Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/183995 |
Resumo: | Recent 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. |
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Kim, Hong SunChen, Yu-ChihNör, FelipeWarner, KristyAndrews, AprilWagner, Vivian PetersenZhang, ZhaochengZhang, ZhixiongMartins, Manoela DominguesPearson, Alexander T.Yoon, EuisikNor, Jacques Eduardo2018-10-26T02:43:29Z20171949-2553http://hdl.handle.net/10183/183995001059517Recent 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.application/pdfengOncotarget. Albany. Vol. 8, no. 59 (Nov. 2017), p. 100339-100352Patologia bucalCélulas-tronco neoplásicasCarcinoma de células escamosasMetástase neoplásicaEndothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vesselsEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSORIGINAL001059517.pdfTexto completo (inglês)application/pdf9779882http://www.lume.ufrgs.br/bitstream/10183/183995/1/001059517.pdfc420a8ecf821c72e5486aec9bbe3bd20MD51TEXT001059517.pdf.txt001059517.pdf.txtExtracted Texttext/plain50178http://www.lume.ufrgs.br/bitstream/10183/183995/2/001059517.pdf.txt314b578fe0705090297c22b7cde7682aMD52THUMBNAIL001059517.pdf.jpg001059517.pdf.jpgGenerated Thumbnailimage/jpeg2328http://www.lume.ufrgs.br/bitstream/10183/183995/3/001059517.pdf.jpg64b248ba855c1d37456fa91be9383fa5MD5310183/1839952018-10-27 03:12:37.64762oai:www.lume.ufrgs.br:10183/183995Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2018-10-27T06:12:37Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels |
title |
Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels |
spellingShingle |
Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels Kim, Hong Sun Patologia bucal Células-tronco neoplásicas Carcinoma de células escamosas Metástase neoplásica |
title_short |
Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels |
title_full |
Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels |
title_fullStr |
Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels |
title_full_unstemmed |
Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels |
title_sort |
Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels |
author |
Kim, Hong Sun |
author_facet |
Kim, Hong Sun Chen, Yu-Chih Nör, Felipe Warner, Kristy Andrews, April Wagner, Vivian Petersen Zhang, Zhaocheng Zhang, Zhixiong Martins, Manoela Domingues Pearson, Alexander T. Yoon, Euisik Nor, Jacques Eduardo |
author_role |
author |
author2 |
Chen, Yu-Chih Nör, Felipe Warner, Kristy Andrews, April Wagner, Vivian Petersen Zhang, Zhaocheng Zhang, Zhixiong Martins, Manoela Domingues Pearson, Alexander T. Yoon, Euisik Nor, Jacques Eduardo |
author2_role |
author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Kim, Hong Sun Chen, Yu-Chih Nör, Felipe Warner, Kristy Andrews, April Wagner, Vivian Petersen Zhang, Zhaocheng Zhang, Zhixiong Martins, Manoela Domingues Pearson, Alexander T. Yoon, Euisik Nor, Jacques Eduardo |
dc.subject.por.fl_str_mv |
Patologia bucal Células-tronco neoplásicas Carcinoma de células escamosas Metástase neoplásica |
topic |
Patologia bucal Células-tronco neoplásicas Carcinoma de células escamosas Metástase neoplásica |
description |
Recent 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. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017 |
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2018-10-26T02:43:29Z |
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1949-2553 |
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Oncotarget. Albany. Vol. 8, no. 59 (Nov. 2017), p. 100339-100352 |
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