Abstract
Angiogenesis is essential for tumor growth and metastasis. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor predominantly expressed in steroidogenic organs like the adrenal gland, ovary, testes, and placenta. EG-VEGF has antiapoptotic, mitogenic, and chemoattractive properties mediated via the two G protein-coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2). We investigated the expression of EG-VEGF and its receptors in a large number of normal adrenal glands (NAG), adrenocortical adenomas (ACA), and carcinomas (ACC) using real-time PCR (NAG, n = 12; ACA, n = 24; and ACC, n = 30) and immunohistochemistry (NAG, n = 9; ACA, n = 23; and ACC, n = 163) and evaluated its impact on patients’ survival. EG-VEGF, PKR1, and PKR2 mRNA and protein are expressed in NAG and the vast majority of ACA and ACC samples. The mean EG-VEGF mRNA expression was significantly lower in ACC (606.5 ± 77.1 copies) compared to NAG (4,043 ± 1,111) and cortisol-producing adenomas (CPA) (4,433 ± 2,378) (p < 0.01 and p < 0.05, respectively). However, cytoplasmic and nuclear EG-VEGF protein expression was either significantly higher or similar in ACC (H score 2.4 ± 0.05, p < 0.05 and 1.7 ± 0.08, n.s., respectively) compared to NAG (1.8 ± 0.14 and 1.7 ± 0.2). Nuclear protein expression of either EG-VEGF or PKR1 or both is predictive for a higher mortality compared to patients without nuclear expression (hazard ratio (HR) = 5.15; 95 % confidence interval (CI) = 1.24–21.36, n = 100, p = 0.02 independent of age, sex, and tumor stage). These findings suggest that EG-VEGF and its receptor PKR1 might play a role in the pathogenesis of adrenocortical tumors and could serve as prognostic markers for this rare malignant disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s12672-015-0236-z) contains supplementary material, which is available to authorized users.
Highlights
Adrenocortical carcinoma (ACC) is a rare and highly malignant tumor whose pathogenesis is largely unclear [11, 13, 15]
endocrine gland-derived vascular endothelial growth factor (VEGF) (EG-VEGF) mRNA was expressed in all normal adrenal glands (NAG) (n=12), adrenocortical adenomas (ACA) (n=24), and ACC (n=30)
The expression of prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) mRNA in NAG, ACA, and ACC was examined on a subset of samples
Summary
Adrenocortical carcinoma (ACC) is a rare and highly malignant tumor whose pathogenesis is largely unclear [11, 13, 15]. Only a few prognostic markers are available to guide treatment decisions. In 2001, the endocrine gland-derived VEGF (EG-VEGF) was identified as the first tissue-specific angiogenic factor predominantly expressed in steroidogenic organs like the adrenal gland, testes, ovary, and placenta. Both EG-VEGF and VEGF have a HIF-1 binding site and are induced by hypoxia. EG-VEGF belongs to the AVIT protein family and shares the amino terminal sequence with prokineticin 2 (mammalian orthologue of Bombina variegata peptide 8), which is not expressed in human adrenal tissue [32].
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