title: Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity.
abstract: Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cells within cancer that contribute to cancer initiation and progression. Cancer-associated fibroblasts (CAFs) are stromal fibroblasts surrounding tumor cells, and they have important roles in tumor growth and tumor progression. It has been suggested that stromal fibroblasts and CSCs/CICs might mutually cooperate to enhance their growth and tumorigenic capacity. In this study, we investigated the effects of fibroblasts on tumor-initiating capacity and stem-like properties of ovarian CSCs/CICs. CSCs/CICs were isolated from the ovarian carcinoma cell line HTBoA as aldehyde dehydrogenase 1 high (ALDH1(high)) population by the ALDEFLUOR assay. Histological examination of tumor tissues derived from ALDH1(high) cells revealed few fibrous stroma, whereas those derived from fibroblast-mixed ALDH1(high) cells showed abundant fibrous stroma formation. In vivo tumor-initiating capacity and in vitro sphere-forming capacity of ALDH1(high) cells were enhanced in the presence of fibroblasts. Gene expression analysis revealed that fibroblast-mixed ALDH1(high) cells had enhanced expression of fibroblast growth factor 4 (FGF4) as well as stemness-associated genes such as SOX2 and POU5F1. Sphere-forming capacity of ALDH1(high) cells was suppressed by small-interfering RNA (siRNA)-mediated knockdown of FGFR2, the receptor for FGF4 which was expressed preferentially in ALDH1(high) cells. Taken together, the results indicate that interaction of fibroblasts with ovarian CSCs/CICs enhanced tumor-initiating capacity and stem-like properties through autocrine and paracrine FGF4-FGFR2 signaling.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.affiliation: 1] Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan [2] Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Mariya
authors.affiliation: 1] Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan [2] Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Asano
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kuroda
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsuzaki
authors.affiliation: Department of Plastic and Reconstructive Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Plastic and Reconstructive Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamauchi
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Emori
authors.affiliation: Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Asanuma
authors.affiliation: Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D051519:Fibroblast Growth Factor 4 / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000401:mortality / Q000473:pathology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000502:physiology; D050697:Retinal Dehydrogenase / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: C496445:FGF4 protein, human; D051519:Fibroblast Growth Factor 4; D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D051497:Receptor, Fibroblast Growth Factor, Type 2