Biomedical subjects

Noriaki Tanaka

Publications and source records attributed to Noriaki Tanaka.

At least 19 recordsLinked to original sources

PubMed2026

NOTCH1 acts as a tumor suppressor that induces early differentiation in head and neck cancer.

Inactivating NOTCH1 mutations in head and neck squamous cell carcinoma (HNSCC) were described over a decade ago, suggesting a tumor suppressor function - unlike its oncogenic role in other tumors. Today, much debate persists regarding a putative oncogenic role in HNSCC as well, with reports that NOTCH1 signaling drives tumor growth and a cancer stem cell (CSC) phenotype. In this work, comprehensive experiments unequivocally demonstrate that NOTCH1 is a tumor suppressor in HNSCC regardless of mutation or activation status and that it reduces CSC frequency. We developed a signature of NOTCH1 activation showing the pathway is associated with very early differentiation, an altered tumor microenvironment, and better prognosis. Clarifying whether NOTCH1 occasionally functions as an oncogenic driver in HNSCC is crucial to prognosis and personalized therapy. The results presented unify the field, reconcile conflicting data, and provide critical insights into the biological and clinical significance of NOTCH1, with broader implications in other squamous carcinomas with NOTCH1 mutations.

Receptor, Notch1↗

PubMed2007

Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells.

PURPOSE: Several models of cancer progression, including clonal evolution, parallel evolution, and same-gene models, have been proposed to date. The purpose of this study is to investigate the authenticity of these models by comparison of accumulated genetic alterations between primary and corresponding metastatic lung cancers. EXPERIMENTAL DESIGN: A whole-genome allelic imbalance scanning using a high-resolution single nucleotide polymorphism array and mutational analysis of the p53, EGFR, and KRAS genes were done on eight sets of primary and metastatic lung cancers. Based on the genotype data, the natural history of each case was deduced, and candidate metastasis suppressor loci were determined. RESULTS: Five to 20 chromosomal regions showed allelic imbalance in each tumor. Accumulated genetic alterations were similar between primary and corresponding metastatic tumors, and the majority(>67%) of genetic alterations detected in metastatic tumors was also detected in the corresponding primary tumors. On the other hand, in seven of the eight cases, there were genetic alterations accumulated only in metastatic tumors. Among these alterations, allelic imbalances at chromosome 11p15 and 11p11-p13 regions were the most frequent ones (4 of 8, 50%). Likewise, four cases showed genetic alterations detected only in primary tumors. CONCLUSIONS: The natural history of each case indicated that the process of metastasis varies among cases, and that all three models are applicable to lung cancer progression. According to the clonal and parallel evolution models, it is possible that a metastasis suppressor gene(s) for lung cancer is present on chromosome 11p.

Adult↗

PubMed2007

Establishment and characterization of a human adenoid cystic carcinoma cell line forming colonies cultured in collagen gel and transplantable in nude mice.

We established a new cell line (ACCNS) from human adenoid cystic carcinoma (AdCC) of the maxilla, using tissue culture techniques and it has been successfully subcultured for more than 100 passages during 2 years. The population doubling time was approximately 39.2 h on a plastic dish. In type I collagen gel culture, the cells formed spherical colonies by day 7 after seeding. The colonies showed tubular and solid structures, and eosinophilic material stained with mucicarmine was revealed in the inner space. Immunohistochemically, ACCNS cells demonstrated expressions of keratin, alpha-smooth muscle actin, vimentin and S-100 protein, similar to those of original AdCC. These findings indicate that ACCNS cells possess the characteristics of AdCC. In addition, inoculation of 4.0x10(6) cells into nude mice developed tumors that were histologically confirmed as undifferentiated carcinoma. Therefore, ACCNS is the first AdCC cell line with tumorigenicity in nude mice. Based on these results, ACCNS provides a useful culture model of AdCC to analyze the biological characteristics and behavior of this tumor.

Animals↗

PubMed2006

Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis.

