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Molecular Aspects of Adrenal Diseases and Carcinoma
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Molecular Aspects of Adrenal Diseases and Carcinoma

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 April 2025 | Viewed by 9484

Special Issue Editor

Dr. Tamás Micsík

E-Mail Website
Guest Editor
Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, H-1085 Budapest, Hungary
Interests: adrenal gland; digital pathology; image analysis; prognostic factors; molecular genetics

Special Issue Information

Dear Colleagues,

The adrenal gland is a rather hidden organ; thus, any pathological process developing in it can provoke wide differential diagnostic issues, as benign and malignant diseases can also affect the organ. After the exclusion of benign diseases and metastases, the malignant counterpart, adrenocortical cancer, is a very difficult diagnosis as not only the criteria of malignancy but also the prognostic factors and thus the behavior of the disease are hardly predictable. There are multiple risk-stratifications of both malignancy and progression; still, these are far for perfect and thus may be subject to considerable debate when defining therapeutic plans.

Nowadays, the revolution in data and molecular sciences as well as in digital pathology and artificial intelligence has the capacity to rephrase the approach to adrenal disease and neoplasia, potentially offering better screening, diagnosis, prognostication and tailored therapy. The aim of our Special Issue is to collect as much new molecular, genetic, prognostic, micro and macroenvironmental data in defining the best and individualized diagnosis and treatment for adrenal disease and neoplasia.

Topics of this Special Issue include, but are not limited to:

  • Tumor microenvironment and macroenvironment;
  • Cancer biomarkers: screening, diagnosis, prognosis;
  • Adrenal disease and cancer therapy: target discovery, drug design, resistance, targeted therapy, theragnostic, personalized medicine;
  • Translational cancer research;
  • High-throughput technologies: genomics, epigenomics, proteomics, metabolomics, microarray, next-generation sequencing, and other omics technologies involved in developing diagnosis and therapy;
  • Genomic and proteomic databases and applications;
  • Digital pathological approach to develop diagnosis, prognostication and treatment;
  • The exploitation of artificial intelligence in diagnosis, prognostication and personalized therapy.

Dr. Tamás Micsík
Guest Editor

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Keywords

  • adrenal neoplasia
  • adrenocortical cancer
  • molecular and genetics
  • omics
  • artificial intelligence digital pathology
  • individualized therapy
  • prognostication

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Published Papers (7 papers)

