title: Anti-YKL-40 antibody and ionizing irradiation synergistically inhibit tumor vascularization and malignancy in glioblastoma.
abstract: Chemo/radiotherapies are the most common adjuvant modality treated for patients with glioblastoma (GBM) following surgery. However, the overall therapeutic benefits are still uncertain, as the mortality remains high. Elevated expression of YKL-40 in GBM was correlated with increases in mural cell-associated vessel coverage, stability and density, and decreases in vessel permeability and disease survival. To explore the potential role of YKL-40 in mural cell-mediated tumor vascularization, we employed an anti-YKL-40 neutralizing antibody (mAY) and ionizing irradiation (IR) in xenografted brain tumor models. Although single treatment with mAY or IR partially increased mouse survival, their combination led to dramatic inhibition in tumor growth and increases in mouse survival. mAY blocked mural cell-mediated vascular stability, integrity and angiogenesis; whereas IR merely promoted tumor cell and vascular cell apoptosis. Vascular radioresistance is at least partially attributed to expression of YKL-40 in mural cells. These divergent effects were also recapitulated in cultured systems using endothelial cells and mural cells differentiated from glioblastoma stem-like cells (GSCs). Dysfunction of intercellular contact N-cadherin was found to mediate mAY-inhibited vascularization. Collectively, the data suggest that the conjunction therapy with mAY and IR synergistically inhibit tumor vascularization and progression. The evidence may shed light on a new adjuvant therapy in clinic.
authors.affiliation: Department of Veterinary and Animal Sciences and.
authors.forename: Rong
authors.initials: R
authors.lastname: Shao
authors.forename: Ralph
authors.initials: R
authors.lastname: Francescone
authors.forename: Nipaporn
authors.initials: N
authors.lastname: Ngernyuang
authors.forename: Brooke
authors.initials: B
authors.lastname: Bentley
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Taylor
authors.forename: Luis
authors.initials: L
authors.lastname: Moral
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
mesh_terms: D054392:Adipokines / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002454:Cell Differentiation; D049109:Cell Proliferation; D000071451:Chitinase-3-Like Protein 1; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D037102:Lectins / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011839:Radiation, Ionizing
chemical_list: D054392:Adipokines; D000911:Antibodies, Monoclonal; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins