title: CXCL1-Chemokine (C-X-C Motif) Receptor 2 Signaling Stimulates the Recruitment of Bone Marrow-Derived Mesenchymal Cells into Diffuse-Type Gastric Cancer Stroma.
abstract: Tumor stromal cells play a critical role in the progression of diffuse-type gastric cancer (DGC). The aim of this study was to clarify where tumor stromal cells originate from and which factor(s) recruits them into the tumor stroma. Immunodeficient mice with bone marrow transplantation from the cytomegalovirus enhancer/chicken β-actin promoter-enhanced green fluorescent protein mice were used for the in vivo experiments. An in vitro study analyzed the chemotaxis-stimulating factor from DGC cells using bone marrow-derived mesenchymal cells (BM-MCs). The influences of chemokine (C-X-C motif) receptor 2 (CXCR2) inhibitor on the migration of BM-MCs were examined both in vitro and in vivo. BM-MCs frequently migrated into stroma of DGC in vivo. The number of migrating BM-MCs was increased by conditioned medium from DGC cells. CXCL1 from DGC cells stimulated the chemoattractant ability of BM-MCs. Both anti-CXCL1 antibody and CXCR2 inhibitor decreased the migration of BM-MCs, stimulated by DGC cells. A CXCR2 inhibitor, SB225002, reduced the recruitment of BM-MCs into the tumor microenvironment in vivo, decreasing tumor size and lymph node metastasis, and prolonging the survival of gastric tumor-bearing mice. These findings suggested that most tumor stromal cells in DGC might originate from BM-MCs. CXCL1 from DGC cells stimulates the recruitment of BM-MCs into tumor stroma via CXCR2 signaling of BM-MCs. Inhibition of BM-MC recruitment via the CXCL1-CXCR2 axis appears a promising therapy for DGC.
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kasashima
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan; Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka, Japan. Electronic address: m9312510@med.osaka-cu.ac.jp.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.affiliation: Department of Hematology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Nakamae
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kisyu
authors.initials: K
authors.lastname: Kitayama
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Masuda
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Haruhito
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tatsunari
authors.initials: T
authors.lastname: Fukuoka
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Hematology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakane
authors.affiliation: Department of Hematology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hino
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masaichi
authors.initials: M
authors.lastname: Ohira
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D049452:Green Fluorescent Proteins; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D059016:Tumor Microenvironment
chemical_list: D000199:Actins; D054360:Chemokine CXCL1; D018925:Chemokines; C475895:Cxcl1 protein, mouse; D023063:Receptors, Interleukin-8B; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins