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Review
. 2016 Aug 1;22(15):3718-24.
doi: 10.1158/1078-0432.CCR-14-2021. Epub 2016 Jun 4.

Molecular Pathways: Endothelial Cell FAK-A Target for Cancer Treatment

Marina Roy-Luzarraga  1 , Kairbaan Hodivala-Dilke  2
Affiliations
Review

Molecular Pathways: Endothelial Cell FAK-A Target for Cancer Treatment

Marina Roy-Luzarraga et al. Clin Cancer Res. .

Abstract

The nonreceptor protein tyrosine kinase, focal adhesion kinase (FAK, also known as PTK2), is a key mediator of signal transduction downstream of integrins and growth factor receptors in a variety of cells, including endothelial cells. FAK is upregulated in several advanced-stage solid tumors and has been described to promote tumor progression and metastasis through effects on both tumor cells and stromal cells. This observation has led to the development of several FAK inhibitors, some of which have entered clinical trials (GSK2256098, VS-4718, VS-6062, VS-6063, and BI853520). Resistance to chemotherapy is a serious limitation of cancer treatment and, until recently, most studies were restricted to tumor cells, excluding the possible roles performed by the tumor microenvironment. A recent report identified endothelial cell FAK (EC-FAK) as a major regulator of chemosensitivity. By dysregulating endothelial cell-derived paracrine (also known as angiocrine) signals, loss of FAK solely in the endothelial cell compartment is able to induce chemosensitization to DNA-damaging therapies in the malignant cell compartment and thereby reduce tumor growth. Herein, we summarize the roles of EC-FAK in cancer and development and review the status of FAK-targeting anticancer strategies. Clin Cancer Res; 22(15); 3718-24. ©2016 AACR.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1
Loss of EC-FAK induces chemosensitivity in malignant cells via the regulation of angiocrine factors. A, wild-type endothelial cells (EC). Upon DNA damage, EC-FAK induces (1) activation of the NF-κB pathway causing (2) increased translocation of the NF-κB subunit p65 into the nucleus and (3) elevated cytokine transcription and secretion. This increase in cytokine secretion by tumor-associated endothelial cells creates a chemoresistant niche protecting tumor cells from DNA damage. B, FAK-null ECs: In contrast, upon DNA damage in EC-Fak–null mice with established tumors, (1) NF-κB activity is reduced (2) inhibiting p65 translocation into the nucleus, thus (3) decreasing cytokine transcription and secretion. Thus, loss of EC-Fak reduces the angiocrine signal that protects malignant cells from DNA damage. How other pathways, including NOTCH–JAG1 or TP53, affect angiocrine signaling controlled by FAK is currently unknown.
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