Tumour angiogenesis regulation by the miR-200 family

Nat Commun. 2013;4:2427. doi: 10.1038/ncomms3427.

Abstract

The miR-200 family is well known to inhibit the epithelial-mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200's role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Cell Movement / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Regulatory Networks / drug effects
  • Humans
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Lung Neoplasms / secondary
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Biological
  • Nanoparticles / administration & dosage
  • Neoplasm Metastasis
  • Neoplasms / blood supply*
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / genetics*
  • Oligonucleotides / pharmacology
  • Oligonucleotides / therapeutic use
  • Pericytes / drug effects
  • Pericytes / pathology
  • Treatment Outcome

Substances

  • Angiogenesis Inhibitors
  • Interleukin-8
  • MIRN200 microRNA, human
  • MicroRNAs
  • Oligonucleotides