title: CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer.
abstract: Cancer-associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. However, the mechanisms underlying these tumor-promoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF-mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co-culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF-573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin β1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF-573,228 at inhibiting GC cell invasion through the suppression of integrin β1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin β1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Izumi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.|Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Sugihara
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Eto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sawayama
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Tadahito
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kiyozumi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kaida
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kurashige
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yukiharu
authors.initials: Y
authors.lastname: Hiyoshi
authors.affiliation: Department of Surgery, Saiseikai Kumamoto Hospital, Kumamoto, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwatsuki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Iwagami
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sakamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Surgery, Saiseikai Kumamoto Hospital, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takamori
authors.affiliation: Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Araki
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D008297:Male; D009361:Neoplasm Invasiveness; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019012:Integrin beta1; D019718:Receptors, CXCR4; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: CXCL12; CXCR4; cancer-associated fibroblasts; gastric cancer; integrin β1