Platelet releasate promotes breast cancer growth and angiogenesis via VEGF-integrin cooperative signalling

Br J Cancer. 2017 Aug 22;117(5):695-703. doi: 10.1038/bjc.2017.214. Epub 2017 Jul 11.


Background: Selective platelet release of pro- or anti-angiogenic factors distinctly regulated angiogenesis. We hypothesised that selective release of platelet angiogenic factors could differently regulate tumour growth.

Methods: Breast cancer cell proliferation, cancer cell-induced endothelial tube formation in vitro, and tumour growth in vivo were studied in the presence of protease-activated receptor 1-stimulated platelet releasate (PAR1-PR; rich in pro-angiogenic factors) or PAR4-PR (rich in anti-angiogenic factors).

Results: The PAR1-PR and PAR4-PR supplementation (10%) similarly enhanced cell proliferation of MCF-7 and MDA-MB-231 breast cancer cells. The cancer cells triggered capillary-like tube formation of endothelial cells that was further enhanced by pro-angiogenic factor-rich PAR1-PR. The VEGF, but not SDF-1α, receptor blockade abolished PAR1-PR/PAR4-PR-enhanced cancer cell proliferation. Integrin blockade by RGDS had identical effects as VEGF inhibition. The Src and ERK inhibition diminished, whereas PI3K and PKC blockade abolished platelet releasate-enhanced cancer cell proliferation. Using a model of subcutaneous implantation of MDA-MB-231 cells in nude mice, PAR1-PR enhanced tumour growth more markedly than PAR4-PR, and seemed to achieve the exaggeration by promoting more profound tumour angiogenesis.

Conclusions: Platelet releasate increases breast cancer cell proliferation through VEGF-integrin cooperative signalling. Pro-angiogenic factor-rich platelet releasate enhances cancer cell-induced angiogenesis more markedly, and thus exaggerates tumour growth in vivo.

MeSH terms

  • Adult
  • Animals
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism*
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology
  • Female
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Integrins / antagonists & inhibitors
  • Integrins / metabolism*
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neovascularization, Pathologic / metabolism*
  • Oligopeptides / pharmacology
  • Phenylurea Compounds / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase C / metabolism
  • Quinolines / pharmacology
  • Receptor, PAR-1 / metabolism*
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, Thrombin / metabolism*
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors


  • CXCR4 protein, human
  • Integrins
  • N-(2,4-difluorophenyl)-N'-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-fluorophenyl)urea
  • Oligopeptides
  • Phenylurea Compounds
  • Quinolines
  • Receptor, PAR-1
  • Receptors, CXCR4
  • Receptors, Thrombin
  • Vascular Endothelial Growth Factor A
  • arginyl-glycyl-aspartyl-serine
  • Phosphatidylinositol 3-Kinases
  • Vascular Endothelial Growth Factor Receptor-2
  • Protein Kinase C
  • protease-activated receptor 4