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Research

Jump to: Review

19 pages, 4197 KiB  
Article
Polyamine Pathway Inhibitor DENSPM Suppresses Lipid Metabolism in Pheochromocytoma Cell Line
by Hans K. Ghayee, Kaylie A. Costa, Yiling Xu, Heather M. Hatch, Mateo Rodriguez, Shelby C. Straight, Marian Bustamante, Fahong Yu, Fatima Smagulova, John A. Bowden and Sergei G. Tevosian
Int. J. Mol. Sci. 2024, 25(18), 10029; https://doi.org/10.3390/ijms251810029 - 18 Sep 2024
Viewed by 1254
Abstract
Pheochromocytomas (PCCs) are tumors arising from chromaffin cells in the adrenal medulla, and paragangliomas (PGLs) are tumors derived from extra-adrenal sympathetic or parasympathetic paraganglia; these tumors are collectively referred to as PPGL cancer. Treatment for PPGL primarily involves surgical removal of the tumor, [...] Read more.
Pheochromocytomas (PCCs) are tumors arising from chromaffin cells in the adrenal medulla, and paragangliomas (PGLs) are tumors derived from extra-adrenal sympathetic or parasympathetic paraganglia; these tumors are collectively referred to as PPGL cancer. Treatment for PPGL primarily involves surgical removal of the tumor, and only limited options are available for treatment of the disease once it becomes metastatic. Human carriers of the heterozygous mutations in the succinate dehydrogenase subunit B (SDHB) gene are susceptible to the development of PPGL. A physiologically relevant PCC patient-derived cell line hPheo1 was developed, and SDHB_KD cells carrying a stable short hairpin knockdown of SDHB were derived from it. An untargeted metabolomic approach uncovered an overactive polyamine pathway in the SDHB_KD cells that was subsequently fully validated in a large set of human SDHB-mutant PPGL tumor samples. We previously reported that treatment with the polyamine metabolism inhibitor N1,N11-diethylnorspermine (DENSPM) drastically inhibited growth of these PCC-derived cells in culture as well as in xenograft mouse models. Here we explored the mechanisms underlying DENSPM action in hPheo1 and SDHB_KD cells. Specifically, by performing an RNAseq analysis, we have identified gene expression changes associated with DENSPM treatment that broadly interfere with all aspects of lipid metabolism, including fatty acid (FA) synthesis, desaturation, and import/uptake. Furthermore, by performing an untargeted lipidomic liquid chromatography–mass spectrometry (LC/MS)-based analysis we uncovered specific groups of lipids that are dramatically reduced as a result of DENSPM treatment. Specifically, the bulk of plasmanyl ether lipid species that have been recently reported as the major determinants of cancer cell fate are notably decreased. In summary, this work suggests an intersection between active polyamine and lipid pathways in PCC cells. Full article
(This article belongs to the Special Issue Molecular Aspects of Adrenal Diseases and Carcinoma)
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17 pages, 4261 KiB  
Article
A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia–CYP21A2-R484Q Mutant Mouse
by Shamini Ramkumar Thirumalasetty, Tina Schubert, Ronald Naumann, Ilka Reichardt, Marie-Luise Rohm, Dana Landgraf, Florian Gembardt, Mirko Peitzsch, Michaela F. Hartmann, Mihail Sarov, Stefan A. Wudy, Nicole Reisch, Angela Huebner and Katrin Koehler
Int. J. Mol. Sci. 2024, 25(10), 5062; https://doi.org/10.3390/ijms25105062 - 7 May 2024
Cited by 1 | Viewed by 1626
Abstract
Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in CYP21A2 [...] Read more.
Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in CYP21A2, causing 21-hydroxylase deficiency (21-OHD). Despite emerging treatment options for CAH, it is not always possible to physiologically replace cortisol levels and counteract hyperandrogenism. Moreover, there is a notable absence of an effective in vivo model for pre-clinical testing. In this work, we developed an animal model for CAH with the clinically relevant point mutation p.R484Q in the previously humanized CYP21A2 mouse strain. Mutant mice showed hyperplastic adrenals and exhibited reduced levels of corticosterone and 11-deoxycorticosterone and an increase in progesterone. Female mutants presented with higher aldosterone concentrations, but blood pressure remained similar between wildtype and mutant mice in both sexes. Male mutant mice have normal fertility with a typical testicular appearance, whereas female mutants are infertile, exhibit an abnormal ovarian structure, and remain in a consistent diestrus phase. Conclusively, we show that the animal model has the potential to contribute to testing new treatment options and to prevent comorbidities that result from hormone-related derangements and treatment-related side effects in CAH patients. Full article
