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Modifying Adhesion Protein Interactions Prevents Metastasis in Mouse Models

By BiotechDaily International staff writers
Posted on 04 Feb 2014
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Image: Normal breast tissue and invasive ductal carcinoma stained brown with antibodies to activated FAK. Blood vessels are indicated by BV (Photo courtesy of Dr. David Schlaepfer, University of California, San Diego).
Image: Normal breast tissue and invasive ductal carcinoma stained brown with antibodies to activated FAK. Blood vessels are indicated by BV (Photo courtesy of Dr. David Schlaepfer, University of California, San Diego).
Cancer investigators have identified a protein critically linked to the process of metastasis by which cancer cells break away from the primary tumor and spread to other parts of the body.

Investigators at the University of California, San Diego (USA) worked with several different mouse cancer models, which they manipulated by pharmacological or genetic means. Of particular interest was the role of the protein focal adhesion kinase (FAK). FAK is a 125-kD 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 cytosolic 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.

Results published in the January 20, 2014, online edition of the Journal of Cell Biology revealed that FAK was active in both tumors and surrounding endothelial cells and that selective FAK inhibition within endothelial cells prevented spontaneous tumor metastasis without alterations in tumor size. In a mouse melanoma model, FAK inhibition in endothelial cells prevented skin tumors from metastasizing to the lungs without affecting primary tumor growth.

The investigators found that at the molecular level tyrosine 658 of the protein vascular endothelial cadherin was a target of FAK in tumor-associated endothelial cells. Cadherins are members of a family of calcium-dependent cell adhesion proteins that preferentially interact in a homophilic manner in cell-cell interactions. They are type I membrane proteins that contribute to the sorting of heterogeneous cell types. Typically, cadherins have five similar extracellular domains, the outermost three of which have Ca2+-binding sites, and an intracellular C-terminal domain that interacts with the actin cytoskeleton.

Cadherin normally helps to maintain an endothelial cell barrier that surrounds the tumor and prevents metastasis. However, when modified by FAK, the cadherin complexes became degraded and blood vessels became porous. Inactivating FAK within endothelial cells prevented this permeability and blocked the ability of tumor cells to pass through endothelial cell barriers.

“Our studies show that pharmacological or genetic inhibition of the endothelial protein focal adhesion kinase, or FAK, prevents tumor spread by enhancing the vessel barrier function,” said senior author Dr. David D. Schlaepfer, professor of reproductive medicine at the University of California, San Diego. “Metastasis is responsible for 90% of cancer-related deaths. This fact alone underscores the need for a better mechanistic understanding of the metastatic process.”

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University of California, San Diego



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