Abstract

Chemoresistance is a serious limitation of cancer treatment1. Until recently, almost all the work done to study this limitation has been restricted to tumour cells2. Here we identify a novel molecular mechanism by which endothelial cells regulate chemosensitivity. We establish that specific targeting of focal adhesion kinase (FAK; also known as PTK2) in endothelial cells is sufficient to induce tumour-cell sensitization to DNA-damaging therapies and thus inhibit tumour growth in mice. The clinical relevance of this work is supported by our observations that low blood vessel FAK expression is associated with complete remission in human lymphoma. Our study shows that deletion of FAK in endothelial cells has no apparent effect on blood vessel function per se, but induces increased apoptosis and decreased proliferation within perivascular tumour-cell compartments of doxorubicin- and radiotherapy-treated mice. Mechanistically, we demonstrate that endothelial-cell FAK is required for DNA-damage-induced NF-κB activation in vivo and in vitro, and the production of cytokines from endothelial cells. Moreover, loss of endothelial-cell FAK reduces DNA-damage-induced cytokine production, thus enhancing chemosensitization of tumour cells to DNA-damaging therapies in vitro and in vivo. Overall, our data identify endothelial-cell FAK as a regulator of tumour chemosensitivity. Furthermore, we anticipate that this proof-of-principle data will be a starting point for the development of new possible strategies to regulate chemosensitization by targeting endothelial-cell FAK specifically.

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Acknowledgements

We thank A. Papachristodoulou, J. Holdsworth and B. Williams for their help with immunostaining and animal husbandry. Also M. Hemann for his critical appraisal of the manuscript. The work was funded by CR-UK (C9218/A12007), AICR (12-1068), Medical Research Council (G0901609), National Cancer Institute (P01 CA95426:JGG); Leukemia Lymphoma Research (11022); and CR-UK PhD studentship (C1443/A9215).

Author information

Author notes

    • Louise E. Reynolds
    • , Silvia Batista
    • , Fevzi Demircioglu
    • , Isabelle Fernandez
    • , Tanguy Lechertier
    • , Delphine M. Lees
    •  & Ping-Pui Wong

    These authors contributed equally to this work.

Affiliations

  1. Adhesion 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

    • Bernardo Tavora
    • , Louise E. Reynolds
    • , Silvia Batista
    • , Fevzi Demircioglu
    • , Isabelle Fernandez
    • , Tanguy Lechertier
    • , Delphine M. Lees
    • , Ping-Pui Wong
    • , Annika Alexopoulou
    •  & Kairbaan M. Hodivala-Dilke
  2. Barts Cancer Institute, CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK

    • George Elia
  3. Centre for Haemato-Oncology, Barts Cancer Institute, CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK

    • Andrew Clear
    •  & John G. Gribben
  4. Institute for Cell and Molecular Biosciences (ICaMB), Medical School, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK

    • Adeline Ledoux
    • , Jill Hunter
    •  & Neil Perkins

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Contributions

The following authors are listed in the author list in alphabetical order: S.B., F.D., I.F., T.L., D.M.L. and P.-P.W. for their equal and combined contribution to the paper. B.T. and K.M.H.-D. designed the experiments. B.T. performed the experiments. L.E.R. did the GM-CSF rescue experiments in vivo, vessel perfusion, doxorubicin delivery, p-STAT3 staining and hypoxia assays. S.B. performed some of the tumour growth and treatment experiments, CD45 analysis, human lymphoma staining and irradiated cytokine responses; F.D. carried out the conditioned media experiments and MTS assays and several histological analyses; I.F. conducted the primary endothelial cell assays; T.L. measured endothelial-cell FAK and blood-vessel FAK levels in human lymphoma; D.M.L. did the transfections and nuclear fractionation experiments; P.-P.W. carried out the transfected cell cytokine arrays. G.E. carried out the histology; A.C. and J.G.G. provided human lymphoma tissue sections and advice; A.L., J.H. and N.P. performed the NF-κB activation assays and A.A. carried out the survival analysis. B.T. and K.M.H.-D. wrote the paper with substantial input from the co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kairbaan M. Hodivala-Dilke.

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DOI

https://doi.org/10.1038/nature13541

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