title: Bevacizumab changes vascular structure and modulates the expression of angiogenic factors in recurrent malignant gliomas.
abstract: Bevacizumab (BV), a monoclonal antibody against vascular endothelial growth factor (VEGF), is currently used in the treatment of malignant glioma. To understand mechanisms of resistance to BV, we investigated morphological changes in tumor vessels and expression of angiogenic factors, such as VEGF, Flt-1, basic fibroblast growth factor (bFGF), and platelet-derived growth factor-BB (PDGF-BB), in four autopsied tumors after BV treatment. Three patients had glioblastomas; the fourth had a secondary glioblastoma that developed from a diffuse astrocytoma. BV was administered because of recurrence following the use of the Stupp regimen in these four patients. We compared the initial surgical specimen with that obtained after death following BV treatment. Immunohistochemical staining of the autopsied tumors showed that Flt-1 expression increased while VEGF expression was significantly reduced. Additionally, other angiogenic factors, particularly bFGF, were enhanced. Interestingly, the proliferation of endothelial cells was reduced, but remarkable proliferation of pericytes was observed. These results suggest that following BV treatment, glioblastomas can grow tumor vessels by expressing various angiogenic factors. These mechanisms might be important for rapid regrowth and blood brain barrier repair after BV treatment. Inhibition of multiple angiogenic factors will be required to control tumor vessels in glioblastoma.
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan. saori.oka@gmail.com.|Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan. saori.oka@gmail.com.
authors.forename: Saori
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.|Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nitta
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.|Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Sawada
authors.affiliation: Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Komori
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Neurosurgery, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.|Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Muragaki
mesh_terms: D000328:Adult; D000077214:Becaplermin; D000068258:Bevacizumab / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D017809:Fatal Outcome; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D005910:Glioma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D000068258:Bevacizumab; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Angiogenesis; Autopsy; Bevacizumab; Glioblastoma; VEGF