Microsatellite instability (MSI) has been associated with colitic cancer. However, reported frequency of MSI was varied and the association of MSI with mismatch repair (MMR) deficiency was unclear. In addition, the occurrence of genetic alterations in stromal cells within ulcerative colitis (UC) is still controversial. We therefore sampled 164 microareas in various pathological lesions of UC with or without colitic cancer and studied the MSI status in relation to the DNA repair protein expressions. A total of 129 microfoci from colorectal tissue of 5 colitic cancer patients and 35 microfoci of 7 UC patients (without neoplasm) were carefully sampled by laser-capture microdissection. MSI was analyzed in each microsamples. The protein expression of MMR genes (MLH1, MSH2, MSH6), O(6)-methylguanine-DNA methyltransferase and p53 were assessed by immunohistochemical analysis. Variety of di-nulcleotide microsatellite markers was altered in individual microfoci from different morphological epithelial lesions, in full range of nonneoplastic epithelium to colitic cancer. Interestingly, MSI was not observed in stromal cells at any sites, including those within colitic cancer/dysplasia lesions. Expression of the MMR proteins was not lost in any of the lesions examined. Microsatellite alterations rather seem to be related to the initiation than to the progression of colitic cancer.

Adolescent↗

PubMed2006

Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes.

Severe acute liver failure, even when transient, must be treated by transplantation and lifelong immune suppression. Treatment could be improved by bioartificial liver (BAL) support, but this approach is hindered by a shortage of human hepatocytes. To generate an alternative source of cells for BAL support, we differentiated mouse embryonic stem (ES) cells into hepatocytes by coculture with a combination of human liver nonparenchymal cell lines and fibroblast growth factor-2, human activin-A and hepatocyte growth factor. Functional hepatocytes were isolated using albumin promoter-based cell sorting. ES cell-derived hepatocytes expressed liver-specific genes, secreted albumin and metabolized ammonia, lidocaine and diazepam. Treatment of 90% hepatectomized mice with a subcutaneously implanted BAL seeded with ES cell-derived hepatocytes or primary hepatocytes improved liver function and prolonged survival, whereas treatment with a BAL seeded with control cells did not. After functioning in the BAL, ES cell-derived hepatocytes developed characteristics nearly identical to those of primary hepatocytes.

Activins↗

PubMed2006

A bioartificial liver device secreting interleukin-1 receptor antagonist for the treatment of hepatic failure in rats.

BACKGROUND: Liver transplantation is the treatment of choice for many patients with fulminant hepatic failure (FHF). A major limitation of this treatment is the lack of available donors. An optimally functioning bio-artificial liver (BAL) device has the potential to provide critical hepatic support to patients with FHF. In this study, we examined the efficacy of combining interleukin-1 (IL-1) receptor blockade with the synthetic function of hepatocytes in a BAL device for the treatment of FHF. MATERIALS AND METHODS: We injected an adenoviral vector encoding human IL-1 receptor antagonist (AdIL-1Ra) into the liver of D-galactosamine (GalN) intoxicated rats via the portal vein. We also transfected primary rat hepatocytes and reversibly immortalized human hepatocytes (TTNT cells) with AdIL-1Ra, and incorporated these transfected hepatocytes into our flat-plate BAL device and evaluated their efficacy in our GalN-induced FHF rat model after 10 h of extracorporeal perfusion. RESULTS: Rats injected with AdIL-1Ra showed significant reductions in the plasma levels of hepatic enzymes. Primary rat hepatocytes transfected with AdIL-1Ra secreted IL-1Ra without losing their original synthetic function. Incorporating these cells into the BAL device and testing in a GalN-induced FHF rat model resulted in significant reductions in plasma IL-6 levels and significantly improved animal survival. Incorporating the AdIL-1Ra transfected TTNT cells in the BAL device and testing in the GalN-induced FHF rat model resulted in significantly reduced plasma IL-6 levels, and a trend toward improved survival was seen. CONCLUSION: Hepatocytes producing IL-1Ra are a promising cell source for BAL devices in the treatment of GalN-induced FHF.

Adenoviridae↗

PubMed2006

Protective effects of nafamostat mesilate on liver injury induced by lipopolysaccharide in rats: possible involvement of CD14 and TLR-4 downregulation on Kupffer cells.

