensional (3D)-organotypic invasive abilities in vitro and tumorigenesis in a mouse xenograft model. RESULTS: Both S100A16 mRNA and protein levels were found to be progressively down-regulated from NHOM to ODL and OSCC. Low S100A16 protein levels in OSCC significantly correlated with reduced 10-year overall survival and poor tumor differentiation. Analysis of two external OSCC microarray datasets showed a positive correlation between the mRNA expression levels of S100A16 and keratinocyte differentiation markers. CaLH3 and H357 cell fractions enriched for differentiated cells either by lack of adherence to collagen IV or FACS sorting for low p75NTR expression expressed significantly higher S100A16 mRNA levels than the subpopulations enriched for less differentiated cells. Corroborating these findings, retroviral mediated S100A16 over-expression and knock-down in CaLH3 and H357 cells led to respective up- and down-regulation of differentiation markers. In vitro functional studies showed significant reduction in cell proliferation, sphere formation and 3D-invasive abilities of CaLH3 and H357 cells upon S100A16 over-expression. These functional effects were associated with concomitant down-regulation of self-renewal (Bmi-1 and Oct 4A) and invasion related (MMP1 and MMP9) molecules. S100A16 over-expression also suppressed tumorigenesis of H357 cells in a mouse xenograft model and the resulting tumor xenografts displayed features/expression of increased differentiation and reduced proliferation/self-renewal. CONCLUSIONS: These results indicate that S100A16 is a differentiation promoting protein and might function as a tumor suppressor in OSCC.

The low-affinity nerve growth factor receptor p75NTR identifies a transient stem cell-like state in oral squamous cell carcinoma cells.

BACKGROUND: Although several markers have been used for enrichment of cells with stem cell-like properties in oral squamous cell carcinoma (OSCC), isolation of a pure subpopulation is still a challenging task. Normal oral and esophageal keratinocyte stem cells have been previously isolated using the low-affinity nerve growth factor receptor p75NTR. OBJECTIVE: To investigate the potential of p75NTR as a marker for identification and isolation of oral cancer cells with stem cell-like properties. METHODS: Subpopulations of cells with high or low expression of p75NTR were sorted from OSCC-derived cells and compared for sphere/colony formation, in vivo tumor formation ability, expression of stem cell-related molecules, cell cycle distribution and drug resistance. RESULTS: p75NTR(High) cells exhibited statistically significant higher stem cell properties than p75NTR(Low) cells in all assays performed. Nevertheless, p75NTR(Low) subpopulation did also exhibit some stem cell features, but to a lesser extent. Propagation of p75NTR(Low) cells for several passages in culture showed that the expression of p75NTR could rise spontaneously. This finding was also supported by the similar expression of p75NTR by the xenografts generated by both subpopulations in NOD\SCID IL2Rg(null) mice. CONCLUSION: p75NTR can be used for isolating a subpopulation enriched for cells with stem cell-like properties in OSCC. De novo generation of p75NTR(High) cells from p75NTR(Low) cells suggests either that there is another subpopulation with stem cell features within the p75NTR(Low) cells, or that the p75NTR(Low) cells can dedifferentiate due to a contextually regulated equilibrium between stem cell-like cells and transit-amplifying neoplastic progenitors.

Loss of S100A14 expression at the tumor-invading front correlates with poor differentiation and worse prognosis in oral squamous cell carcinoma.

BACKGROUND: We previously showed a tumor-suppressive function of S100A14 in oral squamous cell carcinoma (OSCC). This study aimed to examine the prognostic significance and differentiation-related function of S100A14 in OSCC. METHODS: S100A14 expression was examined in 170 OSCCs from Norwegian and Nepalese populations using immunohistochemistry. Pro-differentiation function was investigated by overexpressing and silencing S100A14 expression in OSCC-derived cells. External transcriptomic datasets were used to validate association between S100A14 and differentiation markers in OSCC. RESULT: Loss of S100A14 expression at the invading tumor fronts significantly correlated with poor differentiation and reduced 10-years survival of OSCC-patients. Multivariate Cox analysis identified S100A14 to be an independent prognostic factor. Modulation of S100A14 expression in OSCC-derived cells positively correlated with the expression of differentiation markers. Analysis of external datasets supported the pro-differentiation function of S100A14. CONCLUSION: These results indicate that S100A14 is a pro-differentiation protein and its expression might be useful as a prognostic marker in OSCC.

The use of salivary cytokines as a screening tool for oral squamous cell carcinoma : A review of the literature.

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancer. The 5-year survival rate has remained below 50% over the last two decades, and new tools for early diagnosis are needed. Saliva has been used for diagnosis of several systemic diseases, and its use for diagnosis of OSCC has been sought extensively. Among the many salivary analytes for diagnosis of OSCC, accumulating evidences indicate the possibility of using salivary cytokines. Overproduction of proinflammatory, proangiogenic cytokines by OSCC cells has been reported, and their role in tumor progression and angiogenesis is well established. However, many inflammatory conditions and immunological diseases could affect the levels of cytokines in serum and saliva. This article has reviewed publications in this matter, and some strengths and weaknesses have been pointed out. Conclusively, large-scale investigations are required for validation of the use of salivary cytokines for diagnosis of OSCC, with consideration to the influential role of periodontal inflammation in their levels.

Pattern of malignant tumors registered at a referral oral and maxillofacial hospital in Sudan during 2006 and 2007.

BACKGROUND: A progressive increase in the incidence and mortality of oral cancer is expected in Sudan. However, updated information on the epidemiology and pattern of the disease in the country is needed to draw the attention of the local authorities. AIM: The aim of this study has been to describe the pattern of cancer cases attending a referral oral and maxillofacial hospital in Sudan during the period 2006-2007. SETTINGS AND DESIGN: The investigation was conducted as a cross-sectional study using the hospital records. MATERIALS AND METHODS: From the hospital database, all cancer cases registered during the study period have been reported and their demographic characteristics, clinical information and history of oral habits were included. STATISTICS: Statistical Package for Social Sciences (version 12) was used for data analysis. Frequency distributions of the study variables were made and the association between pairs of variables was examined using the Chi-square test with a level of significance of 0.01. RESULTS AND CONCLUSION: Of the 261 cases included in this study, the most common pattern was found to be an intraoral squamous cell carcinoma (73.6%). The male to female ratio was approximately 3:2. Dropout rates were alarmingly high regardless of the patient's state of residence. The observation of this study indicated that most of the patients seek treatment when the tumor reaches late stage. More public health efforts are therefore needed to investigate the current impact of the problem as well as for prevention and early detection of the cases.