Publication Date:
2014-08-01
Description:
Chemoresistance is a serious limitation of cancer treatment. Until recently, almost all the work done to study this limitation has been restricted to tumour cells. 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-kappaB 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533916/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533916/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tavora, Bernardo -- Reynolds, Louise E -- Batista, Silvia -- Demircioglu, Fevzi -- Fernandez, Isabelle -- Lechertier, Tanguy -- Lees, Delphine M -- Wong, Ping-Pui -- Alexopoulou, Annika -- Elia, George -- Clear, Andrew -- Ledoux, Adeline -- Hunter, Jill -- Perkins, Neil -- Gribben, John G -- Hodivala-Dilke, Kairbaan M -- 12007/Cancer Research UK/United Kingdom -- C9218/A12007/Cancer Research UK/United Kingdom -- G0901609/Medical Research Council/United Kingdom -- P01 CA081534/CA/NCI NIH HHS/ -- P01 CA95426/CA/NCI NIH HHS/ -- England -- Nature. 2014 Oct 2;514(7520):112-6. doi: 10.1038/nature13541. Epub 2014 Jul 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; 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 [2]. ; Barts Cancer Institute, CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. ; Centre for Haemato-Oncology, Barts Cancer Institute, CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. ; Institute for Cell and Molecular Biosciences (ICaMB), Medical School, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079333" target="_blank"〉PubMed〈/a〉
Keywords:
Active Transport, Cell Nucleus/drug effects
;
Animals
;
Apoptosis/drug effects/radiation effects
;
Cell Nucleus/drug effects/metabolism
;
Cell Proliferation/drug effects/radiation effects
;
Cytokines/biosynthesis
;
*DNA Damage/drug effects/genetics
;
Doxorubicin/pharmacology/therapeutic use
;
Drug Resistance, Neoplasm/*drug effects/genetics
;
Endothelial Cells/*drug effects/*enzymology/metabolism
;
Focal Adhesion Protein-Tyrosine Kinases/deficiency/genetics/*metabolism
;
Humans
;
Mice
;
NF-kappa B/metabolism
;
Neoplasms/drug therapy/genetics/pathology/radiotherapy
;
Phosphorylation/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
