Review Paper: Origin and Molecular Pathology of Adrenocortical Neoplasms

Box 8208, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA.
Veterinary Pathology (Impact Factor: 2.04). 04/2009; 46(2):194-210. DOI: 10.1354/vp.46-2-194
Source: PubMed

ABSTRACT Neoplastic adrenocortical lesions are common in humans and several species of domestic animals. Although there are unanswered questions about the origin and evolution of adrenocortical neoplasms, analysis of human tumor specimens and animal models indicates that adrenocortical tumorigenesis involves both genetic and epigenetic alterations. Chromosomal changes accumulate during tumor progression, and aberrant telomere function is one of the key mechanisms underlying chromosome instability during this process. Epigenetic changes serve to expand the size of the uncommitted adrenal progenitor population, modulate their phenotypic plasticity (i.e., responsiveness to extracellular signals), and increase the likelihood of subsequent genetic alterations. Analyses of heritable and spontaneous types of human adrenocortical tumors documented alterations in either cell surface receptors or their downstream effectors that impact neoplastic transformation. Many of the mutations associated with benign human adrenocortical tumors result in dysregulated cyclic adenosine monophosphate signaling, whereas key factors and/or signaling pathways associated with adrenocortical carcinomas include dysregulated expression of the IGF2 gene cluster, activation of the Wnt/beta-catenin pathway, and inactivation of the p53 tumor suppressor. A better understanding of the factors and signaling pathways involved in adrenal tumorigenesis is necessary to develop targeted pharmacologic and genetic therapies.

  • Source
    • "Growth factor cascades of adrenal cortex and adrenocortical tumors have been studied in mice, and knowledge of the role of Inha, Smad, Ctnnb1, and Gata protein-related signaling and gene regulation has been rapidly increasing based on studies utilizing various animal models (reviewed in [5] [16]). Here, we present a Fig. 1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samples⋅ Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR. Expression of the TGF-β signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome. We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHA as a tumor suppressor in humans.
    Pathology - Research and Practice 06/2013; 209(8). DOI:10.1016/j.prp.2013.06.002 · 1.56 Impact Factor
  • Source
    • "Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis and an estimated incidence between 1 and 2 per million population annually [1] [2] [3] [4]. The age distribution is reported as bimodal with a first peak in childhood and a second higher peak in the fourth and fifth decade [3] [4]. Genetic studies performed on ACC were focused on molecular alterations either at the germline level in rare familial diseases or at somatic level in sporadic tumors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. The overall survival is five years from detection. Radical surgery is considered the therapy of choice in the first stages of ACC. However postoperative disease-free survival at 5 years is only around 30% and recurrence rates are frequent. o,p'DDD (ortho-, para'-, dichloro-, diphenyl-, dichloroethane, or mitotane), an adrenolytic drug with significant toxicity and unpredictable therapeutic response, is used in the treatment of ACC. Unfortunately, treatment for this aggressive cancer is still ineffective. Over the past years, the growing interest in ACC has contributed to the development of therapeutic strategies in order to contrast the neoplastic spread. In this paper we discuss the most promising therapies which can be used in this endocrine neoplasia.
    Journal of Oncology 08/2012; 2012:408131. DOI:10.1155/2012/408131
  • Source
    • "The phenomenon of gonadotropin-induced adrenocortical neoplasia is not unique to ferrets and mice. Subcapsular tumors have been reported in the adrenal glands of other gonadectomized animals , including guinea pigs, hamsters, goats, and cats (Bielinska et al., 2009; Meler et al., 2011). Often these tumors produce sex steroids. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the past decade, research on human adrenocortical neoplasia has been dominated by gene expression profiling of tumor specimens and by analysis of genetic disorders associated with a predisposition to these tumors. Although these studies have identified key genes and associated signaling pathways that are dysregulated in adrenocortical neoplasms, the molecular events accounting for the frequent occurrence of benign tumors and low rate of malignant transformation remain unknown. Moreover, the prognosis for patients with adrenocortical carcinoma remains poor, so new medical treatments are needed. Naturally occurring and genetically engineered animal models afford a means to investigate adrenocortical tumorigenesis and to develop novel therapeutics. This comparative review highlights adrenocortical tumor models useful for either mechanistic studies or preclinical testing. Three model species - mouse, ferret, and dog - are reviewed, and their relevance to adrenocortical tumors in humans is discussed.
    Molecular and Cellular Endocrinology 11/2011; 351(1):78-86. DOI:10.1016/j.mce.2011.09.045 · 4.24 Impact Factor
Show more


1 Download
Available from