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Journal of Molecular Medicine

, Volume 85, Issue 11, pp 1175–1186 | Cite as

Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome

  • Jose G. Teodoro
  • Sara K. Evans
  • Michael R. Green
Review

Abstract

The p53 tumor suppressor protein has long been recognized as the central factor protecting humans from cancer. It has been famously dubbed “the guardian of the genome” due to its ability to respond to genotoxic stress, such as DNA damage and other stress signals, and to protect the genome by inducing a variety of biological responses including DNA repair, cell cycle arrest, and apoptosis. However, the tumor suppressive effects of p53 go far beyond its roles in mediating these three processes. There is growing evidence that p53 also exerts its effects on multiple aspects of tumor formation, including suppression of metastasis and, as summarized in this review, inhibition of new blood vessel development (angiogenesis). The p53 protein has been shown to limit angiogenesis by at least three mechanisms: (1) interfering with central regulators of hypoxia that mediate angiogenesis, (2) inhibiting production of proangiogenic factors, and (3) directly increasing the production of endogenous angiogenesis inhibitors. The combination of these effects allows p53 to efficiently shut down the angiogenic potential of cancer cells. Inactivation of p53, which occurs in approximately half of all tumors, reverses these effects; as a consequence, tumors carrying p53 mutations appear more vascularized and are often more aggressive and correlate with poor prognosis for treatment. Thus, the loss of functional p53 during tumorigenesis likely represents an essential step in the switch to an angiogenic phenotype that is displayed by aggressive tumors.

Keywords

p53 tumor suppressor protein Tumor biology Hypoxia Collagen Angiogenic switch Angiogenesis inhibitors 

Abbreviations

MVD

microvessel density

HIF

hypoxia inducible factor

VEGF

vascular endothelial growth factor

PHD

prolyl hydroxylase

HRE

hypoxia responsive element

bFGF

basic fibroblast growth factor

bFGF-BP

bFGF-binding protein

COX-2

cyclooxygenase-2

ECM

extracellular matrix

TSP-1

thrombospondin-1

TGF-β

transforming growth factor-beta

BAI1

brain angiogenesis inhibitor 1

TSRs

thrombospondin type 1 repeats

GD-AIF

glioma-derived angiogenesis inhibitory factor

EPHA2

ephrin receptor A2

α(II)PH

α(II) 4-prolyl hydroxylase

NC1

noncollagen 1

BM

basement membrane

Notes

Acknowledgements

J.G.T. was supported by postdoctoral fellowships from the National Cancer Institute of Canada and the Medical Foundation Charles A. King Trust. M.R.G. is an investigator of the Howard Hughes Medical Institute.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Jose G. Teodoro
    • 1
  • Sara K. Evans
    • 2
  • Michael R. Green
    • 2
  1. 1.McGill Cancer Centre and Department of BiochemistryMcGill UniversityMontrealCanada
  2. 2.Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA

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