Journal
ANGIOGENESIS
Volume 25, Issue 2, Pages 181-203Publisher
SPRINGER
DOI: 10.1007/s10456-021-09819-0
Keywords
B cells; High-mobility group box 1; Angiogenesis; Esophageal squamous cell carcinoma
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Funding
- Theme-based Research Scheme [T12-701/17-R, T12-710/16-RC347/A8363]
- Laboratory for Synthetic Chemistry and Chemical Biology under the Health@InnoHK Program by Innovation and Technology Commission, The Government of Hong Kong Special Administrative Region of the People's Republic of China
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Different functions and profiles of B-cell subsets in various cancers have been reported. In esophageal squamous cell carcinoma (ESCC), proliferating B cells are predominantly found in the peritumoral region with high expression of HMGB1. Cancer-derived HMGB1 modulates B cells to promote angiogenesis in ESCC microenvironment.
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.
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