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Immunophenotypical alterations with impact on the epithelial-mesenchymal transition (EMT) process in salivary gland adenoid cystic carcinomas.

ABSTRACT: Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary glands neoplasms with an indolent clinical course, slow-growing but locally aggressive and quite often with delayed recurrence and distant metastasis. In order to elucidate this tumoral behavior, we conducted an immunohistochemical study investigating the alterations of epithelial phenotype with anti-cytokeratin (CK) AE1?AE3 and anti-E-cadherin antibodies, and the acquisition of mesenchymal phenotype with vimentin, fibronectin, N-cadherin and P-cadherin in salivary ACCs. Thus, we recorded a reduction of CK AE1?AE3, E-cadherin, P-cadherin and fibronectin reactivity in the solid variant and especially in the cells from the periphery of invasive neoplastic proliferations, regardless histological type. These phenotypical alterations suggest the involvement of the epithelial-mesenchymal transition (EMT) process in the progression of salivary ACCs.

SUBMITTER: Belulescu IC

PROVIDER: S-EPMC7728137 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Immunophenotypical alterations with impact on the epithelial-mesenchymal transition (EMT) process in salivary gland adenoid cystic carcinomas.

Belulescu Iulia Cristiana IC Mărgăritescu Claudiu C Dumitrescu Cristiana Iulia CI Munteanu Maria Cristina MC Mărgăritescu Otilia Clara OC

Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie 20200101 1

Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary glands neoplasms with an indolent clinical course, slow-growing but locally aggressive and quite often with delayed recurrence and distant metastasis. In order to elucidate this tumoral behavior, we conducted an immunohistochemical study investigating the alterations of epithelial phenotype with anti-cytokeratin (CK) AE1∕AE3 and anti-E-cadherin antibodies, and the acquisition of mesenchymal phenotype with vimentin, fibro ...[more]

PMID: 32747909

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Project description:Adenoid cystic carcinoma (ACC) is a slow growing, but relentless cancer. Due to its rarity and lack of understanding of its molecular etiology, no standard chemotherapy for ACC currently exists and many patients suffer from recurrent and/or metastatic disease. As such, development of safe and effective therapies is imperative. To describe and summarize existing clinical trial studies and preclinical discoveries, we surveyed the PubMed on developmental therapeutics for ACC. Objective response rates to monotherapy with cytotoxic agents were approximately 10% with cisplatin, 5-FU, gemcitabine, mitoxantrone, epirubicin, vinorelbine and paclitaxel. The most studied combination therapies were cyclophosphamide-doxorubicin-cisplatin (CAP) and cisplatin-vinorelbine, with an objective response rate of 18-31%. Among molecularly targeted drugs, the most studied drugs are inhibitors targeting the vascular endothelial growth factor receptor (VEGFR) to inhibit tumor angiogenesis. Among those, lenvatinib and axitinib showed a relatively high objective response rate of 11-16% and 9-17%, respectively. Given high recurrence rates and chemoresistance of ACC, treatments targeting cancer stem cells (CSC), which function as tumor-initiating cells and drive chemoresistance, may be particularly valuable. CSC have been shown to be targetable via MYB, Notch1, p53 and epigenetic mechanisms. Myb overexpression is characteristic in ACC but was previously thought to present a difficult target due to its nature as a transcription factor. However, due to the development Myb-targeted inhibitors and an ongoing clinical trial of MYB-targeted cancer vaccine therapy, MYB is becoming an increasingly attractive therapeutic target. Drugs targeting NOTCH signaling demonstrated 5-17% response rate in phase I clinical trials. Within the field of epigenetics, treatment with PRMT5 inhibitors has shown 21% partial response rate in phase I clinical trial. Immunotherapies, such as PD-1 inhibitors, are also associated with CSC, but have not been effective against ACC. However, clinical trials of cancer vaccine therapies are actively being conducted. In addition to conventional chemotherapies and inhibitors of angiogenesis, the emergence of new therapies such as immunotherapy and those targeting cancer stemness is expected to bring clinical benefits to patients in the future.

Project description:Salivary adenoid cystic carcinoma (ACC) is an insidious slow-growing cancer with the propensity to recur and metastasise to distant sites. Basal-like breast carcinoma (BBC) is a molecular subtype that constitutes 15-20% of breast cancers, shares histological similarities and basal cell markers with ACC, lacks expression of ER (oestrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2), and, similar to ACC, metastasises predominantly to the lung and brain. Both cancers lack targeted therapies owing to poor understanding of their molecular drivers.Gene expression profiling, immunohistochemical staining, western blot, RT-PCR, and in silico analysis of massive cancer data sets were used to identify novel markers and potential therapeutic targets for ACC and BBC. For the detection and comparison of gene signatures, we performed co-expression analysis using a recently developed web-based multi-experiment matrix tool for visualisation and rank aggregation.In ACC and BBC we identified characteristic and overlapping SOX10 gene signatures that contained a large set of novel potential molecular markers. SOX10 was validated as a sensitive diagnostic marker for both cancers and its expression was linked to normal and malignant myoepithelial/basal cells. In ACC, BBC, and melanoma (MEL), SOX10 expression strongly co-segregated with the expression of ROPN1B, GPM6B, COL9A3, and MIA. In ACC and breast cancers, SOX10 expression negatively correlated with FOXA1, a cell identity marker and major regulator of the luminal breast subtype. Diagnostic significance of several conserved elements of the SOX10 signature (MIA, TRIM2, ROPN1, and ROPN1B) was validated on BBC cell lines.SOX10 expression in ACC and BBC appears to be a part of a highly coordinated transcriptional programme characteristic for cancers with basal/myoepithelial features. Comparison between ACC/BBC and other cancers, such as neuroblastomaand MEL, reveals potential molecular markers specific for these cancers that are likely linked to their cell identity. SOX10 as a novel diagnostic marker for ACC and BBC provides important molecular insight into their molecular aetiology and cell origin. Given that SOX10 was recently described as a principal driver of MEL, identification of conserved elements of the SOX10 signatures may help in better understanding of SOX10-related signalling and development of novel diagnostic and therapeutic tools.

Dataset Information

Immunophenotypical alterations with impact on the epithelial-mesenchymal transition (EMT) process in salivary gland adenoid cystic carcinomas.

Publications

Immunophenotypical alterations with impact on the epithelial-mesenchymal transition (EMT) process in salivary gland adenoid cystic carcinomas.

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