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Hashimoto H.,National Cancer Center Research Institute | Ueda R.,National Cancer Center Research Institute | Narumi K.,National Cancer Center Research Institute | Heike Y.,Exploratory Oncology Research | And 2 more authors.
Cancer Gene Therapy | Year: 2014

Type I interferon (IFN) is a pleiotropic cytokine regulating the cancer cell death and immune response. IFN-α can, as we have also reported, effectively induce an antitumor immunity by the activation of tumor-specific T cells and maturation of dendritic cells in various animal models. Unknown, however, is how the type I IFN alters the immunotolerant microenvironment in the tumors. Here, we found that intratumoral IFN-α gene transfer significantly decreased the frequency of regulatory T cells (Tregs) per CD4 + T cells in tumors. The concentration of a Treg-inhibitory cytokine, interleukin (IL)-6, was correlated with the IFN-α expression level in tumors, and intratumoral CD11c + cells produced IL-6 in response to IFN-α stimulation. To confirm the role of IL-6 in the suppression of Tregs in tumors, an anti-IL-6 receptor antibody was administered in IFN-α-treated mice. The antibody increased the frequency of Tregs in the tumors, and attenuated systemic tumor-specific immunity induced by IFN-α. Furthermore, the IFN-α-mediated IL-6 production increased the frequency of Th17 cells in the tumors, which may be one of the mechanisms for the reduction of Tregs. The study demonstrated that IFN-α gene delivery creates an environment strongly supporting the enhancement of antitumor immunity through the suppression of Tregs. © 2014 Nature America, Inc. All rights reserved.

Nakatsuka R.,Kansai Medical University | Matsuoka Y.,Kansai Medical University | Uemura Y.,Exploratory Oncology Research | Sumide K.,Kansai Medical University | And 5 more authors.
Cell Transplantation | Year: 2015

It is well documented that specialized mesenchymal stem/stromal cells (MSCs) constitute the hematopoietic stem cell (HSC) niche in the bone marrow (BM), and these MSCs support/maintain the HSCs in an undifferentiated state. A number of studies have demonstrated that BM-derived MSCs (BM-MSCs) can support HSCs in vitro. However, it remains unclear whether nonhematopoietic tissue-derived MSC-like cells, such as dental pulp stem cells (DPSCs), have the ability to support HSCs. In this study, we prospectively isolated DPSCs from mouse mandibular incisors by fluorescence-activated cell sorting (FACS) using BM-MSC markers, such as PDGFRα and Sca-1. The PDGFRα and Sca-1 double-positive DPSCs and BM-MSCs showed similar morphologies and expression patterns of MSC markers. The ability of the DPSCs to support hematopoietic stem/progenitor cells (HSPCs) was then analyzed by an in vitro coculture system. Moreover, their HSC-supporting activity was evaluated by in vivo xenotransplantation assays using NOD/Shi-scid/IL-2Rγc null (NOG) mice. Interestingly, the DPSCs supported human cord blood (CB)-derived CD34-positive (CD34+), as well as CD34 negative (CD34-), HSCs. The supporting activities of DPSCs for human CB-derived CD34+ and CD34- HSCs were comparable to those of BM-MSCs. The results of the present study demonstrated, for the first time, that prospectively isolated murine PDGFRα and Sca-1 double-positive DPSCs could support primitive human CD34+ and CD34- HSCs in vitro. © 2015 Cognizant Comm. Corp.

Ando M.,Aichi Cancer Center Hospital | Yamauchi H.,St. Lukes International Hospital | Aogi K.,Shikoku Cancer Center | Shimizu S.,Kanagawa Cancer Center | And 9 more authors.
Breast Cancer Research and Treatment | Year: 2014

Addition of carboplatin to neoadjuvant chemotherapy in HER2-negative breast cancer may improve pathological complete response (pCR) rates. We evaluated the efficacy and safety of carboplatin and weekly paclitaxel (wPTX) followed by cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) as neoadjuvant chemotherapy for HER2-negative breast cancer. Patients with stage II/IIIA HER2-negative breast cancer were randomly assigned to preoperatively receive CP-CEF (four 3-week cycles of carboplatin [area under the curve 5 mg/mL/min, day 1] and wPTX [80 mg/m2, day 1, 8, 15] followed by four 3-week cycles of CEF [500/100/500 mg/m2] or P-CEF (four cycles of wPTX followed by four cycles of CEF). The primary objective was pCR rate. Of 181 eligible patients, 89 were randomly assigned to the CP-CEF and 92 to the P-CEF. Two patients in each arm refused to receive neoadjuvant chemotherapy. Overall 88 patients in the CP-CEF and 91 patients in the P-CEF were assessable for efficacy and safety. The pCR rate in the CP-CEF was significantly higher than that in the P-CEF (31.8 vs. 17.6 %, one-sided P = 0.01). Among patients with triple-negative breast cancer, the pCR rate in the CP-CEF was significantly higher than that in the P-CEF [61.2 (23/37) vs. 26.3 % (10/38), P = 0.003]. Grade 3-4 neutropenia was observed in the CP-CEF more frequently than in the P-CEF (65.9 vs. 38.5 %). Adding carboplatin to neoadjuvant wPTX followed by CEF for HER2-negative breast cancer improved the pCR rate and exacerbated hematotoxicity. © 2014 Springer Science+Business Media New York.