(This article belongs to the Special Issue Molecular Aspects of Adrenal Diseases and Carcinoma)
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14 pages, 4741 KiB  
Article
Evidence of the Role of Inflammation and the Hormonal Environment in the Pathogenesis of Adrenal Myelolipomas in Congenital Adrenal Hyperplasia
by Vipula Kolli, Emily Frucci, Isabela Werneck da Cunha, James R. Iben, Sun A. Kim, Ashwini Mallappa, Tianwei Li, Fabio Rueda Faucz, Electron Kebebew, Naris Nilubol, Martha M. Quezado and Deborah P. Merke
Int. J. Mol. Sci. 2024, 25(5), 2543; https://doi.org/10.3390/ijms25052543 - 22 Feb 2024
Viewed by 1760
Abstract
Adrenal myelolipomas (AML) are composed of mature adipose and hematopoietic components. They represent approximately 3 percent of adrenal tumors and are commonly found in patients with congenital adrenal hyperplasia (CAH). CAH provides a unique environment to explore AML pathogenesis. We aimed to evaluate [...] Read more.
Adrenal myelolipomas (AML) are composed of mature adipose and hematopoietic components. They represent approximately 3 percent of adrenal tumors and are commonly found in patients with congenital adrenal hyperplasia (CAH). CAH provides a unique environment to explore AML pathogenesis. We aimed to evaluate the role of the immune system and hormones that accumulate in poorly controlled CAH in the development of AML. When compared to normal adrenal tissue, CAH-affected adrenal tissue and myelolipomas showed an increased expression of inflammatory cells (CD68, IL2Rbeta), stem cells (CD117) B cells (IRF4), and adipogenic markers (aP2/FABP4, AdipoQ, PPARγ, Leptin, CideA), and immunostaining showed nodular lymphocytic accumulation. Immunohistochemistry staining revealed a higher density of inflammatory cells (CD20, CD3, CD68) in CAH compared to non-CAH myelolipomas. In vitro RNA-sequencing studies using NCI-H295R adrenocortical cells with exogenous exposure to ACTH, testosterone, and 17-hydroxyprogesterone hormones, showed the differential expression of genes involved in cell cycle progression, phosphorylation, and tumorigenesis. Migration of B-lymphocytes was initiated after the hormonal treatment of adrenocortical cells using the Boyden chamber chemotaxis assay, indicating a possible hormonal influence on triggering inflammation and the development of myelolipomas. These findings demonstrate the important role of inflammation and the hormonal milieu in the development of AML in CAH. Full article
(This article belongs to the Special Issue Molecular Aspects of Adrenal Diseases and Carcinoma)
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14 pages, 4360 KiB  
Article
Albumin/Mitotane Interaction Affects Drug Activity in Adrenocortical Carcinoma Cells: Smoke and Mirrors on Mitotane Effect with Possible Implications for Patients’ Management
by Aurora Schiavon, Laura Saba, Gianluca Catucci, Jessica Petiti, Soraya Puglisi, Chiara Borin, Giuseppe Reimondo, Gianfranco Gilardi, Claudia Giachino, Massimo Terzolo and Marco Lo Iacono
Int. J. Mol. Sci. 2023, 24(23), 16701; https://doi.org/10.3390/ijms242316701 - 24 Nov 2023
Viewed by 1442
Abstract
Background: Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). Although it has been used for many years, its mechanism of action remains elusive. H295R cells are, in ACC, an essential tool to evaluate drug mechanisms, although they often [...] Read more.
Background: Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). Although it has been used for many years, its mechanism of action remains elusive. H295R cells are, in ACC, an essential tool to evaluate drug mechanisms, although they often lead to conflicting results. Methods: Using different in vitro biomolecular technologies and biochemical/biophysical experiments, we evaluated how the presence of “confounding factors” in culture media and patient sera could reduce the pharmacological effect of mitotane and its metabolites. Results: We discovered that albumin, the most abundant protein in the blood, was able to bind mitotane. This interaction altered the effect of the drug by blocking its biological activity. This blocking effect was independent of the albumin source or methodology used and altered the assessment of drug sensitivity of the cell lines. Conclusions: In conclusion, we have for the first time demonstrated that albumin does not only act as an inert drug carrier when mitotane or its metabolites are present. Indeed, our experiments clearly indicated that both albumin and human serum were able to suppress the pharmacological effect of mitotane in vitro. These experiments could represent a first step towards the individualization of mitotane treatment in this rare tumor. Full article
(This article belongs to the Special Issue Molecular Aspects of Adrenal Diseases and Carcinoma)
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Review

