Stem cell regulation plays a crucial role during development and homeostasis. Here, an essential source of Wnts from Gli1+ stem/progenitor cells was identified in the murine molar. Loss of Wnt production in Gli1+ apical stem/progenitor cells led to loss of Axin2 at the root apex, mis-regulation of SOX9, loss of BMP and Hh signaling, and truncation of root development. In the absence of Wnt signals, the root epithelium lost its integrity and epithelial identity. This phenotype could be partially mimicked by loss of Sox9 in the Gli1 population. Stabilization of Wnt signaling in the apical papilla led to rapid unordered differentiation of hard tissues and fragmentation of the epithelial root sheath. Wnt signaling from Gli1+ stem/progenitor cells, therefore, orchestrates root development, coordinating mesenchymal and epithelial interactions via SOX9 to regulate stem/progenitor cell expansion and differentiation. Our results demonstrate that disparate stem/progenitor cell populations are unified in their fundamental signaling interactions.
GLI1 fusions involving ACTB, MALAT1, PTCH1 and FOXO4 genes have been reported in a subset of malignant mesenchymal tumors with a characteristic nested epithelioid morphology and frequent S100 positivity. Typically, these multilobulated tumors consist of uniform epithelioid cells with bland nuclei and are organized into distinct nests and cords with conspicuously rich vasculature. We herein expand earlier findings by reporting a case of a 34-year-old female with an epithelioid mesenchymal tumor of the palate. The neoplastic cells stained positive for S100 protein and D2-40, whereas multiple other markers were negative. Genetic alterations were investigated by targeted RNA sequencing, and a PTCH1-GLI1 fusion was detected. Epithelioid mesenchymal tumors harboring a PTCH1-GLI1 fusion are vanishingly rare with only three cases reported so far. Due to the unique location in the mucosa of the soft palate adjacent to minor salivary glands, multilobulated growth, nested epithelioid morphology, focal clearing of the cytoplasm, and immunopositivity for S100 protein and D2-40, the differential diagnoses include primary salivary gland epithelial tumors, in particular myoepithelioma and myoepithelial carcinoma. Another differential diagnostic possibility is the ectomesenchymal chondromyxoid tumor. Useful diagnostic clues for tumors with a GLI1 rearrangement include a rich vascular network between the nests of neoplastic cells, tumor tissue bulging into vascular spaces, and absence of SOX10, GFAP and cytokeratin immunopositivity. Identifying areas with features of GLI1-rearranged tumors should trigger subsequent molecular confirmation. This is important for appropriate treatment measures as PTCH1-GLI1 positive mesenchymal epithelioid neoplasms have a propensity for locoregional lymph node and distant lung metastases.
- MeSH
- dospělí MeSH
- lidé MeSH
- myoepiteliální nádor * patologie MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádory měkkých tkání * patologie MeSH
- nádory slinných žláz * MeSH
- patro měkké patologie MeSH
- protein Gli1 genetika metabolismus MeSH
- proteiny S100 MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- přehledy MeSH
Specific A3 adenosine receptor (A3AR) agonist, 2-chloro-N6-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine (2-Cl-IB-MECA), demonstrates anti-proliferative effects on various types of tumor. In the present study, the cytotoxicity of 2-Cl-IB-MECA was analyzed in a panel of tumor and non-tumor cell lines and its anticancer mechanisms in JoPaca-1 pancreatic and Hep-3B hepatocellular carcinoma cell lines were also investigated. Initially, decreased tumor cell proliferation, cell accumulation in the G1 phase and inhibition of DNA and RNA synthesis was found. Furthermore, western blot analysis showed decreased protein expression level of β-catenin, patched1 (Ptch1) and glioma-associated oncogene homolog zinc finger protein 1 (Gli1), which are components of the Wnt/β-catenin and Sonic hedgehog/Ptch/Gli transduction pathways. In concordance with these findings, the protein expression levels of cyclin D1 and c-Myc were reduced. Using a luciferase assay, it was revealed for the first time a decrease in β-catenin transcriptional activity, as an early event following 2-Cl-IB-MECA treatment. In addition, the protein expression levels of multidrug resistance-associated protein 1 and P-glycoprotein (P-gp) were reduced and the P-gp xenobiotic efflux function was also reduced. Next, the enhancing effects of 2-Cl-IB-MECA on the cytotoxicity of conventional chemotherapy was investigated. It was found that 2-Cl-IB-MECA enhanced carboplatin and doxorubicin cytotoxic effects in the JoPaca-1 and Hep-3B cell lines, and a greater synergy was found in the highly tumorigenic JoPaca-1 cell line. This provides a novel in vitro rationale for the utilization of 2-Cl-IB-MECA in combination with chemotherapeutic agents, not only for hepatocellular carcinoma, but also for pancreatic cancer. Other currently used conventional chemotherapeutics, fluorouracil and gemcitabine, showed synergy only when combined with high doses of 2-Cl-IB-MECA. Notably, experiments with A3AR-specific antagonist, N-[9-Chloro-2-(2-furanyl)(1,2,4)-triazolo(1,5-c)quinazolin-5-yl]benzene acetamide, revealed that 2-Cl-IB-MECA had antitumor effects via both A3AR-dependent and -independent pathways. In conclusion, the present study identified novel antitumor mechanisms of 2-Cl-IB-MECA in pancreatic and hepatocellular carcinoma in vitro that further underscores the importance of A3AR agonists in cancer therapy.
- MeSH
- adenosin analogy a deriváty MeSH
- buněčné linie MeSH
- léková rezistence MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory jater * farmakoterapie MeSH
- nádory slinivky břišní * genetika MeSH
- proliferace buněk MeSH
- protein Gli1 genetika metabolismus MeSH
- proteiny hedgehog MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Multiple familial trichoepitheliomas (MFT) is an autosomal dominantly inherited disease characterized by multiple skin appendage tumors. We describe a patient showing a continuous spectrum of follicular differentiated neoplasms including classical trichoepitheliomas but also infiltrative growing and finally metastasizing malignant follicular differentiated tumors. Germline mutation analysis revealed a nonsense mutation in the cylindromatosis (CYLD) gene. Gene expression analysis by real-time PCR of tumor tissue showed overexpression of glioma-associated oncogene Gli1 mRNA. Treatment with the Hedgehog pathway inhibitor vismodegib resulted in a significant regression of the highly differentiated trichoepitheliomas. Gli upregulation is indicative of an active Hedgehog signaling pathway. We hypothesize that its upregulation is indirectly caused by CYLD mutation which promotes tumor development. Vismodegib treatment could thus provide a new treatment option for patients with this debilitating disorder.
- MeSH
- anilidy terapeutické užití MeSH
- antitumorózní látky terapeutické užití MeSH
- dědičné nádorové syndromy farmakoterapie genetika metabolismus patologie MeSH
- dědičnost MeSH
- deubikvitinizační enzym CYLD genetika MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory kůže farmakoterapie genetika metabolismus patologie MeSH
- nesmyslný kodon MeSH
- počítačová rentgenová tomografie MeSH
- protein Gli1 genetika metabolismus MeSH
- pyridiny terapeutické užití MeSH
- rodokmen MeSH
- signální transdukce účinky léků MeSH
- upregulace MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
