Differential Expression Profiles of Cell-to-Matrix-Related Molecules in Adrenal Cortical Tumors: Diagnostic and Prognostic Implications

Abstract

The molecular mechanisms of adrenocortical carcinoma development are incompletely defined. De-regulation of cellular-to-extracellular matrix interactions and angiogenesis appear among mechanisms associated to the malignant phenotype. Our aim was to investigate, employing PCR-based array profiling, 157 molecules involved in cell-to-matrix interactions and angiogenesis in a frozen series of 6 benign and 6 malignant adrenocortical neoplasms, to identify novel pathogenetic markers. In 14 genes, a significant dysregulation was detected in adrenocortical carcinomas as compared to adenomas, most of them being downregulated. Three exceptions—hyaluronan synthase 1 (HAS-1), laminin α3 and osteopontin genes—demonstrated an increased expression in adrenocortical carcinomas of 4.46, 4.23 and 20.32-fold, respectively, and were validated by immunohistochemistry on a series of paraffin-embedded tissues, including 20 adenomas and 73 carcinomas. Osteopontin protein, absent in all adenomas, was expressed in a carcinoma subset (25/73) (p = 0.0022). Laminin α3 and HAS-1 were mostly expressed in smooth muscle and endothelial cells of the vascular network of both benign and malignant adrenocortical tumors. HAS-1 was also detected in tumor cells, with a more intense pattern in carcinomas. In this group, strong expression was significantly associated with more favorable clinicopathological features. These data demonstrate that cell-to-matrix interactions are specifically altered in adrenocortical carcinoma and identify osteopontin and HAS-1 as novel potential diagnostic and prognostic biomarkers, respectively, in adrenal cortical tumors.

Histopathologic Features of Adrenal Cortical Carcinoma

“…To date, the most relevant results of ACC molecular landscape characterization are represented by (1) the identification of driver genes of adrenocortical tumorigenesis (eg, CTNNB1 and TP53 ), (2) the definition of specific alterations supporting the discrimination between ACA and ACC ( IGF-2 overexpression, homozygous deletions of ZNRF3 and KREMEN1 , TERT amplification/promoter mutations, and chromosomal aneuploidy),25 (3) the description of prognostic subgroups (as identified by targeted gene expression, DNA-methylation signature, and next-generation sequencing) that proved to be particularly relevant in stage I to III ACC,25,144–147 and (4) the identification of drug targetable alterations, even if in a relatively small percentage of cases (up to 16%) 25,148,149…”

“…With the advent of molecular analysis, several mechanisms of ACT tumorigenesis were revealed, together with the additional identification of pathways and specific molecular signatures with clinical and diagnostic relevance. 143 To date, the most relevant results of ACC molecular landscape characterization are represented by (1) the identification of driver genes of adrenocortical tumorigenesis (eg, CTNNB1 and TP53), (2) the definition of specific alterations supporting the discrimination between ACA and ACC (IGF-2 overexpression, homozygous deletions of ZNRF3 and KREMEN1, TERT amplification/promoter mutations, and chromosomal aneuploidy), 25 (3) the description of prognostic subgroups (as identified by targeted gene expression, DNA-methylation signature, and next-generation sequencing) that proved to be particularly relevant in stage I to III ACC, 25,[144][145][146][147] and (4) the identification of drug targetable alterations, even if in a relatively small percentage of cases (up to 16%). 25,148,149 In particular, CTNNB1 activation and TP53 inactivation (and related pathways) are considered key driver mutations in the ACT panorama.…”

Special Issue: Present and Future of Personalised Medicine for Endocrine Cancers

“…The aim of this Special Issue entitled “Present and Future of Personalised Medicine for Endocrine Cancers” was to offer an overview of exciting new research in the area of endocrine tumours that may set the stage for an innovative personalised management and future precision medicine modalities for individualised care. This issue encompasses nine publications on basic, translational and clinical research in different types of endocrine malignancies, including thyroid cancer [ 8 , 9 , 10 , 11 ], adrenocortical neoplasms [ 12 , 13 , 14 ], pheochromocytoma/paraganglioma [ 15 ] and pituitary tumours [ 16 ].…”

“…Looking across diseases, some themes are recurrent, such as the efforts to identify effective biomarkers useful to improve differential diagnosis and/or prognostication of endocrine cancers [ 11 , 12 , 14 , 15 ] or to predict response to treatment [ 10 , 15 ]. More specifically, in the field of thyroid cancers, Piciu et al evaluated the correlation among different prognostic factors in papillary thyroid cancer, including the mutation of the BRAF V600E oncogene and the pathological standardized uptake values at the F18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) [ 9 ].…”

“…Considering adrenocortical tumours, the role of several immunohistochemical markers for the distinction of carcinomas (ACC) from adenomas (ACA) and for prognostic stratification of malignant tumours have been investigated by Angelousi and colleagues, demonstrating that altered reticulin pattern and p53/Ki-67 expression are useful markers for the differential diagnosis of adrenocortical tumours [ 14 ]. Another study showed that cell-to-matrix-related molecules are specifically altered in ACC when compared to ACAs and identified osteopontin and HAS-1 (Hyaluronan Synthase 1) as novel potential diagnostic and prognostic biomarkers, respectively [ 12 ].…”