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Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma
Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494172/ https://www.ncbi.nlm.nih.gov/pubmed/34617194 http://dx.doi.org/10.1007/s10456-021-09819-0 |
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author | Kam, Ngar Woon Wu, Ka Chun Dai, Wei Wang, Ying Yan, Leo Yik Chun Shakya, Reshma Khanna, Rajiv Qin, Yanru Law, Simon Lo, Anthony Wing Ip Lee, Victor Ho Fun Guan, Xin-Yuan Kwong, Dora Lai-Wan |
author_facet | Kam, Ngar Woon Wu, Ka Chun Dai, Wei Wang, Ying Yan, Leo Yik Chun Shakya, Reshma Khanna, Rajiv Qin, Yanru Law, Simon Lo, Anthony Wing Ip Lee, Victor Ho Fun Guan, Xin-Yuan Kwong, Dora Lai-Wan |
author_sort | Kam, Ngar Woon |
collection | PubMed |
description | Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10456-021-09819-0. |
format | Online Article Text |
id | pubmed-8494172 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-84941722021-10-08 Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma Kam, Ngar Woon Wu, Ka Chun Dai, Wei Wang, Ying Yan, Leo Yik Chun Shakya, Reshma Khanna, Rajiv Qin, Yanru Law, Simon Lo, Anthony Wing Ip Lee, Victor Ho Fun Guan, Xin-Yuan Kwong, Dora Lai-Wan Angiogenesis Original Paper Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10456-021-09819-0. Springer Netherlands 2021-10-06 2022 /pmc/articles/PMC8494172/ /pubmed/34617194 http://dx.doi.org/10.1007/s10456-021-09819-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Paper Kam, Ngar Woon Wu, Ka Chun Dai, Wei Wang, Ying Yan, Leo Yik Chun Shakya, Reshma Khanna, Rajiv Qin, Yanru Law, Simon Lo, Anthony Wing Ip Lee, Victor Ho Fun Guan, Xin-Yuan Kwong, Dora Lai-Wan Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma |
title | Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma |
title_full | Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma |
title_fullStr | Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma |
title_full_unstemmed | Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma |
title_short | Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma |
title_sort | peritumoral b cells drive proangiogenic responses in hmgb1-enriched esophageal squamous cell carcinoma |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494172/ https://www.ncbi.nlm.nih.gov/pubmed/34617194 http://dx.doi.org/10.1007/s10456-021-09819-0 |
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