title: Conditional deletion of the focal adhesion kinase FAK alters remodeling of the blood-brain barrier in glioma.
abstract: Gliomas generally infiltrate the surrounding normal brain parenchyma, a process associated with increased vascular permeability (VP) and dysregulation of the blood-brain barrier (BBB). However, the molecular mechanisms underlying glioma-induced VP in the brain remain poorly understood. Using a conditional, endothelium-specific deletion of the focal adhesion kinase (FAK) in the mouse (FAK CKO), we show that FAK is critical for destabilization of the tumor endothelium in tumor-bearing mice, with mutant mice exhibiting a relatively normalized vasculature compared with wild-type mice (FAK WT). Tumor vessels in the FAK CKO mice displayed reduced VP compared with FAK WT mice, resulting in reduced tumor growth. Additionally, FAK CKO mice displayed partial restoration of cell-cell junction proteins in the tumor vessels and astrocyte-endothelium interactions in tumors, revealing an additional role of astrocytes in mediating tumor-induced VP. Together, these results provide genetic evidence that FAK is a mediator of tumor-induced VP in the brain. Our findings may help understand how therapeutics might be used to regulate specific cell-type interactions to restore BBB structure/function in cancer and perhaps other pathologic conditions.
authors.affiliation: Department of Surgery, University of California San Diego, California 92103-8236, USA.
authors.forename: Jisook
authors.initials: J
authors.lastname: Lee
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Borboa
authors.forename: Hyun Bae
authors.initials: HB
authors.lastname: Chun
authors.forename: Andrew
authors.initials: A
authors.lastname: Baird
authors.forename: Brian P
authors.initials: BP
authors.lastname: Eliceiri
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology*; D001932:Brain Neoplasms / Q000098:blood supply* / Q000201:enzymology*; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000172:deficiency*; D005910:Glioma / Q000098:blood supply* / Q000201:enzymology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000201:enzymology; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D013629:Tamoxifen; D051416:Focal Adhesion Protein-Tyrosine Kinases