Extracellular Vesicles in Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders: A Systematic Review.

Extracellular vesicles (EVs) are secreted from most cell types and utilized in a complex network of near and distant cell-to-cell communication. Insight into this complex nanoscopic interaction in the development, progression and treatment of oral squamous cell carcinoma (OSCC) and precancerous oral mucosal disorders, termed oral potentially malignant disorders (OPMDs), remains of interest. In this review, we comprehensively present the current state of knowledge of EVs in OSCC and OPMDs. A systematic literature search strategy was developed and updated to December 17, 2019. Fifty-five articles were identified addressing EVs in OSCC and OPMDs with all but two articles published from 2015, highlighting the novelty of this research area. Themes included the impact of OSCC-derived EVs on phenotypic changes, lymph-angiogenesis, stromal immune response, mechanisms of therapeutic resistance as well as utility of EVs for drug delivery in OSCC and OPMD. Interest and progress of knowledge of EVs in OSCC and OPMD has been expanding on several fronts. The oral cavity presents a unique and accessible microenvironment for nanoparticle study that could present important models for other solid tumours.

Functional and molecular effects of a green tea constituent on oral cancer cells.

BACKGROUND: Green tea is heavily consumed on a global basis for its health benefits. The active ingredient, (-)-epigallocatechin gallate (EGCG), is a major polyphenol demonstrated to inhibit the growth of various non-oral cancer cell lines and interfere with the carcinogenic process, including downregulation of the epidermal growth factor receptor (EGFR). Our aim was to determine the phenotypic changes of oral cancer cells treated with EGCG and concurrently assess the effect on EGFR expression and activation. METHODS: Oral cancer cells (H400 and H357) were treated with 10 µg/mL and 20 µg/mL of EGCG for up to 72 hours. Phenotypic changes were assessed by performing cell proliferation analysis and cell migration (Transwell) assays. Expression of EGFR and its phosphorylated form (p-EGFR) was determined by Western blotting. RESULTS: Cell proliferation of both cell lines was significantly reduced at 48hrs when treated with 20 µg/mL EGCG. However, after 72 hours of treatment the effect of EGCG on cell proliferation ceased. Treatment of both cell lines with 10 µg/mL and 20 µg/mL of EGCG resulted in significant reduction in cell migration. Mechanistically, EGFR expression did not change significantly after treatment with EGCG; however, there was a reduction in its phosphorylated form. CONCLUSION: EGCG transiently inhibits both cell proliferation and migration of oral cavity cancer cells. This effect is associated with a decrease in the expression of phosphorylated EGFR. It is possible that more frequent bursts of EGCG could result in a persistent and sustained cancer inhibition, but this requires further research for clarification.

The role of human papillomavirus in p16-positive oral cancers.

BACKGROUND: The aim of this study was to identify the presence and frequency of human papillomavirus (HPV) nucleic acid in p16-positive oral squamous cell carcinomas (OSCCs), to assess whether the virus was transcriptionally active and to assess the utility of p16 overexpression as a surrogate marker for HPV in OSCC. METHODS: Forty-six OSCC patients treated between 2007 and 2011 with available formalin-fixed paraffin-embedded (FFPE) specimens were included. Twenty-three patients were positive for p16 by immunohistochemistry (IHC) and these were matched with 23 patients with p16-negative tumours. Laser capture microdissection of the FFPE OSCC tissues was undertaken to isolate invasive tumour tissue. DNA was extracted and tested for high-risk HPV types using a PCR-ELISA method based on the L1 SPF10 consensus primers, and a real-time PCR method targeting HPV-16 and HPV-18 E6 region. Genotyping of HPV-positive cases was performed using a reverse line blot hybridization assay (Inno-LiPA). RNAScope® (a chromogenic RNA in situ hybridization assay) was utilized to detect E6/E7 mRNA of known high-risk HPV types for detection of transcriptionally active virus. RESULTS: HPV DNA was found in 3 OSCC cases, all of which were p16 IHC-positive. Two cases were genotyped as HPV-16 and one as HPV-33. Only one of the HPV-16 cases was confirmed to harbour transcriptionally active virus via HPV RNA ISH. CONCLUSION: We have shown that the presence of transcriptionally active HPV rarely occurs in OSCC and that p16 is not an appropriate surrogate marker for HPV in OSCC cases. We propose that non-viral mechanisms are responsible for the majority of IHC p16 overexpression in OSCC.