Characterization of an imatinib-sensitive subset of high-grade human glioma cultures.
High-grade gliomas, including glioblastomas, are malignant brain tumors for which improved treatment is urgently needed. Genetic studies have demonstrated the existence of biologically distinct subsets. Preliminary studies have indicated that platelet-derived growth factor (PDGF) receptor signaling contributes to the growth of some of these tumors. In this study, human high-grade glioma primary cultures were analysed for sensitivity to treatment with the PDGF receptor inhibitor imatinib/Glivec/Gleevec/STI571. Six out of 15 cultures displayed more than 40% growth inhibition after imatinib treatment, whereas seven cultures showed less than 20% growth inhibition. In the sensitive cultures, apoptosis contributed to growth inhibition. Platelet-derived growth factor receptor status correlated with imatinib sensitivity. Supervised analyses of gene expression profiles and real-time PCR analyses identified expression of the chemokine CXCL12/SDF-1 (stromal cell-derived factor 1) as a predictor of imatinib sensitivity. Exogenous addition of CXCL12 to imatinib-insensitive cultures conferred some imatinib sensitivity. Finally, coregulation of CXCL12 and PDGF alpha-receptor was observed in glioblastoma biopsies. We have thus defined the characteristics of a novel imatinib-sensitive subset of glioma cultures, and provided evidence for a functional relationship between imatinib sensitivity and chemokine signaling. These findings will assist in the design and evaluation of clinical trials exploring therapeutic effects of imatinib on malignant brain tumors.
Department of Oncology/Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm, Sweden.
D
D
Hägerstrand
G
G
Hesselager
S
S
Achterberg
U
U
Wickenberg Bolin
M
M
Kowanetz
M
M
Kastemar
C-H
CH
Heldin
A
A
Isaksson
M
M
Nistér
A
A
Ostman
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor