Reduced glioma infiltration in Src-deficient mice.
Malignant brain tumors, such as glioblastoma, are characterized by extensive angiogenesis and permeability of the blood-brain barrier (BBB). The infiltration of glioma cells away from the primary tumor mass is a pathological characteristic of glial tumors. The infiltrating tumor cells represent a significant factor in tumor recurrence following surgical debulking, radiation, and chemotherapy treatments. Vascular endothelial growth factor (VEGF)-mediated vascular permeability (VP) has been associated with the progression of glioma tumor growth and infiltration into surrounding normal brain parenchyma. While VEGF induces a robust VP response in control mice (src+/+ or src+/-), the VP response is blocked in src-/- mice that demonstrate a 'leakage-resistant phenotype' in the brain. We used the Src-deficient mouse model to determine the role of Src in the maintenance of the BBB following orthotopic implantation and growth of glioma cells in the brain. Although solid tumor growth was the same in control and src-/- mice, the infiltrating component of glioma growth was reduced in src-/- mice. Characterization of the expression and localization of the extracellular matrix (ECM) protein fibrinogen was evaluated to determine the effect of a Src-mediated VP defect in the host compartment. These studies indicate that the reduced VP of host brain blood vessels of src-/- mice mediates a reduction in glioma cell invasion in a mouse brain tumor xenograft model.
Division of Cancer Biology, La Jolla Institute for Molecular Medicine, San Diego, CA 92121, USA.
Caren V
CV
Lund
Mai T N
MT
Nguyen
Geoffrey C
GC
Owens
Andrew J
AJ
Pakchoian
Ashkaun
A
Shaterian
Carol A
CA
Kruse
Brian P
BP
Eliceiri
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D002199:Capillary Permeability / Q000502:physiology*; D045744:Cell Line, Tumor; D002560:Cerebrovascular Circulation / Q000502:physiology; D005340:Fibrinogen / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency*
D042461:Vascular Endothelial Growth Factor A; D005340:Fibrinogen; D019061:src-Family Kinases