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dc.contributor.authorKim, Hong Sunpt_BR
dc.contributor.authorChen, Yu-Chihpt_BR
dc.contributor.authorNör, Felipept_BR
dc.contributor.authorWarner, Kristypt_BR
dc.contributor.authorAndrews, Aprilpt_BR
dc.contributor.authorWagner, Vivian Petersenpt_BR
dc.contributor.authorZhang, Zhaochengpt_BR
dc.contributor.authorZhang, Zhixiongpt_BR
dc.contributor.authorMartins, Manoela Dominguespt_BR
dc.contributor.authorPearson, Alexander T.pt_BR
dc.contributor.authorYoon, Euisikpt_BR
dc.contributor.authorNor, Jacques Eduardopt_BR
dc.date.accessioned2018-10-26T02:43:29Zpt_BR
dc.date.issued2017pt_BR
dc.identifier.issn1949-2553pt_BR
dc.identifier.urihttp://hdl.handle.net/10183/183995pt_BR
dc.description.abstractRecent evidence suggests that the metastatic spread of head and neck squamous cell carcinomas (HNSCC) requires the function of cancer stem cells endowed with multipotency, self-renewal, and high tumorigenic potential. We demonstrated that cancer stem cells reside in perivascular niches and are characterized by high aldehyde dehydrogenase (ALDH) activity and high CD44 expression (ALDHhighCD44high) in HNSCC. Here, we hypothesize that endothelial cell-secreted interleukin-6 (IL-6) contributes to tumor progression by enhancing the migratory phenotype and survival of cancer stem cells. Analysis of tissue microarrays generated from the invasive fronts of 77 HNSCC patients followed-up for up to 11 years revealed that high expression of IL-6 receptor (IL-6R) (p=0.0217) or co-receptor gp130 (p=0.0422) correlates with low HNSCC patient survival. We observed that endothelial cell-secreted factors induce epithelial to mesenchymal transition (EMT) and enhance invasive capacity of HNSCC cancer stem cells. Conditioned medium from CRISPR/Cas9-mediated IL-6 knockout primary human endothelial cells is less chemotactic for cancer stem cells in a microfluidics-based system than medium from control endothelial cells (p<0.05). Blockade of the IL-6 pathway with a humanized anti-IL-6R antibody (tocilizumab) inhibited endothelial cell-induced motility in vitro and decreased the fraction of cancer stem cells in vivo. Notably, xenograft HNSCC tumors vascularized with IL-6-knockout endothelial cells exhibited slower tumor growth and smaller cancer stem cell fraction. These findings demonstrate that endothelial cell-secreted IL-6 enhances the motility and survival of highly tumorigenic cancer stem cells, suggesting that endothelial cells can create a chemotactic gradient that enables the movement of carcinoma cells towards blood vessels.en
dc.format.mimetypeapplication/pdfpt_BR
dc.language.isoengpt_BR
dc.relation.ispartofOncotarget. Albany. Vol. 8, no. 59 (Nov. 2017), p. 100339-100352pt_BR
dc.rightsOpen Accessen
dc.subjectPatologia bucalpt_BR
dc.subjectCélulas-tronco neoplásicaspt_BR
dc.subjectCarcinoma de células escamosaspt_BR
dc.subjectMetástase neoplásicapt_BR
dc.titleEndothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vesselspt_BR
dc.typeArtigo de periódicopt_BR
dc.identifier.nrb001059517pt_BR
dc.type.originEstrangeiropt_BR


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