Journal Article

Mesenchymal stem cell‐derived CXCL16 promotes progression of gastric cancer cells by STAT3‐mediated expression of Ror1

Honda, Takashi, Kakeji, Yoshihiro, Hoshi, Kyoka, Ikeda, Taro, Minami, Yasuhiro, Nishita, Michiru

2020

Overview

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. We show that CXCL16 derived from human bone marrow‐derived mesenchymal stem cells (MSC) induces expression of Ror1 through activation of STAT3 in MKN45 gastric cancer cells, resulting in promotion of proliferation and migration of MKN45 cells in vitro. Furthermore, tumor formation of MKN45 cells in nude mice can be accelerated by co–injection of MSC, in a manner that is inhibited by anti–CXCL16 neutralizing antibody and is dependent on Ror1 expression in MKN45 cells. These findings indicate that CXCL16 derived from MSC induces expression of Ror1 through activation of the STAT3 pathway in MKN45 cells, leading to the promotion of tumor formation.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Animals / Antibodies, Neutralizing - pharmacology / Bone marrow / bone marrow‐derived mesenchymal stem cells / Cell Line, Tumor / Cell migration / Cell Movement - genetics / Cell proliferation / Cell Proliferation - genetics / Chemokine CXCL16 - antagonists & inhibitors / Chemokine CXCL16 - genetics / CXCL16 / CXCL16 protein / Disease Progression / Fibroblasts / Gastric cancer / Gene Expression Regulation, Neoplastic - genetics / Heterografts / Humans / Immunoglobulins / Kinases / Membranes / Mesenchymal stem cells / Mesenchymal Stem Cells - metabolism / Mesenchymal Stem Cells - pathology / Metastases / Mice / Original / Paracrine signalling / Plasmids / Protein Binding - genetics / Protein-tyrosine kinase receptors / Proteins / Receptor Tyrosine Kinase-like Orphan Receptors - genetics / Receptors, CXCR6 - genetics / Ror1 / Signal Transduction - genetics / siRNA / STAT3 / Stat3 protein / STAT3 Transcription Factor - genetics / Stem cells / Stomach Neoplasms - genetics / Stomach Neoplasms - pathology / Stromal cells / Tumor cells / Wnt protein / Wnt-5a Protein - genetics