Kinoshita T.,National Cancer Center Hospital East | Kinoshita T.,Aichi Cancer Center Hospital | Saiura A.,Cancer Institute Ariake Hospital | Esaki M.,National Cancer Center Hospital | And 2 more authors.
British Journal of Surgery | Year: 2014

Background The efficacy of surgical resection for gastric cancer liver metastases (GCLMs) is currently debated. Hitherto, no large-scale clinical studies have been conducted. Justified in selected patientsMethods This retrospective multicentre study analysed a database of consecutive patients with either synchronous or metachronous metastases who underwent surgical R0 resection for GCLM between 1990 and 2010. Clinical data were collected from five cancer centres in Japan. Survival curves were assessed, and clinical parameters were evaluated to identify predictors of prognosis.Results A total of 256 patients were enrolled. The mean(s.d.) number of hepatic tumours resected was 2·0(2·4). The surgical mortality rate was 1·6 per cent. Median follow-up was 65 (range 1-261) months. Recurrences were detected in 192 patients (75·0 per cent). The median interval from hepatic resection to recurrence was 7 (range 1-72) months, and the dominant site of recurrence was the liver (72·4 per cent). Actuarial 1-, 3- and 5-year overall and recurrence-free survival rates were 77·3, 41·9 and 31·1 per cent, and 43·6, 32·4 and 30·1 per cent, respectively. Median overall and recurrence-free survival times were 31·1 and 9·4 months respectively. Multivariable analysis identified serosal invasion of the primary gastric cancer (hazard ratio (HR) 1·50; P = 0·012), three or more liver metastases (HR 2·33; P < 0·001) and liver tumour diameter at least 5 cm (HR 1·62; P = 0·005) as independent predictors of poor survival.Conclusion Clinically resectable GCLM is rare, but strict and careful patient selection can lead to long-term survival following R0 surgical resection. © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.

Kawamura H.,Kansai Medical University | Takahashi M.,Kansai Medical University | Uemura Y.,Exploratory Oncology Research | Asano H.,Kyoto Prefectural University of Medicine | And 4 more authors.
Stem Cells | Year: 2015

Hematopoietic stem cells (HSCs) are maintained in a specialized bone marrow (BM) niche, which consists of osteoblasts, endothelial cells, and a variety of mesenchymal stem/stromal cells (MSCs). However, precisely what types of MSCs support human HSCs in the BM remain to be elucidated because of their heterogeneity. In this study, we succeeded in prospectively isolating/establishing three types of MSCs from human BM-derived lineage- and CD45-negative cells, according to their cell surface expression of CD271 and stage-specific embryonic antigen (SSEA)-4. Among them, the MSCs established from the Lineage-CD45-CD271+SSEA-4+ fraction (DP MSC) could differentiate into osteoblasts and chondrocytes, but they lacked adipogenic differentiation potential. The DP MSCs expressed significantly higher levels of well-characterized HSC-supportive genes, including IGF-2, Wnt3a, Jagged1, TGFβ3, nestin, CXCL12, and Foxc1, compared with other MSCs. Interestingly, these osteo-chondrogenic DP MSCs possessed the ability to support cord blood-derived primitive human CD34-negative severe combined immunodeficiency-repopulating cells. The HSC-supportive actions of DP MSCs were partially carried out by soluble factors, including IGF-2, Wnt3a, and Jagged1. Moreover, contact between DP MSCs and CD34-positive (CD34+) as well as CD34-negative (CD34-) HSCs was important for the support/maintenance of the CD34+/- HSCs in vitro. These data suggest that DP MSCs might play an important role in the maintenance of human primitive HSCs in the BM niche. Therefore, the establishment of DP MSCs provides a new tool for the elucidation of the human HSC/niche interaction in vitro as well as in vivo. Stem Cells 2015;33:1554-1565 © 2014 AlphaMed Press.

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