Increased levels of tissue endostatin in human malignant gliomas.
OBJECTIVE
Malignant gliomas are typically angiogenic and express greater amounts of angiogenic factors. We examined glioma tissues for their expression of an endogenous inhibitor of angiogenesis, endostatin, a COOH-terminal fragment of collagen XVIII.


METHODS
We examined frozen tissues from 51 patients with astrocytic tumors (grade 2, 13; grade 3, 9; and grade 4, 29). Frozen tissues were subjected to immunoblot analysis and immunohistochemistry for endostatin. Tumor vascular density was determined by calculating the percentage of tumor capillary vessel areas/tissue section area. Tissue concentrations of vascular endothelial growth factor and basic fibroblast growth factor were examined by enzyme immunoassay.


RESULTS
The levels of endostatin protein estimated by immunoblotting were significantly higher in grade 4 than lower-grade glioma tissues. The immunoreactive bands for endostatin were identified as the fragment derived from noncollagenous domain 1 of collagen XVIII, a peptide 15 residues longer than endostatin toward the NH(2)-terminal end, by NH(2)-terminal amino acid sequencing. In addition to an intense immunoreactivity for endostatin in tumor blood vessels, sections from malignant gliomas showed widely distributed immunoreactivity around tumor cells near the hyperplastic microvessels. The tumor vascular density and the levels of vascular endothelial growth factor in grade 4 glioma tissues were significantly higher than grade 2 and grade 3 gliomas, whereas the levels of basic fibroblast growth factor were the same.


CONCLUSIONS
The results indicate a positive correlation between the levels of tissue endostatin and malignancy grades in gliomas. The endostatin may be released near the tumor blood vessels with hyperplasia to counteract angiogenic stimuli in malignant gliomas.
Morimoto
Takashi
T
Department of Neurosurgery, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Aoyagi
Masaru
M
Tamaki
Masashi
M
Yoshino
Yoshikazu
Y
Hori
Hisae
H
Duan
Lian
L
Yano
Takeo
T
Shibata
Masao
M
Ohno
Kikuo
K
Hirakawa
Kimiyoshi
K
Yamaguchi
Noriko
N
D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000098:blood supply / Q000737:chemistry / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000737:chemistry* / Q000473:pathology; D003094:Collagen / Q000032:analysis* / Q000502:physiology; D043170:Collagen Type XVIII; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000032:analysis; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000032:analysis; D005909:Glioblastoma / Q000098:blood supply / Q000737:chemistry / Q000473:pathology; D005910:Glioma / Q000098:blood supply / Q000737:chemistry* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D008222:Lymphokines / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis* / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D043170:Collagen Type XVIII; D043169:Endostatins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D003094:Collagen