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26 pages, 2255 KiB  
Review
Molecular and Genetics Perspectives on Primary Adrenocortical Hyperfunction Disorders
by Sanggu Kim, Preeti Kumari Chaudhary and Soochong Kim
Int. J. Mol. Sci. 2024, 25(21), 11341; https://doi.org/10.3390/ijms252111341 - 22 Oct 2024
Viewed by 638
Abstract
Adrenocortical disorders encompass a broad spectrum of conditions ranging from benign hyperplasia to malignant tumors, significantly disrupting hormone balance and causing a variety of clinical manifestations. By leveraging next-generation sequencing and in silico analyses, recent studies have uncovered the genetic and molecular pathways [...] Read more.
Adrenocortical disorders encompass a broad spectrum of conditions ranging from benign hyperplasia to malignant tumors, significantly disrupting hormone balance and causing a variety of clinical manifestations. By leveraging next-generation sequencing and in silico analyses, recent studies have uncovered the genetic and molecular pathways implicated in these transitions. In this review, we explored the molecular and genetic alterations in adrenocortical disorders, with a particular focus on the transitions from normal adrenal function to hyperfunction. The insights gained are intended to enhance diagnostic and therapeutic strategies, offering up-to-date knowledge for managing these complex conditions effectively. Full article
(This article belongs to the Special Issue Molecular Aspects of Adrenal Diseases and Carcinoma)
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14 pages, 878 KiB  
Review
Genetic and Molecular Biomarkers in Aggressive Pheochromocytomas and Paragangliomas
by Francesca Torresan, Clelia Iacobone, Francesco Giorgino and Maurizio Iacobone
Int. J. Mol. Sci. 2024, 25(13), 7142; https://doi.org/10.3390/ijms25137142 - 28 Jun 2024
Viewed by 910
Abstract
Pheochromocytomas and paragangliomas (PPGLs) are rare neoplasms producing catecholamines that occur as hereditary syndromes in 25–40% of cases. To date, PPGLs are no longer classified as benign and malignant tumors since any lesion could theoretically metastasize, even if it occurs only in a [...] Read more.
Pheochromocytomas and paragangliomas (PPGLs) are rare neoplasms producing catecholamines that occur as hereditary syndromes in 25–40% of cases. To date, PPGLs are no longer classified as benign and malignant tumors since any lesion could theoretically metastasize, even if it occurs only in a minority of cases (approximately 10–30%). Over the last decades, several attempts were made to develop a scoring system able to predict the risk of aggressive behavior at diagnosis, including the risk of metastases and disease recurrence; unfortunately, none of the available scores is able to accurately predict the risk of aggressive behavior, even including clinical, biochemical, and histopathological features. Thus, life-long follow-up is required in PPGL patients. Some recent studies focusing on genetic and molecular markers (involved in hypoxia regulation, gene transcription, cellular growth, differentiation, signaling pathways, and apoptosis) seem to indicate they are promising prognostic factors, even though their clinical significance needs to be further evaluated. The most involved pathways in PPGLs with aggressive behavior are represented by Krebs cycle alterations caused by succinate dehydrogenase subunits (SDHx), especially when caused by SDHB mutations, and by fumarate hydratase mutations that lead to the activation of hypoxia pathways and DNA hypermethylation, suggesting a common pathway in tumorigenesis. Conversely, PPGLs showing mutations in the kinase cascade (cluster 2) tend to display less aggressive behavior. Finally, establishing pathways of tumorigenesis is also fundamental to developing new drugs targeted to specific pathways and improving the survival of patients with metastatic disease. Unfortunately, the rarity of these tumors and the scarce number of cases enrolled in the available studies represents an obstacle to validating the role of molecular markers as reliable predictors of aggressiveness. Full article
(This article belongs to the Special Issue Molecular Aspects of Adrenal Diseases and Carcinoma)
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15 pages, 1001 KiB  
Review
The Role of the Gap Junction Protein Connexin in Adrenal Gland Tumorigenesis
by Maja Mizdrak, Tina Ticinovic Kurir, Ivan Mizdrak, Marko Kumric, Mladen Krnic and Josko Bozic
Int. J. Mol. Sci. 2024, 25(10), 5399; https://doi.org/10.3390/ijms25105399 - 15 May 2024
Cited by 1 | Viewed by 1054
Abstract
Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible [...] Read more.
Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible role of connexins (Cxs), as major GJ proteins, under both physiological and pathological conditions in the adrenal gland, were evaluated in this review. The databases Web of Science, PubMed and Scopus were searched. Studies were evaluated if they provided data regarding the connexin expression pattern in the adrenal gland, despite current knowledge of this topic not being widely investigated. Connexin expression in the adrenal gland differs according to different parts of the gland and depends on ACTH release. Cx43 is the most studied connexin expressed in the adrenal gland cortex. In addition, Cx26, Cx32 and Cx50 were also investigated in the human adrenal gland. Cx50 as the most widespread connexin, along with Cx26, Cx29, Cx32, Cx36 and Cx43, has been expressed in the adrenal medulla with distinct cellular distribution. Considerable effort has recently been directed toward connexins as therapeutically targeted molecules. At present, there exist several viable strategies in the development of potential connexin-based therapeutics. The differential and hormone-dependent distribution of gap junctions within adrenal glands, the relatively large gap junction within this gland and the increase in the gap junction size and number following hormonal treatment would indicate that gap junctions play a pivotal role in cell functioning in the adrenal gland. Full article
(This article belongs to the Special Issue Molecular Aspects of Adrenal Diseases and Carcinoma)
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