Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222, China.
Department of Gastroenterology, The First Affiliated Hospital of Shihezi University, Shihezi, 832002, China.
Cell Commun Signal. 2023 Oct 5;21(1):274. doi: 10.1186/s12964-023-01127-y.
Our previous study found that bone marrow-derived mesenchymal stem cells (BMSCs) promote Helicobacter pylori (H pylori)-associated gastric cancer (GC) progression by secreting thrombospondin-2 (THBS2). Extracellular vesicles (EVs) are important carriers for intercellular communication, and EVs secreted by BMSCs have been shown to be closely related to tumor development. The aim of this study was to investigate whether BMSC-derived microvesicles (MVs, a main type of EV) play a role in H. pylori-associated GC by transferring THBS2.
BMSCs and THBS2-deficient BMSCs were treated with or without the supernatant of H. pylori for 12 h at a multiplicity of infection of 50, and their EVs were collected. Then, the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on the GC cell line MGC-803 were assessed by in vitro proliferation, migration, and invasion assays. In addition, a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model were constructed to evaluate the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on GC development and metastasis in vivo.
BMSC-derived MVs could be readily internalized by MGC-803 cells. BMSC-derived MVs after H. pylori treatment significantly promoted their proliferation, migration and invasion in vitro (all P < 0.05) and promoted tumor development and metastasis in a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model in vivo (all P < 0.05). The protein expression of THBS2 was significantly upregulated after H. pylori treatment in BMSC-derived MVs (P < 0.05). Depletion of the THBS2 gene reduces the tumor-promoting ability of BMSC-MVs in an H. pylori infection microenvironment both in vitro and in vivo.
Overall, these findings indicate that MVs derived from BMSCs can promote H. pylori-associated GC development and metastasis by delivering the THBS2 protein. Video Abstract.
我们之前的研究发现骨髓间充质干细胞（BMSCs）通过分泌血栓素-2（THBS2）促进幽门螺杆菌（H pylori）相关胃癌（GC）的进展。细胞外囊泡（EVs）是细胞间通讯的重要载体，并且已经证明 BMSCs 分泌的 EVs 与肿瘤的发展密切相关。本研究旨在通过转移 THBS2 来探讨 BMSC 衍生的微泡（MV，EV 的主要类型）是否通过转移 THBS2 在 H. pylori 相关 GC 中发挥作用。
用或不用 H. pylori 上清液（感染复数为 50）处理 BMSCs 和 THBS2 缺陷型 BMSCs 12 小时，收集其 EVs。然后，通过体外增殖、迁移和侵袭实验评估 BMSC 衍生的 MV 和 THBS2 缺陷型 BMSC 衍生的 MV 对 GC 细胞系 MGC-803 的影响。此外，构建了皮下异种移植肿瘤模型、裸鼠腹腔转移模型和尾静脉注射转移模型，以评估 BMSC 衍生的 MV 和 THBS2 缺陷型 BMSC 衍生的 MV 对体内 GC 发展和转移的影响。
BMSC 衍生的 MV 可被 MGC-803 细胞轻易内化。H. pylori 处理后的 BMSC 衍生的 MV 在体外显著促进其增殖、迁移和侵袭（均 P<0.05），并在皮下异种移植肿瘤模型、裸鼠腹腔转移模型和尾静脉注射转移模型中促进体内肿瘤发展和转移（均 P<0.05）。H. pylori 处理后，BMSC 衍生的 MV 中 THBS2 的蛋白表达显著上调（P<0.05）。在 H. pylori 感染微环境中，THBS2 基因缺失降低了 BMSC-MVs 的促肿瘤能力，无论是在体外还是在体内。
总的来说，这些发现表明，BMSCs 衍生的 MV 可以通过递送 THBS2 蛋白促进 H. pylori 相关 GC 的发展和转移。
