Analysis of circulating tumor cells derived from advanced gastric cancer

• Published in: International journal of cancer 2015-08, Vol.137 (4), p.991-998
• Main Authors: Toyoshima, Kosei, Hayashi, Akira, Kashiwagi, Masahide, Hayashi, Naoko, Iwatsuki, Masaaki, Ishimoto, Takatsugu, Baba, Yoshifumi, Baba, Hideo, Ohta, Yoshikazu
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - biosynthesis; Biomarkers; Cancer; CD44; Cell Adhesion Molecules - biosynthesis; Cell Lineage; Cells; circulating tumor cells; Epithelial Cell Adhesion Molecule; Gastric cancer; Gene Expression Regulation, Neoplastic; Heterografts; HIV; Human immunodeficiency virus; Humans; Hyaluronan Receptors - biosynthesis; Leukocyte Common Antigens - biosynthesis; Leukocyte Common Antigens - blood; Medical research; Mice; Neoplastic Cells, Circulating - metabolism; Neoplastic Cells, Circulating - pathology; Prognosis; Stomach Neoplasms - blood; Stomach Neoplasms - pathology; tumorigenicity; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29455

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. What's new? Circulating tumor cells (CTCs) are found in the peripheral blood of metastatic cancer patients, and may offer prognostic biomarkers for several types of cancer. In this study, the authors evaluated whether CTCs from advanced gastric cancer patients are actually tumorigenic. Injecting peripheral blood mononuclear cells (PBMCs) from these patients into mice produced tumors, while PBMCs from healthy volunteers did not. CTCs from gastric cancer patients may thus offer a potential therapeutic target, as well as a tool for further investigation.