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PMID: 19654314 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

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

Cancer research ·Vol. 69 ·No. 16 ·2009-08-15 ·Pages 6721-9

Chen A, Cuevas I, Kenny PA, Miyake H, Mace K, Ghajar C, Boudreau A, Bissell MJ, Bissell M, Boudreau N

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 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.

MeSH Terms
Angiogenesis Inducing Agents/metabolism Cell Movement/genetics,physiology Cell Polarity/genetics,physiology Cell Proliferation Cell Transformation, Neoplastic/genetics,metabolism,pathology Cells, Cultured Cluster Analysis Endothelial Cells/metabolism,physiology Gene Expression Gene Expression Profiling Humans Hypoxia-Inducible Factor 1, alpha Subunit/genetics,metabolism Mammary Glands, Human/metabolism,pathology,physiology Models, Biological Neovascularization, Pathologic/genetics,metabolism Oligonucleotide Array Sequence Analysis Phenotype Vascular Endothelial Growth Factor A/genetics,metabolism
Chemicals
Angiogenesis Inducing Agents HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Vascular Endothelial Growth Factor A
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Chen Amy
Department of Surgery, University of California at San Francisco, 94143, USA.
Cuevas Ileana
Kenny Paraic A
Miyake Hiroshi
Mace Kimberley
Ghajar Cyrus
Boudreau Aaron
Bissell Mina J
Bissell Mina
Boudreau Nancy
References (49)
49 references, click to expand
  1. Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells.
    J Cell Biol. 2004 Feb 16;164(4):603-12 PMID: 14769856
  2. Hypoxia and oxidative stress in breast cancer. Hypoxia and tumourigenesis.
    Breast Cancer Res. 2001;3(5):318-22 PMID: 11597321
  3. The invasive phenotype in HMT-3522 cells requires increased EGF receptor signaling through both PI 3-kinase and ERK 1,2 pathways.
    Cell Commun Adhes. 2002 Mar-Apr;9(2):87-102 PMID: 12487410
  4. Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts.
    J Natl Cancer Inst. 2002 Oct 2;94(19):1494-503 PMID: 12359858
  5. Distinct angiogenic patterns are associated with high-grade in situ ductal carcinomas of the breast.
    J Pathol. 1997 Feb;181(2):207-12 PMID: 9120727
  6. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells.
    Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9064-8 PMID: 1384042
  7. Breast cancer-induced angiogenesis: multiple mechanisms and the role of the microenvironment.
    Breast Cancer Res. 2003;5(3):140-6 PMID: 12793895
  8. Antiangiogenic therapy for cancer: an update.
    Cancer J. 2007 Nov-Dec;13(6):345-8 PMID: 18032969
  9. beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium.
    Cancer Cell. 2002 Sep;2(3):205-16 PMID: 12242153
  10. Sustained expression of Hif-1alpha in the diabetic environment promotes angiogenesis and cutaneous wound repair.
    Wound Repair Regen. 2007 Sep-Oct;15(5):636-45 PMID: 17971009
  11. Tumor angiogenesis.
    Adv Cancer Res. 1974;19(0):331-58 PMID: 4605404
  12. Mitogen-activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells.
    Int J Cancer. 1999 Jul 19;82(2):268-73 PMID: 10389762
  13. Tumour biology: herceptin acts as an anti-angiogenic cocktail.
    Nature. 2002 Mar 21;416(6878):279-80 PMID: 11907566
  14. Angiogenesis as a biologic and prognostic indicator in human breast carcinoma.
    EXS. 1997;79:113-56 PMID: 9002231
  15. beta-Catenin regulates vascular endothelial growth factor expression in colon cancer.
    Cancer Res. 2003 Jun 15;63(12):3145-53 PMID: 12810642
  16. The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression.
    Mol Oncol. 2007 Jun;1(1):84-96 PMID: 18516279
  17. Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1.
    Int J Cancer. 2005 Jun 10;115(2):202-13 PMID: 15688401
  18. Increased Sp1 phosphorylation as a mechanism of hepatocyte growth factor (HGF/SF)-induced vascular endothelial growth factor (VEGF/VPF) transcription.
    J Cell Sci. 2003 Jan 15;116(Pt 2):225-38 PMID: 12482909
  19. HOXA10 regulates p53 expression and matrigel invasion in human breast cancer cells.
    Cancer Biol Ther. 2004 Jun;3(6):568-72 PMID: 15044858
  20. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.
    Nat Cell Biol. 2000 Oct;2(10):737-44 PMID: 11025665
  21. Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model.
