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TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity

Marina Stantic1, Habib A M Sakil1, Hanna Zirath1

  • 1Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.

Proceedings of the National Academy of Sciences of the United States of America
|December 24, 2014
PubMed

Insights

The tumor suppressor TAp73 regulates blood vessel formation in tumors. Loss of TAp73 promotes tumor angiogenesis, while the oncogenic ΔNp73 isoform drives it, impacting cancer progression.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • The p53-family member TAp73 acts as a tumor suppressor, regulating cell cycle and apoptosis.
  • The role of TAp73 in tumor angiogenesis remains largely unexplored.
  • Aberrant p73 isoform expression is implicated in various cancers.

Purpose of the Study:

  • To investigate the role of TAp73 in tumor angiogenesis.
  • To elucidate the mechanisms by which TAp73 influences blood vessel formation in tumors.
  • To examine the interplay between TAp73, ΔNp73, and angiogenic pathways.

Main Methods:

  • Analysis of tumor vascularization in TAp73-deficient models.
  • Assessment of endothelial cell junction integrity.
  • Correlation of ΔNp73 expression with angiogenesis in human breast cancer samples.
  • Investigation of HIF-1α pathway activation.

Main Results:

  • Loss of TAp73 leads to highly vascularized tumors with increased vessel permeability due to disrupted endothelial-cadherin junctions.
  • The oncogenic ΔNp73 isoform promotes blood vessel formation.
  • Elevated ΔNp73 levels correlate with increased angiogenesis in human breast cancer.
  • TAp73 inhibition causes HIF-1α accumulation and up-regulation of its target genes.

Conclusions:

  • TAp73 acts as a negative regulator of tumor angiogenesis by repressing proangiogenic factors.
  • Dysregulation of TAp73 and ΔNp73 balance is critical for activating the angiogenic switch.
  • Targeting TAp73 or ΔNp73 may offer therapeutic strategies for inhibiting tumor growth and progression.
Keywords:
HIF-1 alphaangiogenesisp73tumor microenvironmentvascular permeability

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