Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan.
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan.
Cancer Sci. 2020 Apr;111(4):1254-1265. doi: 10.1111/cas.14339. Epub 2020 Feb 25.
Bone marrow-derived mesenchymal stem or stromal cells (MSC) have been shown to be recruited to various types of tumor tissues, where they interact with tumor cells to promote their proliferation, survival, invasion and metastasis, depending on the type of the tumor. We have previously shown that Ror2 receptor tyrosine kinase and its ligand, Wnt5a, are expressed in MSC, and Wnt5a-Ror2 signaling in MSC induces expression of CXCL16, which, in turn, promotes proliferation of co-cultured MKN45 gastric cancer cells via the CXCL16-CXCR6 axis. However, it remains unclear how CXCL16 regulates proliferation of MKN45 cells. Here, we show that knockdown of CXCL16 in MSC by siRNA suppresses not only proliferation but also migration of co-cultured MKN45 cells. We also show that MSC-derived CXCL16 or recombinant CXCL16 upregulates expression of Ror1 through activation of STAT3 in MKN45 cells, leading to promotion of proliferation and migration of MKN45 cells in vitro. Furthermore, co-injection of MSC with MKN45 cells in nude mice promoted tumor formation in a manner dependent on expression of Ror1 in MKN45 cells, and anti-CXCL16 neutralizing antibody suppressed tumor formation of MKN45 cells co-injected with MSC. These results suggest that CXCL16 produced through Ror2-mediated signaling in MSC within the tumor microenvironment acts on MKN45 cells in a paracrine manner to activate the CXCR6-STAT3 pathway, which, in turn, induces expression of Ror1 in MKN45 cells, thereby promoting tumor progression.
骨髓间充质干细胞（MSC）已被证明可招募到各种类型的肿瘤组织中，在那里它们与肿瘤细胞相互作用，促进其增殖、存活、侵袭和转移，具体取决于肿瘤的类型。我们之前已经表明，Ror2 受体酪氨酸激酶及其配体 Wnt5a 在 MSC 中表达，并且 MSC 中的 Wnt5a-Ror2 信号诱导 CXCL16 的表达，CXCL16 反过来又通过 CXCL16-CXCR6 轴促进共培养的 MKN45 胃癌细胞的增殖。然而，CXCL16 如何调节 MKN45 细胞的增殖仍不清楚。在这里，我们通过 siRNA 敲低 MSC 中的 CXCL16，不仅抑制了共培养的 MKN45 细胞的增殖，而且抑制了其迁移。我们还表明，MSC 衍生的 CXCL16 或重组 CXCL16 通过激活 MKN45 细胞中的 STAT3 上调 Ror1 的表达，从而促进 MKN45 细胞在体外的增殖和迁移。此外，在裸鼠中共同注射 MSC 和 MKN45 细胞以依赖于 MKN45 细胞中 Ror1 的表达的方式促进肿瘤形成，并且抗-CXCL16 中和抗体抑制与 MSC 共同注射的 MKN45 细胞的肿瘤形成。这些结果表明，肿瘤微环境中 MSC 中通过 Ror2 介导的信号产生的 CXCL16 以旁分泌方式作用于 MKN45 细胞，激活 CXCR6-STAT3 途径，从而诱导 MKN45 细胞中 Ror1 的表达，从而促进肿瘤进展。
