Highlights d Human OSCCs are marked by polarized clusters of CD8 + or CD4 + T cell-enriched tumors d In a mouse model of carcinogen-induced OSCC, late Treg cell ablation exacerbates OSCC d Exacerbation of OSCC following Treg cell ablation is dependent on effector T cells
The human P-glycoprotein (Pgp) encoded by the MDR1 gene is as a transmembrane drug transporter that mediates the efflux of drugs from cells. It confers multidrug resistance in cancer cells that overexpress MDR1. In addition, basal expression of MDR1 in organs such as liver, kidney, and colon affects the pharmacokinetics of drug uptake and excretion for agents that are substrates for Pgp transport. Nuclear receptors such as SXR and CAR have been suggested as possible master regulators of xenobiotic- and drug-inducible expression of MDR1 and of other genes involved in drug metabolism in drug processing organs. However, the mechanism of MDR1 regulation in tumors or in normal, non-malignant tissue, particularly in response to xenobiotics, has yet to be demonstrated in vivo. To facilitate the mechanistic study of MDR1 gene regulation in vivo, we previously reported a mouse model that allows non-invasive bioimaging of the mdr1 gene expression in vivo and in real time by inserting a firefly luciferase (fLUC) gene into the murine mdr1a genetic locus by homologous recombination.1 To determine the role of PXR, the murine homologue of SXR, in drug-mediated induction of mdr1a, we crossed mdr1a.fLUC mice with PXR knockout mice. Pregnenolone-16α-carbonitrile (PCN), a known SXR substrate, induced intestinal mdr1a.fLUC expression in the PXR wild type background but not the PXR knockout background. Notably, mdr1a.fLUC was re-inducible over three rounds of drug dosing, which could be measured longitudinally in our real-time assessment of gene expression. TCPOBOP, a known CAR ligand, induced mdr1a.fLUC in both the wild type and knockout background, consistent with the idea that mdr1a is also regulated by the CAR nuclear receptor. The chemotherapeutic agent docetaxel induced mdr1a.fLUC in the PXR wild type background but induction was dramatically reduced in the PXR KO background; paclitaxel gave only low-level induction in both genetic backgrounds. This result is consistent with the reported ligand specificity of mouse PXR. Future studies in a CAR-null background will determine if the observed effect of paclitaxel on mdr1a expression is mediated through CAR. These studies demonstrate the utility of our murine imaging model for the in vivo study of mdr1 gene regulation in real time. Studies with additional chemotherapeutic drugs and genetic backgrounds will establish the variety of agents capable of inducing mdr1a at the transcriptional level and the trans-acting factors that are involved in such induction.
1Gu et al. Proc Natl Acad Sci 106:5394-5399 (2009)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 701. doi:10.1158/1538-7445.AM2011-701
Salivary gland neoplasms are both rare and strikingly heterogeneous in their morphology, a combination that may result in vexingly broad differential diagnoses. This is particularly true of myoepithelial-rich tumors, as neoplastic myoepithelial cells can assume a multiplicity of phenotypes, and associated epithelial cells may be present to varying degrees. An accurate diagnosis requires a thorough familiarity with characteristic morphology and conversance with appropriate ancillary studies. Here, we review 4 myoepithelial-rich tumors (myoepithelioma, myoepithelial carcinoma, myoepithelial-rich pleomorphic adenoma, and epithelial-myoepithelial carcinoma), comparing and contrasting their characteristic morphology, immunohistochemical profiles, and cytogenetic/molecular features, with an emphasis on accurate and efficient narrowing of the differential diagnosis.
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