Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations.
Several studies have supported the hypothesis that adrenocortical tumor formation is the result of a multistep process. The angiogenic switch has been proposed to be a key step in tumor progression from adenoma to carcinoma. In this study we measured the cytosolic concentrations of three proteins involved in angiogenesis [namely platelet-derived endothelial cell growth factor vascular endothelial cell growth factor A (VEGF-A), and thrombospondin-1 (TSP1)] in a series of 43 human sporadic adrenocortical tumors. The tumors were classified as adenomas (n = 18), transitional tumors (n = 12), or carcinomas (n = 13) according to the histological criteria defined by Weiss. Platelet-derived endothelial cell growth factor/thymidine phosphorylase levels were not significantly different among these three groups. One hundred percent of the adenomas and 73% of the transitional tumors showed VEGF-A concentrations under the threshold value of 107 ng/g protein, whereas 75% of the carcinomas had VEGF-A concentrations above this threshold value. Similarly, 89% of the adenomas showed TSP1 concentrations above the threshold value of 57 microg/g protein, whereas only 25% of the carcinomas and 33% of the transitional tumor samples did so. Insulin-like growth factor II overexpression, a common genetic alteration of adrenocortical carcinomas, was significantly correlated with higher VEGF-A and lower TSP1 concentrations. The tumors from the 6 patients with tumor recurrence after surgical ablation showed significantly higher VEGF-A values than the carcinomas and the transitional tumors from patients that did not relapse. Taken together, these data suggest that a decrease in TSP1 expression is an event that precedes an increase in VEGF-A expression during adrenocortical tumor progression. The population of premalignant tumors with low TSP1 and normal VEGF-A levels could represent a selective target for antiangiogenic therapies.
de Fraipont
F
F
INSERM U-244, Département de Biologie Moléculaire et Structurale/Biochimie des Régulations Cellulaires Endocrines, Commissariat à l'Energie Atomique, F-38054 Grenoble, France.
El Atifi
M
M
Gicquel
C
C
Bertagna
X
X
Chambaz
E M
EM
Feige
J J
JJ
D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D000328:Adult; D000368:Aged; D015415:Biomarkers; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003600:Cytosol / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D019700:Thrombospondin 1 / Q000096:biosynthesis* / Q000235:genetics; D013939:Thymidine Phosphorylase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D015415:Biomarkers; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D007335:Insulin-Like Growth Factor II; D013939:Thymidine Phosphorylase