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Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
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Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy

Bernardo Tavora1, Louise E Reynolds2, Silvia Batista2

  • 1Adhesion and Angiogenesis Laboratory, Centre for Tumour Biology, Barts Cancer Institute, CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

Nature
|August 1, 2014
PubMed

Insights

Targeting focal adhesion kinase (FAK) in endothelial cells enhances tumor cell sensitivity to chemotherapy. This novel mechanism inhibits tumor growth and shows clinical relevance in human lymphoma remission.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Endothelial Cell Biology

Background:

  • Chemoresistance remains a significant obstacle in cancer therapy.
  • Previous research primarily focused on tumor cells, overlooking other cellular contributions.
  • Endothelial cells play a crucial, yet understudied, role in regulating treatment efficacy.

Purpose of the Study:

  • To identify novel molecular mechanisms by which endothelial cells influence cancer chemoresistance.
  • To investigate the role of focal adhesion kinase (FAK) in endothelial cells in regulating tumor cell sensitivity to DNA-damaging therapies.
  • To explore the therapeutic potential of targeting endothelial FAK for improved cancer treatment outcomes.

Main Methods:

  • Genetic deletion of FAK in endothelial cells in mouse models.
  • Administration of DNA-damaging therapies (doxorubicin, radiotherapy).
  • Assessment of tumor growth, apoptosis, proliferation, and NF-κB activation.
  • Analysis of cytokine production in endothelial cells in vitro and in vivo.
  • Correlation of FAK expression with clinical remission in human lymphoma patients.

Main Results:

  • Targeting FAK in endothelial cells sensitized tumor cells to DNA-damaging agents, inhibiting tumor growth in mice.
  • Endothelial FAK deletion did not impair blood vessel function but enhanced tumor cell apoptosis and reduced proliferation.
  • Endothelial FAK is essential for DNA-damage-induced NF-κB activation and subsequent cytokine production, which are reduced upon FAK loss.

Conclusions:

  • Endothelial cell FAK is a critical regulator of tumor chemoresistance.
  • Targeting endothelial FAK represents a novel strategy to enhance the efficacy of DNA-damaging cancer therapies.
  • Low FAK expression in tumor vasculature correlates with complete remission in human lymphoma, supporting clinical relevance.

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