title: Fibroblast Growth Factor-2 facilitates the growth and chemo-resistance of leukemia cells in the bone marrow by modulating osteoblast functions.
abstract: Stromal cells and osteoblasts play major roles in forming and modulating the bone marrow (BM) hematopoietic microenvironment. We have reported that FGF2 compromises stromal cell support of normal hematopoiesis. Here, we examined the effects of FGF2 on the leukemia microenvironment. In vitro, FGF2 significantly decreased the number of stromal-dependent and stromal-independent G0-leukemia cells in the stromal layers. Accordingly, CML cells placed on FGF2-treated stromal layers were more sensitive to imatinib. Conversely, FGF2 increased the proliferation of osteoblasts via FGFR1 IIIc, but its effects on osteoblast support of leukemia cell growth were limited. We next treated a human leukemia mouse model with Ara-C with/without systemic FGF2 administration. BM sections from FGF2-treated mice had thickened bone trabeculae and increased numbers of leukemia cells compared to controls. Leukemia cell density was increased, especially in the endosteal region in FGF2/Ara-C -treated mice compared to mice treated with Ara-C only. Interestingly, FGF2 did not promote leukemia cell survival in Ara-C treated spleen. Microarray analysis showed that FGF2 did not alter expression of many genes linked to hematopoiesis in osteoblasts, but modulated regulatory networks involved in angiogenesis and osteoblastic differentiation. These observations suggest that FGF2 promotes leukemia cell growth in the BM by modulating osteoblast functions.
authors.affiliation: Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., Otsu, Shiga, Japan.
authors.forename: Keiki
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Departments of Hematology, Nagoya Medical Center, Nagoya, Aichi, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Miyata
authors.affiliation: Department of Transfusion Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Departments of Hematology, Japanese Red Cross Nagoya Daiini Hospital, Nagoya, Aichi, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Saito
authors.affiliation: Departments of Hematology, Shimane University, Izumo, Shimane, Japan.
authors.forename: Ritsuro
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Departments of Hematology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hayakawa
authors.affiliation: Depertment of Hematology and Oncology, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishiwaki
authors.affiliation: Laboratory of Cellular Dynamics, World Premier International Research Center Initiative-Immunology Frontier Research Center, Osaka University, Suita, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mizuno
authors.affiliation: Departments of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.affiliation: Department of Transfusion Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Tumor Immunology, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
authors.affiliation: Department of Hematology, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Takami
authors.affiliation: Departments of Hematology, Nagoya Medical Center, Nagoya, Aichi, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003561:Cytarabine; D016222:Fibroblast Growth Factor 2; D000068877:Imatinib Mesylate