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Bcl9 Depletion Modulates Endothelial Cell in Tumor Immune Microenvironment in Colorectal Cancer Tumor.

ABSTRACT: Tumor endothelial cells are an important part of the tumor microenvironment, and angiogenesis inhibitory therapy has shown potential in tumor treatment. However, which subtypes of tumor endothelial cells are distributed in tumors, what are the differences between tumor endothelial cells and normal endothelial cells, and what is the mechanism of angiogenesis inhibitory therapy at the histological level, are all need to be resolved urgently. Using single-cell mRNA sequencing, we analyzed 12 CT26 colon cancer samples from mice, and found that knockdown of the downstream factor BCL9 in the Wnt signaling pathway or inhibitor-mediated functional inhibition can modulate tumor endothelial cells at a relatively primitive stage, inhibiting their differentiation into further extracellular matrix construction and angiogenesis functions. Furthermore, we propose a BCL9-endo-Score based on the differential expression of cells related to different states of BCL9 functions. Using published data sets with normal endothelial cells, we found that this score can characterize endothelial cells at different stages of differentiation. Finally, in the The Cancer Genome Atlas (TCGA) pan-cancer database, we found that BCL9-endo-Score can well predict the prognosis of diseases including colon cancer, kidney cancer and breast cancer, and identified the markers of these tumor subtypes, provide a basis for the prognosis prediction of patients with such types of tumor. Our data also contributed knowledge for tumor precision treatment with angiogenesis inhibitory therapy by targeting the Wnt signaling pathway.

SUBMITTER: Wei Z

PROVIDER: S-EPMC7856347 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Bcl9 Depletion Modulates Endothelial Cell in Tumor Immune Microenvironment in Colorectal Cancer Tumor.

Wei Zhuang Z Feng Mei M Wu Zhongen Z Shen Shuru S Zhu Di D

Frontiers in oncology 20210119

Tumor endothelial cells are an important part of the tumor microenvironment, and angiogenesis inhibitory therapy has shown potential in tumor treatment. However, which subtypes of tumor endothelial cells are distributed in tumors, what are the differences between tumor endothelial cells and normal endothelial cells, and what is the mechanism of angiogenesis inhibitory therapy at the histological level, are all need to be resolved urgently. Using single-cell mRNA sequencing, we analyzed 12 CT26 c ...[more]

PMID: 33552975

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Project description:Sporadic apoptosis of tumour cells is a commonly observed feature of colorectal cancer (CRC) and strongly correlates with adverse patient prognosis. The uptake of apoptotic cell debris by neutrophils induces a non-inflammatory, pro-regenerative, and hence potentially pro-tumorigenic phenotype. In this study, we therefore sought to investigate the impact of apoptotic CRC cells on neutrophils and its consequence on other immune cells of the tumour microenvironment. Apoptosis induced by combined TNFα-treatment and UV-C irradiation, as well as various chemotherapeutic agents, led to a substantial release of neutrophil-attracting chemokines, most importantly interleukin-8 (IL-8), in both primary patient-derived and established CRC cells. Accordingly, conditioned media of apoptotic tumour cells selectively stimulated chemotaxis of neutrophils, but not T cells or monocytes. Notably, caspase-inhibition partially reduced IL-8 secretion, suggesting that caspase activity might be required for apoptosis-induced IL-8 release. Moreover, apoptotic tumour cell-conditioned media considerably prolonged neutrophil lifespan and induced an activated CD66bhighCD11bhighCD62Llow phenotype, comparable to that of tumour-associated neutrophils in CRC patients, as assessed by flow cytometry of dissociated CRC tissues. Immunohistochemical analyses of 35 CRC patients further revealed a preferential accumulation of neutrophils at sites of apoptotic tumour cells defined by the expression of epithelial cell-specific caspase-cleaved cytokeratin-18. The same areas were also highly infiltrated by macrophages, while T cells were virtually absent. Notably, neutrophils induced an M2-like CD86lowCD163+CD206+ phenotype in co-cultured monocyte-derived macrophages and suppressed LPS-induced pro-inflammatory cytokine release. In an in vitro transwell model, IL-8 blockade efficiently prevented neutrophil-induced anti-inflammatory macrophage polarisation by inhibiting neutrophil migration towards IL-8 gradients generated by apoptotic CRC cells. To conclude, our data suggest that apoptotic cancer cells release chemotactic factors that attract neutrophils into the tumour, where their interaction with neighbouring macrophages might promote an immunologically unfavourable tumour microenvironment. This effect may contribute to tumour recurrence after chemotherapy-induced apoptosis.

Project description:ObjectiveTo explore the regulatory role of miR-4772 in the formation of tumor immune microenvironment in ovarian cancer.MethodsThe optimal cutoff level of PD-L1 expression was calculated based on data from 294 ovarian cancer patients in the TCGA database. The differentially expressed genes (DEGs) between high and low PD-L1 expression groups were screened, and the important DEGs were identified by correlation analysis. WGCNA analysis was performed to select the weighted genes and PD-L1-related miRNAs, from which the hub genes were obtained by intersection analysis. ssGSEA analysis was used to evaluate the effect of PD-L1 and miR-4772 expressions on the tumor immune microenvironment in ovarian cancer. KEGG analysis was used to identify the involved signal pathways, and the interactions between the hub genes were mapped by protein-protein interaction (PPI) analysis. Survival analysis was carried out to identify the survival-related hub genes, and the results were validated using the data of 399 patients with ovarian cancer from GEO database and the sequencing results of SKOV3 cells transfected with miR-4772 mimics or inhibitor.ResultsAccording the optimal cutoff level of PD-L1 expression of 1.31582 (90th quantile), the patients were divided into high- and low-PD-L1 expression groups. A total of 840 DEGs were identified, including 549 significantly up-regulated genes and 291 down-regulated genes. Among them, 20 important DEGs were found to closely correlate with miR-4772 expression, and WGCNA analysis identified 48 weighted genes significantly correlated with miR-4772. Twelve genes were identified as both key DEGs and weighted genes and were treated as the hub genes. ssGSEA analysis showed that both the patients with high PD-L1 expressions and those with high miR-4772 expressions showed more active immune infiltration and functional activity. The 12 hub genes were involved mainly in immune-related signaling pathways, and PPI analysis suggested significant interactions among the hub genes. The two hub genes CD96 and TBX21 showed close correlation with the survival of ovarian cancer patients. The sequencing results of SKOV3 cells transfected with miR-4772 mimics or inhibitor showed that the changes in miR-4772 expression level caused obvious changes in the expressions of the 12 hub genes and PD-L1.ConclusionMiR-4772 plays a regulatory role in the formation of tumor immune microenvironment in ovarian cancer by regulating 12 hub genes.

Dataset Information

Bcl9 Depletion Modulates Endothelial Cell in Tumor Immune Microenvironment in Colorectal Cancer Tumor.

Publications

Bcl9 Depletion Modulates Endothelial Cell in Tumor Immune Microenvironment in Colorectal Cancer Tumor.

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