Identification and Characterization of CXCR4-Positive Gastric Cancer Stem Cells

• Published in: PloS one 2015-06, Vol.10 (6), p.e0130808-e0130808
• Main Authors: Fujita, Takeshi, Chiwaki, Fumiko, Takahashi, Ryou-u, Aoyagi, Kazuhiko, Yanagihara, Kazuyoshi, Nishimura, Takao, Tamaoki, Masashi, Komatsu, Masayuki, Komatsuzaki, Rie, Matsusaki, Keisuke, Ichikawa, Hitoshi, Sakamoto, Hiromi, Yamada, Yasuhide, Fukagawa, Takeo, Katai, Hitoshi, Konno, Hiroyuki, Ochiya, Takahiro, Yoshida, Teruhiko, Sasaki, Hiroki
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Ascites; Bone morphogenetic proteins; Breast cancer; Cancer; Cell cycle; Cell differentiation; Cell division; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical properties; Chemokines; CXCR4 protein; Cytotoxicity; Differentiation (biology); DNA microarrays; Gastric cancer; Growth factors; Hospitals; Humans; In vivo methods and tests; Leukemia; Medical prognosis; Medicine; Metastases; Metastasis; Mice; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; Patients; Peritoneum; Prognosis; Receptors, CXCR4 - metabolism; Solid tumors; Stem cell transplantation; Stem cells; Stomach cancer; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Surgery; Taxoids - pharmacology; Transforming growth factor; Transforming Growth Factor beta - pharmacology; Transforming growth factor-b; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0130808

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.