Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma
Autor: | Ying Wang, Reshma Shakya, Anthony Wing Ip Lo, Rajiv Khanna, Ka Chun Wu, Xin Yuan Guan, Leo Y. C. Yan, Dora L.W. Kwong, Yanru Qin, Wei Dai, Simon Law, Ngar-Woon Kam, Victor Ho-Fun Lee |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Cancer Research
Esophageal Neoplasms Physiology Angiogenesis medicine.medical_treatment Clinical Biochemistry chemical and pharmacologic phenomena HMGB1 Umbilical vein Transcriptome Mice High-mobility group box 1 Esophageal squamous cell carcinoma Cell Line Tumor medicine Human Umbilical Vein Endothelial Cells Tumor Microenvironment Animals Humans HMGB1 Protein Cell Proliferation Tube formation Tumor microenvironment Original Paper B cells biology Neovascularization Pathologic Chemistry Glycyrrhizic Acid Gene Expression Regulation Neoplastic Cytokine Cell culture Cancer research biology.protein |
Zdroj: | Angiogenesis |
ISSN: | 1573-7209 0969-6970 |
Popis: | 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. |
Databáze: | OpenAIRE |
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