Endothelial cell migration and vascular endothelial growth factor expression are the result of loss of breast tissue polarity

Amy Chen, Ileana Cuevas, Paraic A. Kenny, Hiroshi Miyake, Kimberley Mace, Cyrus Ghajar, Aaron Boudreau, Mina Bissell, Nancy Boudreau

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Recruiting a new blood supply is a rate-limiting step in tumor progression. In a three-dimensional model of breast carcinogenesis, disorganized, proliferative transformed breast epithelial cells express significantly higher expression of angiogenic genes compared with their polarized, growtharrested nonmalignant counterparts. Elevated vascular endothelial growth factor (VEGF) secretion by malignant cells enhanced recruitment of endothelial cells (EC) in heterotypic cocultures. Significantly, phenotypic reversion of malignant cells via reexpression of HoxD10, which is lost in malignant progression, significantly attenuated VEGF expression in a hypoxia-inducible factor 1α-independent fashion and reduced EC migration. This was due primarily to restoring polarity: forced proliferation of polarized, nonmalignant cells did not induce VEGF expression and EC recruitment, whereas disrupting the architecture of growth-arrested, reverted cells did. These data show that disrupting cytostructure activates the angiogenic switch even in the absence of proliferation and/or hypoxia and restoring organization of malignant clusters reduces VEGF expression and EC activation to levels found in quiescent nonmalignant epithelium. These data confirm the importance of tissue architecture and polarity in malignant progression.

Original languageEnglish (US)
Pages (from-to)6721-6729
Number of pages9
JournalCancer research
Volume69
Issue number16
DOIs
StatePublished - Aug 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chen, A., Cuevas, I., Kenny, P. A., Miyake, H., Mace, K., Ghajar, C., Boudreau, A., Bissell, M., & Boudreau, N. (2009). Endothelial cell migration and vascular endothelial growth factor expression are the result of loss of breast tissue polarity. Cancer research, 69(16), 6721-6729. https://doi.org/10.1158/0008-5472.CAN-08-4069