MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells.

TitleMicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsPlummer PN, Freeman R, Taft RJ, Vider J, Sax M, Umer BA, Gao D, Johns C, Mattick JS, Wilton SD, Ferro V, McMillan NAJ, Swarbrick A, Mittal V, Mellick AS
JournalCancer Res
Volume73
Issue1
Pagination341-52
Date Published2013 Jan 01
ISSN1538-7445
KeywordsAnimals, Bone Marrow Cells, Breast Neoplasms, Carcinoma in Situ, Carcinoma, Ductal, Breast, Carcinoma, Lewis Lung, Cell Differentiation, Endothelial Cells, Female, Flow Cytometry, Humans, Immunohistochemistry, In Situ Hybridization, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, Neovascularization, Pathologic, Polymerase Chain Reaction, Stem 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.

DOI10.1158/0008-5472.CAN-12-0271
Alternate JournalCancer Res
PubMed ID22836757