PLoS ONE (Jan 2015)

Identification and Characterization of CXCR4-Positive Gastric Cancer Stem Cells.

  • Takeshi Fujita,
  • Fumiko Chiwaki,
  • Ryou-u Takahashi,
  • Kazuhiko Aoyagi,
  • Kazuyoshi Yanagihara,
  • Takao Nishimura,
  • Masashi Tamaoki,
  • Masayuki Komatsu,
  • Rie Komatsuzaki,
  • Keisuke Matsusaki,
  • Hitoshi Ichikawa,
  • Hiromi Sakamoto,
  • Yasuhide Yamada,
  • Takeo Fukagawa,
  • Hitoshi Katai,
  • Hiroyuki Konno,
  • Takahiro Ochiya,
  • Teruhiko Yoshida,
  • Hiroki Sasaki

DOI
https://doi.org/10.1371/journal.pone.0130808
Journal volume & issue
Vol. 10, no. 6
p. e0130808

Abstract

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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.