title: MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells.
abstract: Bone marrow-derived endothelial progenitor cells (EPC) contribute to the angiogenesis-dependent growth of tumors in mice and humans. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. miRNAs have emerged as key regulators of several cellular processes including angiogenesis; however, whether miRNAs contribute to bone marrow-mediated angiogenesis has remained unknown. Here, we show that genetic ablation of miRNA-processing enzyme Dicer, specifically in the bone marrow, decreased the number of circulating EPCs, resulting in angiogenesis suppression and impaired tumor growth. Furthermore, genome-wide deep sequencing of small RNAs revealed tumor EPC-intrinsic miRNAs including miR-10b and miR-196b, which have been previously identified as key regulators of HOX signaling and adult stem cell differentiation. Notably, we found that both miR-10b and miR-196b are responsive to vascular endothelial growth factor stimulation and show elevated expression in human high-grade breast tumor vasculature. Strikingly, targeting miR-10b and miR-196b led to significant defects in angiogenesis-mediated tumor growth in mice. Targeting these miRNAs may constitute a novel strategy for inhibiting tumor angiogenesis.
authors: School of Medical Science, Griffith University, Parklands Dr, Gold Coast, Australia.
authors: Prue N
authors: PN
authors: Plummer
authors: Ruth
authors: R
authors: Freeman
authors: Ryan J
authors: RJ
authors: Taft
authors: Jelena
authors: J
authors: Vider
authors: Michael
authors: M
authors: Sax
authors: Brittany A
authors: BA
authors: Umer
authors: Dingcheng
authors: D
authors: Gao
authors: Christopher
authors: C
authors: Johns
authors: John S
authors: JS
authors: Mattick
authors: Stephen D
authors: SD
authors: Wilton
authors: Vito
authors: V
authors: Ferro
authors: Nigel A J
authors: NA
authors: McMillan
authors: Alexander
authors: A
authors: Swarbrick
authors: Vivek
authors: V
authors: Mittal
authors: Albert S
authors: AS
authors: Mellick
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018827:Carcinoma, Lewis Lung; D002454:Cell Differentiation / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D035683:MicroRNAs