TGF-β刺激MSC转化为肿瘤相关成纤维细胞促进急性淋巴细胞白血病侵袭的机制研究

髓外浸润与白血病细胞侵袭性增强密切相关。肿瘤相关成纤维细胞（CAF）作为肿瘤微环境中的重要基质成分，我们前期研究发现CAF显著促进急性淋巴细胞白血病（ALL）细胞的侵袭进程，而TGF-β可能为ALL微环境中刺激骨髓间充质干细胞（BM-MSC）向CAF转化的关键因子，进而提出我们的假说：ALL微环境中表达升高的TGF-β通过SDF-1/CXCR4信号轴刺激MSC转化为CAF，一方面，CAF分泌多种细胞因子介导网络分子变化促进白血病细胞生存、浸润；另一方面，激活的SDF-1/CXCR4信号轴活化下游PI3K/AKT信号通路介导白血病细胞与CAF之间相互作用，为CAF促进白血病细胞的迁移、侵袭提供便利条件，进而推进ALL侵袭转移进程。本项目将从临床样本、三维细胞培养及动物实验水平共同验证ALL微环境中活化的CAF调节白血病细胞侵袭性改变的假说，为ALL伴髓外浸润患者寻找更有效的靶标提供新的思路。

Extramedullary infiltration is closely related to the increased invasion of leukemia cells. Cancer-associated fibroblasts (CAF) are an important matrix component in the tumor microenvironment. Our previous research found that CAF significantly promoted the invasion of acute lymphoblastic leukemia (ALL) cells, and TGF-β may be a key factor in stimulating the conversion of bone marrow mesenchymal stem cells (BM-MSC) to CAF in the ALL microenvironment, then put forward our hypothesis: TGF-β with increased expression in the ALL microenvironment stimulates the conversion of MSC to CAF through the SDF-1/CXCR4 signal axis. On the one hand, CAF secretes a variety of cytokines to mediate network molecular changes to promote leukemia cell survival and infiltration; on the other hand, the activated SDF-1/CXCR4 signal axis activates the downstream PI3K/AKT signaling pathway to mediate the interaction between leukemia cells and CAF, which provide a convenient condition for CAF to promote the migration and invasion of leukemia cells, further promote the process of ALL invasion and metastasis. This project will jointly verify the hypothesis that activated CAF in the ALL microenvironment regulates leukemic cell invasive changes from clinical samples, three-dimensional cell culture and animal experiment levels, which provide new ideas for ALL patients with extramedullary infiltration to find more effective targets.