Nafamostat mesilate (NM) is a synthetic protease inhibitor with various biological effects. To determine its effect on liver injury related to sepsis, we investigated the effects of NM on lipopolysaccharide (LPS)-induced liver injury. Wistar rats were allocated into two groups; the NM group underwent intraperitoneal NM administration 30 min before LPS administration, and the control group underwent PBS administration. Serum AST and ALT levels were significantly decreased in NM-treated rats. Reduced levels of TNF-alpha, IL-1beta, and IFN-gamma were observed after LPS administration in NM-treated rats. No significant differences were observed in IL-6 levels between the NM and the control group. In contrast, HGF levels were significantly increased only in control rats. NM treatment decreased protein and mRNA levels of TLR-4 and CD14. Our data suggest that NM treatment has protective effects against LPS-induced hepatotoxicity through downregulation of TLR4 and CD14 in liver, which decreased TNF-alpha, IL-1beta, and IFN-gammaproduction in liver.

Animals↗

PubMed2006

In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus.

Currently available methods for detection of tumors in vivo such as computed tomography and magnetic resonance imaging are not specific for tumors. Here we describe a new approach for visualizing tumors whose fluorescence can be detected using telomerase-specific replication-competent adenovirus expressing green fluorescent protein (GFP) (OBP-401). OBP-401 contains the replication cassette, in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of E1 genes, and the GFP gene for monitoring viral replication. When OBP-401 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. Our results indicate that OBP-401 causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This technology is adaptable to detect lymph node metastasis in vivo as a preclinical model of surgical navigation.

Adenoviridae↗

PubMed2006

Effect of nicotine on IL-18-initiated immune response in human monocytes.

Nicotine is thought to inhibit the production of proinflammatory cytokines from macrophages through an anti-inflammatory pathway that is dependent on nicotinic acetylcholine receptor alpha7 subunit (alpha7-nAChR). IL-18, an important proinflammatory cytokine, is reported to induce the expression of adhesion molecules on monocytes, thus enhancing cell-to-cell interactions with T-cells and contributing to IL-18-initiated cytokine production. Accordingly, inhibition of IL-18 suppresses systemic inflammatory responses. In the present study, we found that nicotine inhibited the IL-18-enhanced expression of ICAM-1, B7.2, and CD40 on monocytes, and the production of IL-12, IFN-gamma, and TNF-alpha by PBMC. A nonselective and a selective alpha7-nAChR antagonist, mecamylamine, and alpha-bungarotoxin abolished the effects of nicotine, suggesting that this depends on alpha7-nAChR stimulation. It is reported that nicotine induces prostaglandinE2 (PGE(2)) production in PBMC through the up-regulation of cyclooxygenase (COX)-2 expression. PGE(2) is known to activate the EP2/EP4-receptor, leading to an increase in cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity. Consistent with this, we found that COX-2 and PKA inhibitors prevented the effects of nicotine on adhesion molecule expression and cytokine production, indicating that the mechanism of action of nicotine may be via endogenous PGE(2) production.

Antigens, CD↗

PubMed2006

alpha7 Nicotinic acetylcholine receptor stimulation inhibits lipopolysaccharide-induced interleukin-18 and -12 production in monocytes.

Nicotine inhibited interleukin (IL)-18 and -12 production in lipopolysaccharide (LPS)-stimulated monocytes, and the action of nicotine was antagonized by a non-selective and a selective alpha7 nicotinic acetylcholine receptor (alpha7-nAChR) antagonist, suggesting that the stimulation of alpha7-nAChR may be involved in the action of nicotine. Nicotine is reported to induce prostaglandin E(2) (PGE(2)) production in monocytes through the up-regulation of cyclooxygenase (COX)-2 expression. PGE(2) is known to increase cAMP levels and to activate protein kinase A (PKA). COX-2 and PKA inhibitors prevented the action of nicotine, indicating that the mechanism of action of nicotine may be via endogenous PGE(2) production.

Bungarotoxins↗

PubMed2006

Heparanase promotes angiogenesis through Cox-2 and HIF1alpha.

