Endothelial cell migration and vascular endothelial growth factor expression are the result of loss of breast tissue polarity.
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 1alpha-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.
Chen
Amy
A
Department of Surgery, University of California at San Francisco, 94143, USA.
Cuevas
Ileana
I
Kenny
Paraic A
PA
Miyake
Hiroshi
H
Mace
Kimberley
K
Ghajar
Cyrus
C
Boudreau
Aaron
A
Bissell
Mina J
MJ
Bissell
Mina
M
Boudreau
Nancy
N
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016000:Cluster Analysis; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A