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Given the poor prognosis of many human cancers in which tropomyosin receptor kinase B (TRKB) is highly expressed, we investigated the involvement of brain-derived neurotrophic factor (BDNF)\/TRKB pathway in PGC cells using clinical specimens and observed upregulation of TRKB and BDNF. In primary culture systems of patient-derived PGC cells and cancer-associated fibroblasts (CAFs), PGC cells co-cultured with CAFs exhibited significant upregulation of BDNF and epithelial-mesenchymal transition (EMT). Similar results were observed in PGC cells treated with conditioned medium from co-cultures of PGC cells with CAFs. Administration of TRK inhibitors suppressed BDNF-induced cell migration in PGC cells. Immunohistochemical and clinicopathological analyses of tumors from patients with PGC revealed that BDNF and TRKB were highly expressed in both tumor cells and stromal cells such as CAFs, and TRKB expression levels in PGC cells were significantly correlated with aggressive features, including vascular invasion, nodal metastasis, and poor prognosis. Collectively, these data suggest that the BDNF\/TRKB pathway regulates PGC cell aggressiveness via crosstalk with CAFs and is a potential therapeutic target for PGC harboring invasive and metastatic features.<\/jats:p>","DOI":"10.1038\/s41598-022-22377-9","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T12:05:59Z","timestamp":1666267559000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["BDNF\/TRKB axis provokes EMT progression to induce cell aggressiveness via crosstalk with cancer-associated fibroblasts in human parotid gland cancer"],"prefix":"10.1038","volume":"12","author":[{"given":"Kazumasa","family":"Moriwaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Wada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Kuwabara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Ayani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Terada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Higashino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Kawata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michio","family":"Asahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"22377_CR1","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1007\/s10147-021-01901-3","volume":"26","author":"Y Inaka","year":"2021","unstructured":"Inaka, Y., Kawata, R., Haginomori, S.I., et al. Symptoms and signs of parotid tumors and their value for diagnosis and prognosis: A 20-year review at a single institution. Int. J. Clin. Oncol. 26, 1170\u20131178 (2021).","journal-title":"Int. J. Clin. Oncol."},{"key":"22377_CR2","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1007\/s10147-018-1266-7","volume":"23","author":"A Nishikado","year":"2018","unstructured":"Nishikado, A. et al. A clinicopathological study of parotid carcinoma: 18-year review of 171 patients at a single institution. Int. J. Clin. Oncol. 23, 615\u2013624 (2018).","journal-title":"Int. J. Clin. Oncol."},{"key":"22377_CR3","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.ijom.2011.12.020","volume":"41","author":"D Stodulski","year":"2012","unstructured":"Stodulski, D., Mikaszewski, B. & Stankiewicz, C. Signs and symptoms of parotid gland carcinoma and their prognostic value. Int. J. Oral Maxillofac. Surg. 41, 801\u2013806 (2012).","journal-title":"Int. J. Oral Maxillofac. 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