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Loss of Endothelial Cell Enzyme Restores Sensitivity to Chemotherapy and Radiation in Nearby Tumor Cells

By BiotechDaily International staff writers
Posted on 04 Aug 2014
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SARTORIUS AG
Cancer researchers have found that an enzyme produced by cells in the blood vessels that serve tumors triggers the release of signaling molecules that stimulate the repair of damage to the tumor cells caused by treatment with radiation or chemotherapeutic agents.

Investigators at Queen Mary University (London, United Kingdom) examined the role of the enzyme focal adhesion kinase (FAK) in noncancerous endothelial cells in regions of tumor growth.

FAK is a 125-kDa protein that is known to participate in focal adhesion dynamics between cells with a role in motility and cell survival. FAK is a highly conserved, nonreceptor tyrosine kinase originally identified as a substrate for the oncogene protein, tyrosine kinase v-src. This cytoplasmic kinase has been implicated in diverse cellular roles including cell locomotion, mitogen response, and cell survival. FAK is typically located at structures known as focal adhesions, which are multiprotein structures that link the extracellular matrix (ECM) to the cytoplasmic cytoskeleton. It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.

In the current study, the investigators blocked FAK activity in the cells lining blood vessels in a mouse tumor model. They found that deletion of FAK in endothelial cells had no apparent effect on blood vessel function but induced increased apoptosis and decreased proliferation of tumor cells in doxorubicin- and radiotherapy-treated mice. Mechanistically, they demonstrated that endothelial-cell FAK was required for DNA-damage-induced NF-kappaB activation in vivo and in vitro and for the production of cytokines from endothelial cells. Loss of endothelial-cell FAK reduced DNA-damage-induced cytokine production, thus enhancing chemosensitization of tumor cells to DNA-damaging therapies in vitro and in vivo.

Additional data published in the July 27, 2014, online edition of the journal Nature revealed that that low blood vessel FAK expression was associated with complete remission in human lymphoma.

First author Dr. Bernardo Tavora, a postdoctoral associate at Queen Mary University, said, "This work shows that sensitivity to cancer treatment is related to our own body mistakenly trying to shield the cancer from cell-killing effects caused by radiotherapy and chemotherapy. Although taking out FAK from blood vessels will not destroy the cancer by itself, it can remove the barrier cancer uses to protect itself from treatment."

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