title: Identification and Characterization of CXCR4-Positive Gastric Cancer Stem Cells.
abstract: Diffuse-type solid tumors are often composed of a high proportion of rarely proliferating (i.e., dormant) cancer cells, strongly indicating the involvement of cancer stem cells (CSCs) Although diffuse-type gastric cancer (GC) patients have a poor prognosis due to high-frequent development of peritoneal dissemination (PD), it is limited knowledge that the PD-associated CSCs and efficacy of CSC-targeting therapy in diffuse-type GC. In this study, we established highly metastatic GC cell lines by in vivo selection designed for the enrichment of PD-associated GC cells. By microarray analysis, we found C-X-C chemokine receptor type 4 (CXCR4) can be a novel marker for highly metastatic CSCs, since CXCR4-positive cells can grow anchorage-independently, initiate tumors in mice, be resistant to cytotoxic drug, and produce differentiated daughter cells. In clinical samples, these CXCR4-positive cells were found from not only late metastasis stage (accumulated ascites) but also earlier stage (peritoneal washings). Moreover, treatment with transforming growth factor-β enhanced the anti-cancer effect of docetaxel via induction of cell differentiation/asymmetric cell division of the CXCR4-positive gastric CSCs even in a dormant state. Therefore, differentiation inducers hold promise for obtaining the maximum therapeutic outcome from currently available anti-cancer drugs through re-cycling of CSCs.
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan; Second Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Chiwaki
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Ryou-u
authors.initials: RU
authors.lastname: Takahashi
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Aoyagi
authors.affiliation: Division of Translational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tamaoki
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Komatsuzaki
authors.affiliation: Kanamecho Hospital, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsusaki
authors.affiliation: Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan; Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Fukagawa
authors.affiliation: Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Katai
authors.affiliation: Second Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konno
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C514936:CXCR4 protein, mouse; D019718:Receptors, CXCR4; D043823:Taxoids; D016212:Transforming Growth Factor beta; D000077143:Docetaxel