Browse by author
Lookup NU author(s): Dr Adeline Ledoux,
Dr Jill Hunter,
Professor Neil PerkinsORCiD
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
Chemoresistance is a serious limitation of cancer treatment(1). Until recently, almost all the work done to study this limitation has been restricted to tumour cells(2). 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-kappa B 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.
Author(s): Tavora B, Reynolds LE, Batista S, Demircioglu F, Fernandez I, Lechertier T, Lees DM, Wong PP, Alexopoulou A, Elia G, Clear A, Ledoux A, Hunter J, Perkins N, Gribben JG, Hodivala-Dilke KM
Publication type: Article
Publication status: Published
Print publication date: 02/10/2014
Online publication date: 27/07/2014
Acceptance date: 29/05/2014
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Publishing Group
Altmetrics provided by Altmetric