Dorival Mendes Rodrigues-Junior, Soon Sim Tan, Sai Kiang Lim, Hui Sun Leong, Matias Eliseo Melendez, Cintia Regina Niederauer Ramos, Luciano de Souza Viana, Daniel S W Tan, Andre Lopes Carvalho, N Gopalakrishna Iyer, Andre Luiz Vettore, Circulating extracellular vesicle-associated TGFβ3 modulates response to cytotoxic therapy in head and neck squamous cell carcinoma, Carcinogenesis, Volume 40, Issue 12, December 2019, Pages 1452–1461, https://doi.org/10.1093/carcin/bgz148
Abstract:
Management of locally advanced head and neck squamous cell carcinoma (HNSCC) requires a multi-prong approach comprising surgery, radiation and/or chemotherapy, yet outcomes are limited. This is largely due to a paucity of biomarkers that can predict response to specific treatment modalities. Here, we evaluated TGFβ3 protein levels in extracellular vesicles (EVs) released by HNSCC cells as a predictor for response to chemoradiation therapy (CRT). To this end, specific EV-fractions were isolated from cell lines or HNSCC patient plasma, and TGFβ3 protein was quantified. In patients treated with CRT, TGFβ3 levels were found to be significantly higher in plasma EV-fractions or non-responders compared with responders. High levels of TGFβ3 levels in Annexin V-EVs were associated with the worst progression-free survival. In vitro experiments demonstrated that TGFβ3 silencing sensitized HNSCC cells to cytotoxic therapies, and this phenotype could be rescued by treatment with exogenous. In addition, specific EV-fractions shed by cisplatin-resistant cells were sufficient to transfer the resistant phenotype to sensitive cells through activation of TGFβ-signaling pathway. Therefore, our data show that TGFβ3 transmitted through EV plays a significant role in response to cytotoxic therapy, which can be exploited as a potential biomarker for CRT response in HNSCC patients treated with curative intent.
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Funding Info:
This study was supported by grants from National Cancer Centre Singapore Research Foundation (#NMRC/CSA-INV/011/2016) and Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP (#2015/09182-0)
Description:
This is a pre-copyedited, author-produced version of an article accepted for publication in Carcinogenesis following peer review. The version of record Dorival Mendes Rodrigues-Junior, Soon Sim Tan, Sai Kiang Lim, Hui Sun Leong, Matias Eliseo Melendez, Cintia Regina Niederauer Ramos, Luciano de Souza Viana, Daniel S W Tan, Andre Lopes Carvalho, N Gopalakrishna Iyer, Andre Luiz Vettore, Circulating extracellular vesicle-associated TGFβ3 modulates response to cytotoxic therapy in head and neck squamous cell carcinoma, Carcinogenesis, Volume 40, Issue 12, December 2019, Pages 1452–1461, https://doi.org/10.1093/carcin/bgz148 is available online at: https://doi.org/10.1093/carcin/bgz148