title: Analysis of circulating tumor cells derived from advanced gastric cancer.
abstract: Studies in circulating tumor cells (CTCs) have proceeded to be accepted as prognostic markers in several types of cancers. But they are still limited because many are mainly from enumeration of CTCs. Here, we tried to evaluate the tumorigenicity of CTCs from advanced gastric cancer patients (n = 42). Peripheral blood mononuclear cells (PBMC) from the patients were separated into CD45 negative and positive fractions and both were subcutaneously injected into immunodeficient mice. Within 5 months nine tumor-like-structures from six patients but not from healthy volunteers were established. They were durable for passages and all had been confirmed human origin. Eight of the nine tumor-like-structures were from nonauthorized CTC containing cells expressing CD45 and B-cell markers. On the contrary, one of them was developed from CD45(-) PBMC fraction of a patient with bone marrow metastasis reflecting authorized CTCs. Histopathology showed common features with that of original gastric tumor. The cells isolated from the tumor-like-structure expressed EpCAM and CEA further supporting they were from the original tumor. Moreover the cells were CD44 positive to varying degree and a limiting dilution study showed that the CD44(+/high) fraction had tumorigenicity. The CD44 was dominantly in the form of CD44 variant 8-10. The CD44(+/high) cells had higher expression of the glutamate/cysteine transporter xCT compared with the CD44(-/low) cells. Our results showed the existence of tumor-initiating cells in blood of advanced gastric cancer patients and they could be a therapeutic target and prospective tool for further investigations.
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, 251-8555, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Toyoshima
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, 251-8555, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, 251-8555, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Kashiwagi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-0811, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-0811, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwatsuki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-0811, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-0811, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, 860-0811, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, 251-8555, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohta
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D019070:Cell Lineage; D000071858:Epithelial Cell Adhesion Molecule; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000097:blood; D051379:Mice; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D013274:Stomach Neoplasms / Q000097:blood* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human
keywords: CD44; circulating tumor cells; gastric cancer; tumorigenicity