Editors' ChoiceCancer

Chemoresistance Mediated by the Endothelium

Science Signaling  07 Oct 2014:
Vol. 7, Issue 346, pp. ec275
DOI: 10.1126/scisignal.2005999

Targeting the blood vessels to prevent their formation is not a new strategy in cancer therapy. However, this approach can have unintended negative effects for treatment, such as preventing delivery of immune cells or drugs targeting the tumor cells. Using tumor xenograft models in mice, Tavora et al. allowed the tumors to grow and then knocked out focal adhesion kinase (FAK)—a kinase that regulates cell adhesion and motility as well as transcription, depending on its intracellular location—specifically in the endothelial cells (ECFAKKO). DNA-damaging therapies (doxorubicin or irradiation) inhibited tumor growth more effectively in the ECFAKKO mice than in the control ECFAKWT mice. Analysis of the tumors near the vessels revealed an increase in apoptotic cells and a reduction in proliferating cells in the therapy-treated ECFAKKO mice. Conditioned medium from FAK-null or wild-type endothelial cells exposed to either of the DNA-damaging conditions either sensitized (FAK-null) or protected (wild-type) tumor cells in culture from DNA-damaging treatments, suggesting that the endothelial cells release factors that alter the tumor’s response. Transcriptional analysis of genes encoding cytokines showed that doxorubicin induced an increase in cytokine gene expression in the FAK wild-type endothelial cells but not in the FAK-null cells. Many cytokine genes are regulated by the transcription factor nuclear factor κB (NF-κB). Endothelial cells exhibited FAK-dependent induction of an NF-κB reporter gene and nuclear translocation of NF-κB in response to doxorubicin. Increased nuclear localization of NF-κB was also observed in the wild-type tumor-associated endothelium, but not in the FAK-null endothelium in mice exposed to doxorubicin. Consistent with the tumors responding to the cytokines produced by the endothelial cells in response to DNA-damaging treatments, tumors of the treated ECFAKWT mice, but not those of the ECFAKKO mice, had an increased proportion of cells with phosphorylated STAT3, a cytokine signaling mediator. Analysis of lymphoma patient samples showed that resistance to doxorubicin treatment correlated with a high abundance of FAK in the endothelium. Comparison of patient samples before and after relapse showed an increase in the abundance of endothelial cell FAK in the samples taken after relapse. Thus, DNA-damaging therapies stimulate endothelial cells to produce FAK-dependent prosurvival signals to the tumors, suggesting that blocking these signals rather than inhibiting blood vessel growth may enhance the efficacy of DNA-damaging therapies.

B. Tavora, L. E. Reynolds, S. Batista, F. Demircioglu, I. Fernandez, T. Lechertier, D. M. Lees, P.-P. Wong, A. Alexopoulou, G. Elia, A. Clear, A. Ledoux, J. Hunter, N. Perkins, J. G. Gribben, K. M. Hodivala-Dilke, Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy. Nature 514, 112–116 (2014). [PubMed]

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