Objectives: Endocrine gland-derived vascular endothelial growth factor (EG-VEGF; also termed prokineticin-1) has been identified as a mitogen preferable for the endothelium of steroidogenic glands (1). EG-VEGF and its receptors (prokineticin receptors 1 and 2; PKR1 and 2) are highly expressed in the normal adrenal gland and an autocrine mitogenic loop has been proposed (2). Therefore, we investigated the expression of EG-VEGF and its receptors in adrenocortical carcinoma (ACC) samples and correlated theses results with clinical outcome data.
Methods: EG-VEGF, PKR1, and PKR2 mRNA expression was assessed by real-time PCR in 30 ACC and 12 normal adrenal glands. In addition, these factors were analyzed by immunohistochemistry with specific antibodies using tissue microarrays including samples from 151 ACCs, 15 adrenocortical adenomas, and five normal adrenal glands. We also correlated EG-VEGF protein expression with clinical outcome in patients with ACC using KaplanMaier and cox-regression analysis.
Results: The mRNA of EG-VEGF and its receptor were highly abundant in most ACC samples and the expression in ACC was comparable to the normal adrenal gland and the adenomas. EG-VEGF protein was detectable in the cytoplasm of 150/151 (99%) and in the nucleus of 131/151 (87%) ACC samples including 90 (60%) and 27 (18%) samples with strong staining. There was no significant correlation with tumor stage. In >90% of ACC samples at least one of the receptors PKR1 or 2 was detectable. Patients with no nuclear staining for EG-VEGF had a significant better, stage-adjusted overall survival (hazard ratio for death: 0.33 (95% CI 0.120.90; P=0.03).
Conclusion: EG-VEGF and its receptors are expressed in the vast majority of ACC samples and EG-VEGF expression correlates with clinical outcome. Therefore, EG-VEGF seems to be an interesting therapeutic target for future studies.