Heparanase has been given attention for its role in the invasion and metastasis of various cancers for years. We have also investigated and reported the role of heparanase in several human cancers, including gastric, esophageal and colon carcinomas. Other than the critical role of heparanase in tumor invasion and metastasis, it is also believed that heparanase is involved in angiogenesis, another feature of tumor progression which is complicatedly mediated by many molecules, including cyclooxygenese-2 (Cox-2). Thus, our recent study elucidated a possible relationship of heparanase with Cox-2 upon tumor angiogenesis. Based upon our study, three major transcription factor binding sites containing NF-kappaB, NF-IL-6 and CRE sites seemed to have a compensative and cooperative role in heparanase-induced Cox-2 upregulation. On the other hand, tumor hypoxia often occurs in most tumors and Cox-2-induced HIF1alpha overexpression has recently been shown in various cancers. Here we believe that heparanase may also be involved in tumor hypoxia through the induction of HIFalpha either directly or indirectly through the Cox-2 pathway. This hypothesis indicates a possible novel function of heparanase and its link to HIF1alpha and Cox-2, and therefore this function would give us a clue about potential new strategies for cancer therapy.

Animals↗

PubMed2006

Development of a novel beta-cell specific promoter system for the identification of insulin-producing cells in in vitro cell cultures.

Recently, it has been reported that islet transplantation into patients with Type 1 diabetes may achieve insulin independence for a year or longer [Shapiro et al., Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen, N Engl J Med. 343 (2000) 230-238]. However, the amount of donor islet tissue is limited, therefore, multiple approaches are being explored to generate insulin-producing cells in vitro. Some promising results have been obtained using mouse and human stem cells and progenitor cells [Soria et al., From stem cells to beta cells: new strategies in cell therapy of diabetes mellitus, Diabetologia. 4 (2001) 407-415; Lechner et al., Stem/progenitor cells derived from adult tissues: potential for the treatment of diabetes mellitus, Am J Physiol Endocrinol Metab. 284 (2003) 259-266; Bonner-Weir et al., In vitro cultivation of human islets from expanded ductal tissue, Proc Natl Acad Sci U S A, 97 (2000) 7999-8004; Assady et al., Insulin production by human embryonic stem cells, 50 (2001) Diabetes 1691-1697]. However, the efficiency of obtaining populations with high numbers of differentiated cells has been poor. In order to improve the efficiency of producing and selecting insulin-producing cells from undifferentiated cells, we have designed a novel beta-cell specific and glucose responsive promoter system designated pGL3.hINS-363 3x. This artificial promoter system exhibits significant luciferase activity not only in insulin-producing MIN6 m9 cells but also in isolated human islets. The pGL3.hINS-363 3x construct shows no activity in non-insulin-producing cells in low glucose conditions (2 mM glucose) but demonstrates significant activity and beta-cell specificity in high glucose conditions (16 mM glucose). Furthermore, pGL3.hINS-363 3x shows significant promoter activity in differentiated AR42J cells that can produce insulin after activin A and betacellulin treatment. Here, we describe a novel beta-cell specific and glucose responsive artificial promoter system designed for analyzing and sorting beta-like insulin-producing cells that have differentiated from stem cells or other progenitor cells.

Animals↗

PubMed2006

Enhanced antitumor efficacy of telomerase-selective oncolytic adenoviral agent OBP-401 with docetaxel: preclinical evaluation of chemovirotherapy.

Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase-specific replication-competent adenovirus (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) promoter regulates viral replication, efficiently killed human tumor cells. We further constructed OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single-agent therapy with OBP-401 as well as of combining OBP-401 with chemotherapeutic agents. Infection of OBP-401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other chemotherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP-401 also inhibited the growth of human cancer cells. Quantitative real-time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP-401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP-401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP-401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human cancers.

Adenoviridae↗

PubMed2006

The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach.

