The angiopoietin 1/angiopoietin 2 balance as a prognostic marker in primary glioblastoma multiforme.
OBJECTIVE
In the present study, the authors analyzed the ANGPT1/ANGPT2 balance in the context of therapeutic outcome in 62 patients with primary glioblastomas multiforme (GBMs).


METHODS
The tumor tissue used was obtained in adult patients who underwent neurosurgical debulking. Microvessel density was assessed by morphometric analysis. Double immunostaining for Ki 67/CD34 and cleaved caspase-3/CD34 was used to investigate the proliferation and apoptotic fraction of both endothelial and tumor cells. The expression of VEGFs (A-D) was evaluated on immunohistochemistry. To measure tumor vascular stabilization, the ANGPT1/ANGPT2 mRNA balance was determined using real-time reverse transcriptase polymerase chain reaction.


RESULTS
Within the hypoxic perinecrotic tumor area, the apoptotic fraction of endothelial cells was positively correlated with VEGFA expression (p < 0.001). Higher levels of VEGFA correlated with greater proliferation of endothelial cells in the intermediate tumor area (p = 0.031). Vascular endothelial growth factor D was significantly more highly expressed within the perinecrotic tumor area compared with the intermediate tumor area (p < 0.001). Multivariate analysis showed a significant association between the ANGPT1/ANGPT2 balance and the survival time of patients with GBMs (p = 0.035).


CONCLUSIONS
The results of the present study suggest that the ANGPT1/ANGPT2 balance has prognostic value in patients with primary GBMs. The authors' findings support the need for further studies of the feasibility of antiangiogenic therapy in primary GBMs, with a special focus on the normalization of tumor vasculature.
Sie
Mariska
M
Department of Pediatrics, Pediatric Oncology Division, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, The Netherlands.
Wagemakers
Michiel
M
Molema
Grietje
G
Mooij
Jan Jakob A
JJ
de Bont
Eveline S J M
ES
den Dunnen
Wilfred F A
WF
D000368:Aged; D042683:Angiopoietin-1 / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000378:metabolism* / Q000601:surgery*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000601:surgery*; D006801:Humans; D007150:Immunohistochemistry; D017567:Karnofsky Performance Status; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D019635:Neurosurgical Procedures; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000032:analysis / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D053148:Caspase 3