Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells

Oncotarget. 2015 Apr 30;6(12):10016-29. doi: 10.18632/oncotarget.3540.

Abstract

Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.

Keywords: Stat3; Stat3 inhibitor; VEGFR2; brain endothelial cells; brain metastasis.

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

  • Animals
  • Brain Neoplasms / prevention & control
  • Brain Neoplasms / secondary*
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Communication / drug effects*
  • Cell Communication / physiology
  • Cell Line, Tumor
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology*
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Pyridines / pharmacology*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism*
  • Tyrphostins / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / biosynthesis
  • Xenograft Model Antitumor Assays

Substances

  • Pyridines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tyrphostins
  • WP1066
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2