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Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in

Iris Helfrich1, Inka Scheffrahn, Sönke Bartling

  • 1Department of Dermatology, University Hospital Essen, Essen, Germany. iris.helfrich@uk-essen.de

The Journal of Experimental Medicine
|March 3, 2010
PubMed

Insights

Vessel maturation, including pericyte coverage, influences anti-angiogenic therapy response in melanoma. Mature vessels resist vascular endothelial growth factor (VEGF) inhibitors, suggesting new combination therapy strategies.

Area of Science:

  • Oncology
  • Vascular Biology
  • Cancer Therapy

Background:

  • Angiogenesis, crucial for tumor growth, involves endothelial cell proliferation and pericyte stabilization.
  • Current anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) have limited clinical efficacy.
  • The role of vessel maturation in therapeutic response remains incompletely understood.

Purpose of the Study:

  • To investigate the hypothesis that vessel maturation level impacts response to anti-angiogenic therapies in melanoma.
  • To evaluate vascular networks in a murine melanoma model and human melanoma metastases.

Main Methods:

  • Treatment of MT/ret transgenic mice with melanomas using PTK787/ZK222584 (anti-VEGF therapy).
  • Analysis of human melanoma metastases from patients at clinical relapse during bevacizumab treatment.
  • Assessment of vascular characteristics including vessel diameter, pericyte coverage, and specific marker expression (desmin, NG-2, PDGF-βR, α-SMA).

Main Results:

  • Tumor vessels resistant to anti-VEGF therapy exhibited increased diameter and mature pericyte coverage.
  • Resistant vessels showed immunoreactivity for desmin, NG-2, platelet-derived growth factor receptor beta, and alpha smooth muscle actin.
  • Vessel mural cell differentiation and vascular wall stabilization correlated with resistance to anti-angiogenic therapy.

Conclusions:

  • Vessel maturation and stabilization are critical determinants of response to anti-angiogenic therapy in melanoma.
  • Findings support the development of rational, second-generation anti-angiogenic combination therapies.
  • A novel murine model is provided for studying anti-angiogenic therapy resistance in melanoma.

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