Accumulation of CD133-positive glioma cells after high-dose irradiation by Gamma Knife surgery plus external beam radiation.
OBJECTIVE
Recent evidence suggests that a glioma stem cell subpopulation might contribute to radioresistance in malignant gliomas. To investigate this hypothesis, the authors examined recurrent malignant gliomas for histopathological changes after high-dose irradiation with Gamma Knife surgery (GKS) and external beam radiation therapy (EBRT).


METHODS
Thirty-two patients with malignant gliomas (Grade 3 in 8 patients, Grade 4 in 24) underwent GKS in combination with EBRT. Serial MR and L-[methyl-(11)C] methionine PET images were employed to assess remnant or recurrent tumors after GKS. Twelve patients underwent surgical removal after GKS and EBRT. Histological sections were subjected to immunohistochemistry for MIB-1, factor VIII, and stem cell markers, nestin and CD133.


RESULTS
The site of GKS treatment failure was local in 16 (76.2%) of 21 patients with glioblastomas showing progression; in 9 of these 16 patients, the recurrence clearly arose within the target lesion of GKS. Histopathological examination after GKS and EBRT showed variable mixtures of viable tumor tissues and necrosis. Viable tumor tissues exhibited high MIB-1 indices but reduced numbers of tumor blood vessels. There was marked accumulation of CD133-positive glioma cells, particularly in remnant tumors within the necrotic areas, in sections obtained after GKS plus EBRT, whereas CD133-positive cells appeared very infrequently in primary sections prior to adjuvant treatment.


CONCLUSIONS
The results indicate that CD133-positive glioma stemlike cells can survive high-dose irradiation, leading to recurrence, despite prolonged damage to tumor blood vessels. This could be an essential factor limiting the effectiveness of GKS plus EBRT for malignant gliomas.
Tamura
Kaoru
K
Department of Neurosurgery, Medical and Dental University, Tokyo, Japan.
Aoyagi
Masaru
M
Wakimoto
Hiroaki
H
Ando
Noboru
N
Nariai
Tadashi
T
Yamamoto
Masaaki
M
Ohno
Kikuo
K
D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D001808:Blood Vessels / Q000528:radiation effects; D001932:Brain Neoplasms / Q000175:diagnosis / Q000532:radiotherapy* / Q000601:surgery*; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis / Q000532:radiotherapy* / Q000601:surgery*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis; D010455:Peptides / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011836:Radiation Tolerance; D016634:Radiosurgery; D011878:Radiotherapy; D055815:Young Adult
D000071916:AC133 Antigen; D015703:Antigens, CD; D015415:Biomarkers; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides