Genetic, transcriptional, and morphological differences have been reported in pancreatic ductal adenocarcinoma (PDAC) cases. We recently found that epithelial or mesenchymal features were enhanced in three-dimensional (3D) cultures compared to two-dimensional (2D) cultures. In this study, we examined the differences in the morphological and functional characteristics of eight PDAC cell lines in 2D and 3D cultures. Most PDAC cells showed similar pleomorphic morphologies in 2D culture. Under 3D culture, PDAC cells with high E-cadherin and low vimentin expression levels (epithelial) formed small round spheres encircled with flat lining cells, whereas those with high vimentin and low E-cadherin expression levels (mesenchymal) formed large grape-like spheres without lining cells and were highly proliferative. In 3D culture, gemcitabine was more effective for the spheres formed by PDAC cells with epithelial features, while abraxane was more effective on those with mesenchymal features. The expression levels of drug transporters were highest PDAC cells with high vimentin expression levels. These findings indicate that PDAC cells possess various levels of epithelial and mesenchymal characteristics. The 3D-culture method is useful for investigating the diversity of PDAC cell lines and may play important roles in the development of personalized early diagnostic methods and anticancer drugs for PDAC.
Malignant gliomas are the most aggressive human primary brain tumors and are currently incurable. Immunotherapies have the potential to target glioma and glioma stem cells (GSCs) that are resistant to conventional therapies. We previously identified SOX6 as a human glioma antigen and demonstrated that vaccination with SOX6 DNA induced cytotoxic T lymphocytes (CTLs) specific for glioma, thereby exerting therapeutic antitumor responses in glioma-bearing mice. In this study, we attempted to identify SOX6-derived peptides as specific targets for effective and safe T-cell-mediated immunotherapy targeting SOX6-positive glioma and GSCs. In vitro stimulation with human leukocyte antigen (HLA)-A*2402 (A24)-restricted peptides, RFENLGPQL (SOX6 504 ) and PYYEEQARL (SOX6 628 ) or the HLA-A*0201 (A2)-restricted peptide, ALFGDQDTV (SOX6 447 ) was capable of inducing SOX6 peptide-specific CTLs in peripheral blood mononuclear cells derived from healthy donors and glioma patients. These CTLs were able to lyse a majority of glioma cell lines and a GSC line derived from human glioblastoma in an HLA Class I-restricted and an antigen-dependent manner. Furthermore, peptide vaccines of SOX6 628 , which was conserved in the murine SOX6 protein and expected to bind to major histocompatibility complex (MHC) H-2 d , induced CTLs specific for SOX6 628 in H-2 d mice. Normal autologous cells from mice, in which SOX6-specific immune responses were generated, were not destroyed. These results suggest that these SOX6 peptides are potnetially immunogenic in HLA-A24 or -A2 positive glioma patients and should be considered as a promising strategy for safe and effective T-cell-based immunotherapy of patients with gliomas.
In anergic T cells, T-cell receptor (TCR)-These results imply that TAB1-mediated activation of p38␣ in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.
The aims of this study were to determine whether the appearance of stromal myofibroblasts and the expression of tenascin-C (Tn-C) correlate with the grade of malignancy in canine mammary tumors and to determine the main cellular source of Tn-C in these tumors. Single or double immunostaining using antibodies against a-smooth muscle actin (a-SMA) and Tn-C was performed on serial sections of normal canine mammary glands as well as those with lobular hyperplasia, simple adenoma, and simple carcinoma. Thirty-nine of 42 simple carcinomas (93%) exhibited stromal a-SMA-positive myofibroblasts and Tn-C expression. Only 6 of 11 cases of simple adenoma (55%) showed these changes, whereas no changes were observed in normal mammary gland tissue or cases of lobular hyperplasia. The distribution of stromal Tn-C correlated with the presence of myofibroblasts. However, Tn-C immunoreactivity was also occasionally observed in the basement membrane zone surrounding the myoepithelial layer in normal tissue, benign lesions, and tubulopapillary carcinomas. This pattern of staining was not related to the presence of myofibroblasts. The appearance of stromal myofibroblasts and expression of Tn-C were significantly correlated with higher histological grades of malignancy and vascular/lymphatic invasion in simple carcinomas. Stromal myofibroblasts appear to be a major cellular source of Tn-C and play an important role in the development of canine mammary tumors. The Tn-C expressed in the basement membrane zone of normal, hyperplastic, and neoplastic mammary tissue, which is likely produced by neighboring myoepithelial cells, may differ functionally from the Tn-C produced by myofibroblasts.
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