Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?

Sbiera, Iuliu; Kircher, Stefan; Altieri, Barbara; Fassnacht, Martin; Kroiß, Matthias; Sbiera, Silviu

doi:10.3390/cancers13071736

Cited by 8 publications

(6 citation statements)

References 63 publications

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“…This indicates that the different members of the pathway have similar expression patterns between the normal and benign adrenocortical tissues but different from the ACC. Interestingly, the expression in all adrenocortical tissues clustered again separately from the expression in other normal and neoplastic tissues of both epithelial and mesenchymal origin indicating that adrenocortical tissues represent a particular tissue type as we could show before ( 43 ). A defining property of FGFs and their receptors is that they bind to heparin and heparan sulfate and are therefore intimately connected with the extracellular matrix of tissues ( 44 ) where they play an important role during epithelial morphogenesis ( 45 ).…”

Section: Discussionsupporting

confidence: 68%

Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications

Sbiera

Kircher

Altieri³

et al. 2021

Front. Endocrinol.

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Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 – 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 – 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.

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Section: Discussionsupporting

confidence: 68%

Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications

Sbiera

Kircher

Altieri³

et al. 2021

Front. Endocrinol.

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“…Of note, Sbiera et al showed that in ACC, there is no indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, higher SLUG expression (mesenchymal marker) was associated with clinical markers indicating aggressiveness [45].…”

Section: Discussionmentioning

confidence: 99%

Adrenocortical Cancer: A 20-Year Experience of a Single Referral Center in Prognosis and Outcomes

et al. 2021

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Adrenocortical carcinoma (ACC) is a rare but very aggressive endocrine malignancy with poor survival. Histopathology is important for diagnosis, while in some cases immunohistochemical markers and gene profiling of the resected tumor may be superior to current staging systems to determine prognosis. We aimed to present the 20-year experience at a tertiary hospital in patients with ACCs and correlate the immunohistochemical characteristics of ACCs with the clinical and morphological characteristics of the tumors and the survival of the patients. Forty-five patients with ACC were included in the study. All the resections were R0. The tumor size and weight, the disease stage (ENSAT classification), Weiss score and Helsinki score were examined along with immunohistochemical expression of inhibin-A, melan A, calretinin, Ki67, synaptophysin, p53, vimentin, CKAE1/AE3. The male to female ratio was 1:1.37. The median age at diagnosis was 55.5 years (IQR 19–77). The median size of ACCs was 9 cm (IQR 3.5–22 cm) and the median weight 127 g (IQR 18–1400 g). The median follow up period was 18 months (IQR 1–96). Ki67 varied from<1% to 75% (median: 16.4%). The expression of melan-A and lower expression of Ki-67 (≤4) were independently associated with longer OS time (p=0.01 and p=0.04, respectively). In multivariable analysis, tumor volume>400 cm3 (p=0.046), Weiss score>5 (p=0.007) and overexpression of p53 (p=0.036) were independent risk factors for shorter survival. Adrenocortical carcinoma is a rare and very aggressive endocrine malignancy. The most important factors that determine long-term prognosis of ACC are the disease stage at diagnosis, the Weiss score, and the Ki67 index. Immunohistochemical markers such as melan A could also serve as prognostic factors.

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“…β-Catenin silencing in H295R cells resulted in a decreased proliferation in vitro, abrogated tumor growth in vivo 16 and led to the down-regulation of the transcription factor Slug, 17 which is associated with a more aggressive phenotype of ACC. 18 Besides alterations of the Wnt/β-Catenin signaling pathway, massive deregulations of microRNA (miRNA) expression have been identified in ACC. 8,9,19,20 MiRNAs are small noncoding RNA of about 22 nucleotides-long, 21 which repress their target gene expression at the post-transcriptional level, either by inducing mRNA cleavage, destabilization or inhibition of translation.…”

Section: Introductionmentioning

confidence: 99%

Aberrant activation of Wnt/β-Catenin signaling pathway drives the expression of poor prognosis-associated microRNAs in adrenocortical cancer with a major impact on miR-139-5p and its host gene PDE2A

Cristante

Sayed

Denis

et al. 2023

Preprint

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Adrenocortical carcinoma (ACC) is a rare malignancy with dismal prognosis. Deregulated microRNA (miRNA) expression has been implicated in ACC aggressiveness. Nevertheless, the mechanisms underlying such deregulations remain unknown. Aberrant Wnt/β-Catenin signaling has been reported in about 40% of ACC and is associated with poor outcome. Here, we investigated the link between constitutive activation of Wnt/β-Catenin pathway and miRNA expression alterations in ACC. Inducible shRNA-mediated gene silencing of β-Catenin (β-Cat) was performed in ACC cells expressing constitutively active β-Catenin. The miRnome of ACC cells was analyzed using RNA-Sequencing. Selected miRNAs and mRNAs were validated using quantitative PCR and functional experiments with an emphasis on miR-139-5p, its host gene phosphodiesterase 2A (PDE2A) and its target gene N-Myc Downstream-Regulated Gene 4 (NDRG4). Prognostic values of Wnt/β-Catenin pathway components or mutational status and their correlations with miRNA/mRNA expressions were determined in COMETE-ENSAT and TCGA cohorts. We carried out the first miRnome analysis in β-Catenin-deficient (β-Cat-) ACC cells. Twelve upregulated miRNAs and 42 downregulated miRNAs among which miR-139-5p and miRNAs of the 14q32 locus were identified in β-Cat- cells. Downregulation of selected poor prognosis-associated miRNAs was confirmed using RT-qPCR. Remarkably, the expression of the intronic miR-139-5p was decreased by 90% in β-Cat- cells with a concomitant repression of its host gene PDE2A and upregulation of its target gene NDRG4. In ACC patients, miR-139-5p levels were highly correlated with the levels of PDE2A and anti-correlated with those of NDRG4. MiR-139-5p and PDE2A expressions were higher in patients with mutations in components of Wnt/β-Catenin signaling pathway or high expression of LEF1, with LEF1 proving a better predictor of prognosis than Wnt/β-Catenin signaling pathway mutational status. Our findings indicate that in addition to inducing protein-coding genes in ACC, constitutively active Wnt/β-Catenin signaling upregulates the expression of a subset of miRNAs involved in tumour aggressiveness and poor clinical outcome.

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Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?

Cited by 8 publications

References 63 publications

Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications

Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications

Adrenocortical Cancer: A 20-Year Experience of a Single Referral Center in Prognosis and Outcomes

Aberrant activation of Wnt/β-Catenin signaling pathway drives the expression of poor prognosis-associated microRNAs in adrenocortical cancer with a major impact on miR-139-5p and its host gene PDE2A

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