Effect of a single high-dose gamma irradiation on cultured cells in human cerebral arteriovenous malformation.
OBJECTIVE
The purpose of this study was to analyze the effect of single high-dose gamma irradiation at a cellular biological level on tissue cultures obtained in patients who underwent surgery for cerebral arteriovenous malformation (AVM).


METHODS
The cell proliferation indices and changes in activation of p53, p21Waf-1, and mdm-2 were determined. Additionally, immunohistochemical investigations for vimentin, desmin, alpha-smooth muscle actin (alpha-SMA), glial fibrillary acidic protein, Factor VIII-related antigen (F-VIII), cytokeratin, S100, and transforming growth factor-beta (TGFbeta) were performed on cultured AVM cells after a single high-dose irradiation. Normal human brain microvessel endothelial (HBE) cells and aortic smooth muscle cells served as controls. The proliferation index decreased on the 5th day after irradiation and remained depressed over the observation period in the irradiated AVM cultures. The p53, p21Waf-1, and mdm-2 messenger RNA measurements showed considerable elevation both in AVM cultures and HBE cells after 15-Gy irradiation, which indicated apoptosis. Immunohistochemistry revealed strong vimentin positivity in the nonirradiated cultures, which gradually decreased in the irradiated cultures. Transforming growth factor-beta positivity was demonstrated in the irradiated specimens, indicating transformation of fibroblastic cells into activated myofibroblastic elements. This transformation was confirmed by demonstrating elevated SMA expression as well in the radiation-treated fibroblasts.


CONCLUSIONS
The presence of TGFbeta and alpha-SMA activity in the irradiated AVM cells suggests that along with the genetically confirmed apoptotic activity, fibroblast transformation into myofibroblasts might be one of the mechanisms leading to shrinkage and obliteration of AVMs after single high-dose gamma irradiation.
Major
Otto
O
National Institute of Neurosurgery, Budapest, Hungary. majoott@mailer.oiti.hu
Szeifert
György T
GT
Fazekas
Ilona
I
Vitanovics
Dusan
D
Csonka
Eva
E
Kocsis
Béla
B
Bori
Zoltán
Z
Kemeny
Andras A
AA
Nagy
Zoltán
Z
D000199:Actins / Q000032:analysis; D000963:Antimetabolites / Q000493:pharmacokinetics; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002455:Cell Division / Q000528:radiation effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000528:radiation effects*; D005720:Gamma Rays; D006801:Humans; D002538:Intracranial Arteriovenous Malformations; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000032:analysis; D016634:Radiosurgery; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014746:Vimentin / Q000032:analysis
D000199:Actins; D000963:Antimetabolites; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D014746:Vimentin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D001973:Bromodeoxyuridine