BackgroundPheochromocytoma and neuroblastoma are the most common neural crest-derived tumors in adults and children, respectively. We have performed a large-scale in silico analysis of altogether 1784 neuroblastoma and 531 pheochromocytoma samples to establish similarities and differences using analysis of mRNA and microRNA expression, chromosome aberrations and a novel bioinformatics analysis based on cooperative game theory.MethodsDatasets obtained from Gene Expression Omnibus and ArrayExpress have been subjected to a complex bioinformatics analysis using GeneSpring, Gene Set Enrichment Analysis, Ingenuity Pathway Analysis and own software.ResultsComparison of neuroblastoma and pheochromocytoma with other tumors revealed the overexpression of genes involved in development of noradrenergic cells. Among these, the significance of paired-like homeobox 2b in pheochromocytoma has not been reported previously. The analysis of similar expression patterns in neuroblastoma and pheochromocytoma revealed the same anti-apoptotic strategies in these tumors. Cancer regulation by stathmin turned out to be the major difference between pheochromocytoma and neuroblastoma. Underexpression of genes involved in neuronal cell-cell interactions was observed in unfavorable neuroblastoma. By the comparison of hypoxia- and Ras-associated pheochromocytoma, we have found that enhanced insulin like growth factor 1 signaling may be responsible for the activation of Src homology 2 domain containing transforming protein 1, the main co-factor of RET. Hypoxia induced factor 1α and vascular endothelial growth factor signaling included the most prominent gene expression changes between von Hippel-Lindau- and multiple endocrine neoplasia type 2A-associated pheochromocytoma.ConclusionsThese pathways include previously undescribed pathomechanisms of neuroblastoma and pheochromocytoma and associated gene products may serve as diagnostic markers and therapeutic targets.

The currently available medical treatment options of adrenocortical cancer (ACC) are limited. In our previous meta-analysis of adrenocortical tumor genomics data, ACC was associated with reduced retinoic acid production and retinoid X receptor-mediated signaling. Our objective has been to study the potential antitumoral effects of 9-cis retinoic acid (9-cisRA) on the ACC cell line NCI-H295R and in a xenograft model. Cell proliferation, hormone secretion, and gene expression have been studied in the NCI-H295R cell line. A complex bioinformatics approach involving pathway and network analysis has been performed. Selected genes have been validated by real-time qRT-PCR. Athymic nude mice xenografted with NCI-H295R have been used in a pilot in vivo xenograft model. 9-cisRA significantly decreased cell viability and steroid hormone secretion in a concentration- and time-dependent manner in the NCI-H295R cell line. Four major molecular pathways have been identified by the analysis of gene expression data. Ten genes have been successfully validated involved in: (1) steroid hormone secretion (HSD3B1, HSD3B2), (2) retinoic acid signaling (ABCA1, ABCG1, HMGCR), (3) cell-cycle damage (GADD45A, CCNE2, UHRF1), and the (4) immune response (MAP2K6, IL1R2). 9-cisRA appears to directly regulate the cell cycle by network analysis. 9-cisRA also reduced tumor growth in the in vivo xenograft model. In conclusion, 9-cisRA might represent a promising new candidate in the treatment of hormone-secreting adrenal tumors and adrenocortical cancer.

Gene-expression changes might be involved in the adrenal action of mitotane and in the inhibition of hormone secretion.

Adrenocortical cancer is a rare tumor with poor prognosis. Whereas most cases occur in a sporadic setting, there are very rare hereditary forms that are important for the understanding of tumor pathogenesis. The hereditary syndromes associated with adrenocortical cancer are: Li-Fraumeni's syndrome, Beckwith-Wiedemann's syndrome and familial adenomatous polyposis, whereas multiple endocrine neoplasia type 1, Carney's complex and McCune-Albright's syndrome mostly predispose to benign adrenocortical tumors. Overexpression of insulin like growth factor 2, activation of Wnt/beta-catenin and cAMP-protein kinase A signaling, as well as mutations of p53 and MEN1 genes are regarded as major pathogenetic mechanisms. Options for medical treatment of adrenocortical cancer are rather limited. Recently published molecular-bioinformatical studies have revealed several previously unknown pathogenetic pathways that may even represent potential drug targets. In this study, the pathogenesis of hereditary tumor syndromes, the alterations in sporadic tumors and the most recent molecular-bioinformatical observations are discussed.

Introduction: Dysregulation of adipokine secretion and action is a characteristic feature of obesity and a key clinical feature of Cushing's syndrome (CS). We have investigated whether endogenous glucocorticoid excess influences adipose tissue-derived gene expression. Material and methods: mRNA expression of adipokines; adiponectin, resistin, tumour necrosis factor-a, interleukin-6 (IL-6), angiotensinogen (AGT), plasminogen activator inhibitor type 1, retinol binding protein 4, visfatin, and cystatin C was assessed by quantitative real-time RT-PCR in visceral adipose tissue removed during abdominal surgery of eight patients with CS, and six control patients. Results: We did not find any significant difference in the investigated genes; however, the almost significant overexpression of AGT and underexpression of IL-6 might be noteworthy (p = 0.06 in both cases). Conclusions: No significant differences were found in the expression of the investigated genes known as cardiometabolic risk factors. This indicates that there are no major differences between endogenous hypercortisolism or diet-induced obesity regarding the expression of adipokines involved in cardiometabolic disorders. However, the difference in AGT and IL-6 expression might be included in pathways affecting fat distribution in CS.