Constitutive expression of growth-related oncogene and its receptor in oligodendrogliomas.
OBJECTIVE
Gliomas may result from transformation of glial precursor cells. In the developing rat central nervous system (CNS), a paracrine pathway involving the cytokines growth-related oncogene (GRO1) and platelet-derived growth factor (PDGF) A chain closely regulates oligodendrocyte precursor cell number. The purpose of the present study was to analyze whether abnormal expression and activity of the GRO1-PDGF pathway is present in human gliomas.


METHODS
Tumor specimens were studied to compare the messenger ribonucleic acid with the protein expression of components of the GRO1-PDGF pathway. Neutralizing antibodies were used in vitro to analyze whether the pathway contributed to tumor cell proliferation.


RESULTS
Immunohistochemistry demonstrated that all components of the GRO1-PDGF pathway (GRO1 protein, its receptor CXCR2, PDGF A chain, and its receptor PDGFalphaR) were expressed by tumor cells in 6 (86%) of 7 of oligodendrogliomas as well as by 0 of 4 diffuse astrocytomas (World Health Organization Grades II and III) and 2 (18%) of 11 glioblastomas. Analysis by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay showed CXCR2 messenger ribonucleic acid and GRO1 protein expression were present in oligodendrogliomas. Functional analyses with neutralizing antibodies limited bromodeoxyuridine incorporation in vitro by oligodendroglioma tumor cells, demonstrating a requirement for the GRO1-PDGF pathway in the proliferation of these cells.


CONCLUSIONS
The GRO1-PDGF pathway was primarily expressed and functional in oligodendrogliomas. The tightly controlled paracrine pathway that regulates oligodendrocyte precursor proliferation in the developing rodent CNS was constitutively active in most oligodendrogliomas in the present study. The presence of this aberrantly functioning oncogenic pathway in a subset of primary CNS tumors opens new avenues to glioma treatment that are based directly on the biology of the proliferative glial cell type, a novel strategy for primary CNS tumor therapy.
Robinson
S
S
Division of Pediatric Neurological Surgery, Rainbow Babies and Children's Hospital, Cleveland, Ohio 44106, USA. shenandoah.robinson@uhhs.com
Cohen
M
M
Prayson
R
R
Ransohoff
R M
RM
Tabrizi
N
N
Miller
R H
RH
D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000032:analysis*; D005909:Glioblastoma / Q000473:pathology; D006133:Growth Substances / Q000032:analysis*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009837:Oligodendroglioma / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000032:analysis*; D023063:Receptors, Interleukin-8B / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000473:pathology
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D023063:Receptors, Interleukin-8B