THBS4/integrin α2 axis mediates BM-MSCs to promote angiogenesis in gastric cancer associated with chronic Helicobacter pylori infection
THBS4/integrin α2 axis mediates BM-MSCs to promote angiogenesis in gastric cancer associated with chronic Helicobacter pylori infection
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THBS4/整合素α2轴介导BM-MSC促进慢性幽门螺杆菌感染相关胃癌血管生成
DOI：
10.21203/rs.3.rs-366308/v1
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Lin R
中科院分区：
文献类型：
--
作者：
He L;Wang W;Shi H;Jiang C;Yao H;Zhang Y;Qian W;Lin R
背景：骨髓间充质干细胞参与幽门螺杆菌（H. pylori）诱发胃癌的机制尚不清楚。本研究旨在探讨骨髓间充质干细胞在H.幽门诱发胃癌主要方法：小鼠接受全骨髓移植，然后感染H。幽门。提取骨髓间充质干细胞，移植于慢性感染H.幽门螺杆菌。采用苏木精-伊红染色、免疫组织化学染色和免疫荧光法检测小鼠胃组织中肿瘤生长和血管生成。鸡绒毛尿囊膜试验、异种移植肿瘤模型和人脐静脉内皮细胞管形成试验用于体内和体外血管生成研究。从移植到H. pylori感染的小鼠结果：骨髓间充质干细胞可向慢性粘膜损伤部位迁移，促进慢性H相关肿瘤血管生成。幽门感染BM-MSC迁移到慢性粘膜损伤部位诱导THBS 4上调，这在人胃癌中也很明显，并与血管形成增加和预后不良相关。THBS 4/整合素α2轴通过促进内皮细胞PI 3 K/AKT通路促进血管生成。结论：BM-MSCs在慢性H. pylori感染微环境，主要由THBS 4/整合素α2轴介导，其激活内皮细胞中的PI 3 K/AKT通路并最终诱导新肿瘤血管的形成。
Background: BM-MSCs contribute to Helicobacter pylori (H. pylori)-induced gastric cancer, but their mechanism is still unclear. The aim of our study was to investigate the specific role and mechanism of BM-MSCs in H. pylori-induced gastric cancer. Main methods: Mice received total bone marrow transplants and were then infected with H. pylori. BM-MSCs were extracted and transplanted into the gastric serosal layer of mice chronically infected with H. pylori. Hematoxylin and eosin staining, immunohistochemistry staining and immunofluorescence were performed to detect tumor growth and angiogenesis in mouse stomach tissues. Chicken chorioallantoic membrane assays, xenograft tumor models, and human umbilical vein endothelial cell tube formation assays were used for in vivo and in vitro angiogenesis studies. THBS4 was screened from RNA-seq analysis of gastric tissues of BM-MSCs transplanted into H. pylori-infected mice. Results: BM-MSCs can migrate to the site of chronic mucosal injury and promote tumor angiogenesis associated with chronic H. pylori infection. Migration of BM-MSCs to the site of chronic mucosal injury induced the upregulation of THBS4, which was also evident in human gastric cancer and correlated with increased blood vessel formation and worse outcome. The THBS4/integrin α2 axis promoted angiogenesis by facilitating the PI3K/AKT pathway in endothelial cells. Conclusions: Our results revealed a novel proangiogenic effect of BM-MSCs in the chronic H. pylori infection microenvironment, primarily mediated by the THBS4/integrin α2 axis, which activates the PI3K/AKT pathway in endothelial cells and eventually induces the formation of new tumor vessels.
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影响因子：
24.5
作者：
Song, Shumei;Chen, Qiongrong;Ajani, Jaffer A.
通讯作者：
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影响因子：
2.8
作者：
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影响因子：
1.9
作者：
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通讯作者：
Luo, Xingguang
影响因子：
8
作者：
Muppala S;Xiao R;Krukovets I;Verbovetsky D;Yendamuri R;Habib N;Raman P;Plow E;Stenina-Adognravi O
通讯作者：
Stenina-Adognravi O
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DOI：
10.1186/s13046-015-0172-3
发表时间：
2015-05-20
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Li W;Zhou Y;Yang J;Zhang X;Zhang H;Zhang T;Zhao S;Zheng P;Huo J;Wu H
通讯作者：
Wu H