title: CD49f(high) cells retain sphere-forming and tumor-initiating activities in human gastric tumors.
abstract: Identification of gastric tumor-initiating cells (TICs) is essential to explore new therapies for gastric cancer patients. There are reports that gastric TICs can be identified using the cell surface marker CD44 and that they form floating spheres in culture, but we could not obtain consistent results with our patient-derived tumor xenograft (PDTX) cells. We thus searched for another marker for gastric TICs, and found that CD49f(high) cells from newly-dissected gastric cancers formed tumors with histological features of parental ones while CD49f(low) cells did not when subcutaneously injected into immunodeficient mice. These results indicate that CD49f, a subunit of laminin receptors, is a promising marker for human gastric TICs. We established a primary culture system for PDTX cells where only CD49f(high) cells could grow on extracellular matrix (ECM) to form ECM-attaching spheres. When injected into immunodeficient mice, these CD49f(high) sphere cells formed tumors with histological features of parental ones, indicating that only TICs could grow in the culture system. Using this system, we found that some sphere-forming TICs were more resistant than gastric tumor cell lines to chemotherapeutic agents, including doxorubicin, 5-fluorouracil and doxifluridine. There was a patient-dependent difference in the tumorigenicity of sphere-forming TICs and their response to anti-tumor drugs. These results suggest that ECM plays an essential role for the growth of TICs, and that this culture system will be useful to find new drugs targeting gastric TICs.
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukamachi
authors.forename: Hyang Sook
authors.initials: HS
authors.lastname: Seol
authors.forename: Shu
authors.initials: S
authors.lastname: Shimada
authors.forename: Chikako
authors.initials: C
authors.lastname: Funasaka
authors.forename: Kanako
authors.initials: K
authors.lastname: Baba
authors.forename: Ji Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Park
authors.forename: Mi Jeung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Keiji
authors.initials: K
authors.lastname: Kato
authors.forename: Mikito
authors.initials: M
authors.lastname: Inokuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.forename: Jeong Hwan
authors.initials: JH
authors.lastname: Yook
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kojima
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jang
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Yuasa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005467:Floxuridine / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D039503:Integrin alpha6 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D039503:Integrin alpha6; D005467:Floxuridine; D004317:Doxorubicin; D005472:Fluorouracil; C025034:doxifluridine