1. Endothelial Cell Migration and Vascular Endothelial Growth Factor Expression Are the Result of Loss of Breast Tissue Polarity
- Author
-
Amy, Chen, Ileana, Cuevas, Paraic A, Kenny, Hiroshi, Miyake, Kimberley, Mace, Cyrus, Ghajar, Aaron, Boudreau, Mina J, Bissell, Mina, Bissell, and Nancy, Boudreau
- Subjects
Vascular Endothelial Growth Factor A ,Cancer Research ,medicine.medical_specialty ,Angiogenic Switch ,Endothelium ,Gene Expression ,Biology ,Models, Biological ,Article ,chemistry.chemical_compound ,Cell Movement ,Internal medicine ,Cell polarity ,medicine ,Cluster Analysis ,Humans ,Mammary Glands, Human ,Cells, Cultured ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,Neovascularization, Pathologic ,Gene Expression Profiling ,Cell Polarity ,Endothelial Cells ,Cell migration ,Hypoxia-Inducible Factor 1, alpha Subunit ,Endothelial stem cell ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Endocrinology ,Cell Transformation, Neoplastic ,Phenotype ,Oncology ,chemistry ,Tumor progression ,Cancer research ,Angiogenesis Inducing Agents - 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, growth-arrested 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. [Cancer Res 2009;69(16):6721–9]
- Published
- 2009