Localization of the endothelin system in human diffuse astrocytomas.
BACKGROUND
Endothelin-1 (ET-1), a vasoconstrictor and mitogen, has recently been implicated in the pathogenesis of human glioblastoma, neuroblastoma, and meningioma. ET-1, formed by proteolysis of the propeptide big ET-1 by endothelin-converting enzyme-1 (ECE-1), mediates its cellular actions through ETA and ETB receptors. Because only immunoreactive ET-1 has been observed within human astrocytic tumor cells, the authors investigated the localization of the entire ET-1 system (ET-1 mRNA, ET-1, ECE-1, ETA and ETB receptors) in surgical samples of human diffuse astrocytomas WHO Grade II (n = 6).


METHODS
ET-1 mRNA expression was elucidated by in situ reverse transcriptase polymerase chain reaction (RT-PCR) using synthetic primers. Polyclonal antibodies were used to localize ET-1, ECE-1, ETA and ETB receptors by immunocytochemistry.


RESULTS
All ET components were detected in the six tumor samples. Intense (3+) cytoplasmic ET-1 mRNA labeling was observed in more than 75% of cells in all 6 astrocytomas. Up to 75% of tumor cells displayed intense ET-1 and ECE-1 immunolabeling distributed throughout their cytoplasm. Immunoreactive ETA and ETB receptors, observed in 25% to 75% of astrocytic tumor cells, were of moderate intensity. In addition, all components of the ET system were seen within endothelial cells of tumor blood vessels.


CONCLUSIONS
The presence of ET-1 mRNA, ECE-1, and ET-1 within tumor astrocytes suggests local ET synthesis and processing. The mitogenic and antiapoptotic properties of ET-1, as well as the vasodilatory signaling of ETB receptors, may promote tumorigenesis.
Naidoo
Vinogran
V
Department of Pharmacology, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
Naidoo
Strinivasen
S
Mahabeer
Rajeshree
R
Raidoo
Deshandra M
DM
D000328:Adult; D016282:Aspartic Acid Endopeptidases / Q000032:analysis*; D001254:Astrocytoma / Q000737:chemistry* / Q000209:etiology; D019332:Endothelin-1 / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008666:Metalloendopeptidases / Q000032:analysis*; D012333:RNA, Messenger / Q000032:analysis; D044022:Receptor, Endothelin A / Q000032:analysis*; D044023:Receptor, Endothelin B / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes