| Abstract: |
Fibroblast growth factors (FGFs) are important regulators of hematopoiesis and have been implicated in the tumorigenesis of solid tumors. Recent evidence suggests that FGF signaling through FGF receptors (FGFRs) may play a role in the proliferation of subsets of acute myeloid leukemias (AMLs). However, the precise mechanism and specific FGF receptors that support leukemic cell growth are not known. We show that FGF-2, through activation of FGFR1β signaling, promotes survival, proliferation and migration of AML cells. Stimulation of FGFR1β results in phosphoinositide 3-kinase (PI3-K)/Akt activation and inhibits chemotherapy-induced apoptosis of leukemic cells. Neutralizing FGFR1-specific antibody abrogates the physiologic and chemoprotective effects of FGF-2/FGFR1β signaling and inhibits tumor growth in mice xenotransplanted with human AML. These data suggest that activation of FGF-2/FGFR1β supports progression and chemoresistance in subsets of AML. Therefore, FGFR1 targeting may be of therapeutic benefit in subsets of AML. © 2006 Nature Publishing Group. All rights reserved. |
| Keywords: |
signal transduction; cancer chemotherapy; controlled study; aged; aged, 80 and over; intercellular signaling peptides and proteins; acute granulocytic leukemia; human cell; genetics; nonhuman; drug targeting; chemotherapy; antineoplastic agent; protein function; cell proliferation; animal cell; mouse; animal; metabolism; mouse mutant; animals; mice; animal tissue; cell survival; gene targeting; apoptosis; cell growth; antineoplastic combined chemotherapy protocols; animal experiment; animal model; cell motion; drug effect; drug resistance; drug screening; drug resistance, neoplasm; mice, scid; tumor cells, cultured; xenograft model antitumor assays; cell line, tumor; phosphorylation; phosphatidylinositol 3 kinase; fibroblast growth factor 2; gene activation; cell culture; messenger rna; rna, messenger; signal peptide; leukemia cell; leukemia, myeloid; tumor cell line; cell migration; cell movement; antibodies; protein subunit; protein subunits; cell stimulation; antibody; fibroblast growth factor; receptor, fibroblast growth factor, type 1; fibroblast growth factor receptor 1; acute disease; growth inhibition; cell signaling; myeloid leukemia; animal studies; neutralizing antibody; fibroblast growth factor receptor; acute myeloid leukemia; xenotransplantation; agouti related protein; agouti-related protein; fgfr1 protein, human
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