    Cancer Res. 2005 Aug 15;65(16):7177-85 PMID: 16103068
  22. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets.
    J Biol Chem. 2003 Aug 8;278(32):29655-60 PMID: 12777372
  23. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice.
    Science. 2001 Aug 17;293(5533):1323-6 PMID: 11509733
  24. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast.
    Clin Cancer Res. 1999 May;5(5):1041-56 PMID: 10353737
  25. Macrophages define the invasive microenvironment in breast cancer.
    J Leukoc Biol. 2008 Sep;84(3):623-30 PMID: 18467655
  26. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma.
    Cell. 2008 Nov 28;135(5):865-78 PMID: 19041750
  27. Cancer: looking outside the genome.
    Nat Rev Mol Cell Biol. 2000 Oct;1(1):76-9 PMID: 11413493
  28. Targeting TACE-dependent EGFR ligand shedding in breast cancer.
    J Clin Invest. 2007 Feb;117(2):337-45 PMID: 17218988
  29. Summaries of Affymetrix GeneChip probe level data.
    Nucleic Acids Res. 2003 Feb 15;31(4):e15 PMID: 12582260
  30. Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: the role of extracellular matrix and its degrading enzymes.
    Cold Spring Harb Symp Quant Biol. 2005;70:343-56 PMID: 16869771
  31. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis.
    J Natl Cancer Inst. 2001 Feb 21;93(4):309-14 PMID: 11181778
  32. Regulation of mammalian translation factors by nutrients.
    Eur J Biochem. 2002 Nov;269(22):5338-49 PMID: 12423332
  33. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD.
    Cell. 2004 Feb 6;116(3):457-66 PMID: 15016379
  34. STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination.
    Exp Mol Med. 2008 Oct 31;40(5):479-85 PMID: 18985005
  35. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies.
    J Cell Biol. 1997 Apr 7;137(1):231-45 PMID: 9105051
  36. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms.
    Cancer Res. 2006 Mar 15;66(6):3197-204 PMID: 16540671
  37. Angiogenesis: the role of the microenvironment in flipping the switch.
    Curr Opin Genet Dev. 2001 Feb;11(1):35-40 PMID: 11163148
  38. HOXB7: a key factor for tumor-associated angiogenic switch.
    Cancer Res. 2001 Sep 1;61(17):6532-9 PMID: 11522651
  39. ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini.
    Nat Cell Biol. 2001 Sep;3(9):785-92 PMID: 11533657
  40. A new mathematical model for relative quantification in real-time RT-PCR.
    Nucleic Acids Res. 2001 May 1;29(9):e45 PMID: 11328886
  41. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes.
    Cancer Cell. 2004 Jul;6(1):7-10 PMID: 15261137
  42. Sustained expression of homeobox D10 inhibits angiogenesis.
    Am J Pathol. 2002 Dec;161(6):2099-109 PMID: 12466126
  43. Repression of vascular endothelial growth factor expression by the zinc finger transcription factor ZNF24.
    Cancer Res. 2007 Sep 15;67(18):8736-41 PMID: 17875714
  44. Molecular regulation of angiogenesis and lymphangiogenesis.
    Nat Rev Mol Cell Biol. 2007 Jun;8(6):464-78 PMID: 17522591
  45. HMEC-1: establishment of an immortalized human microvascular endothelial cell line.
    J Invest Dermatol. 1992 Dec;99(6):683-90 PMID: 1361507
  46. Regulation of STAT3 by direct binding to the Rac1 GTPase.
    Science. 2000 Oct 6;290(5489):144-7 PMID: 11021801
  47. Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells.
    J Cell Biol. 2002 Jul 8;158(1):165-74 PMID: 12105188
  48. Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology.
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14821-6 PMID: 9843973
  49. HIFs, hypoxia, and vascular development.
    Curr Top Dev Biol. 2004;62:37-54 PMID: 15522738
Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-08-4069
Published
2009-08-15
Epub
2009-00-04
Pages
6721-9
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC2760003
Subset
IM
Grants
NCI NIH HHS · R01CA064786 · United States
NCI NIH HHS · U54 CA126552 · United States
NCI NIH HHS · U54 CA112970 · United States
NCI NIH HHS · R01 CA057621 · United States
NCI NIH HHS · R01 CA064786-08 · United States
NCI NIH HHS · R01 CA064786 · United States
NCI NIH HHS · U54CA126552 · United States
NCI NIH HHS · U54CA112970 · United States
NCI NIH HHS · R01CA057621 · United States
NCI NIH HHS · U54 CA126552-03 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1158/0008-5472.CAN-08-4069 PMC Full Text View journal details
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