Focal Adhesion Kinase (FAK) is a compelling cancer target as it both aids tumor growth and promotes metastasis. However, to date, little has been known about the molecular mechanisms behind these relationships. In a new study, published in the January issue of The Journal of Cell Biology, researchers in David Schlaepfer’s lab at the University of California San Diego Cancer Center, show that specific FAK phosphorylation events contribute to metastasis by promoting vascular permeability in endothelial cells.
Vascular endothelial cadherin (VEC), helps endothelial cells bind together closely, making it harder for cancer cells to spread. Vascular endothelial growth factor (VEGF), produced in numerous cancers, is VEC’s worst enemy; by binding to and activating the receptor VEGFR-2, VEGF triggers the phosphorylation of VEC, loosening the binds between endothelial cells, and allowing cancer cells to slip through and enter the bloodstream.
While much remains unknown about the relationship between VEGFR-2 activation and VEC phosphorylation, concurrent FAK accumulation at cell to cell junctions has suggested the protein’s involvement.
To further explore this relationship between VEGFR-2 activation and FAK, researchers gave a FAK inhibitor to mice with fast-spreading breast cancer and mice with ovarian tumors. In both cases, the FAK inhibitor prevented phosphorylation of VEC tyrosine 658. Researchers then injected VEGF into mice with an enzymatically inactive variant of FAK and into control mice. VGEF prompted phosphorylation of VEC tyrosine 658 in the control mice but not in those containing inactive FAK, suggesting the presence of FAK as crucial to successful VEFR-2 activated VEC phosphorylation.
Furthermore, mice that expressed a kinase dead version of FAK in their endothelial cells had far fewer tumor cells in their lungs than control mice; blocking endothelial FAK curbed metastasis.
The work, says senior author David Schlaepfer, places FAK in the pathway that controls vascular permeability and further supports the possibility that FAK inhibitors – already being tested in clinical trials due to their ability to restrain tumor growth – provide the added benefit of curbing metastasis.