Signet-ring cell carcinoma (SRC) of the stomach exhibits diffuse growth and invasion without forming ducts. Destruction of the surrounding basal membrane and angiogenesis appear to be required for SRC to exhibit marked invasion and growth. We recently reported that heparanase (HPA) and cyclooxygenase-2 (COX-2) were strongly correlated with microvessel density, and that COX-2 expression is up-regulated by HPA in esophageal cancer. In this study, we examined the relationship between HPA expression and that of COX-2 in SRC of the stomach. We examined HPA and COX-2 expression in 3 cell lines derived from SRC of the stomach and in 50 SRC lesions of stomach by immunohistochemistry (IHC), in situ hybridization, and reverse transcriptase-polymerase chain reaction (RT-PCR). We also examined the relationships among HPA expression, COX-2 expression, and the clinicopathologic features of SRC, mean age, sex, invasion depth, regional lymph node metastasis, lymphatic invasion, and venous blood vessel invasion. Of the 3 cell lines, 2 exhibited both HPA and COX-2 mRNA expression on RT-PCR. Of the 3 cell lines, 1 exhibited only HPA mRNA expression on RT-PCR. Heparanase expression was confirmed in 23 (46%) of 50 tumor samples by IHC. COX-2 expression was confirmed in 25 (50%) of the 50 tumor samples by IHC. In situ hybridization revealed messenger RNA expression in the same area as in that revealed by IHC. A close correlation was noted between HPA and COX-2 expressions (P < .0001). The present study thus elucidated the biologic features of SRC of the stomach related to growth and angiogenesis.

Adult↗

PubMed2006

Hypothesis: the antitumor activities of statins may be mediated by IL-18.

Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, are thought to reduce the risk of cancer through the inhibition of Ras farnesylation and serum lipid level. A pleiotropic proinflammatory cytokine, interleukin-18 (IL-18), is reported to exhibit significant antitumor activities through the activation of cytotoxic T lymphocytes and natural killer cells and the inhibition of angiogenesis. Previously, we found that pravastatin, fluvastatin, and simvastatin induced the production of IL-18 in human monocytes. The addition of mevalonate abolished the IL-18 production induced by pravastatin, fluvastatin, and simvastatin, indicating that the IL-18 production might be a result of the inhibition of HMG-CoA reductase. We present a new hypothesis that the production of IL-18 might play roles in the action of statins on cancer.

Humans↗

PubMed2006

Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes.

The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients' prognosis by the histamine receptor type 2 (H2R) antagonist cimetidine. This agent, but not the H2R antagonists ranitidine and famotidine, induced the production of an antitumor cytokine, interleukin (IL)-18, by human monocytes and dendritic cells (DC). In fact, ranitidine and famotidine antagonized cimetidine-induced IL-18 production. Cimetidine induced the activation of caspase-1, which is reported to modify immature IL-18 to mature/active IL-18, and the elevation of intracellular cAMP, leading to the activation of protein kinase A (PKA). The PKA inhibitor H89 abolished the IL-18 production induced by cimetidine. Moreover, the effects of cimetidine on IL-18 production were reproduced in peripheral blood mononuclear cells from wild-type mice, but not in those from H2R knockout mice. In conclusion, cimetidine, a partial agonist for H2R, has a pharmacological profile different from ranitidine and famotidine, possibly contributing to its antitumor activity on gastrointestinal cancers.

Animals↗

PubMed2006

Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 x 10(9) to 1 x 10(11) plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response. RESULTS: Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease. CONCLUSION: Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

Aged↗

PubMed2006

Prolonged survival of mice with acute liver failure with transplantation of monkey hepatocytes cultured with an antiapoptotic pentapeptide V5.

BACKGROUND: Because hepatocyte transplantation has been considered to be an attractive method to treat acute liver failure (ALF), efficient recovery of hepatocytes and maintenance of differentiated hepatocyte functions is of extreme importance. We here report the usefulness of an antiapoptotic pentapeptide V5, composed of Val-Pro-Met-Leu-Lys, in the monkey hepatocyte cultures. METHODS: We evaluated albumin production, metabolizing abilities of ammonia, lidocaine, and diazepam of monkey hepatocytes cultured with V5. The protein expression of apoptosis-associated molecules was analyzed using power blot analysis. An unwoven cloth inoculated with V5-treated monkey hepatocytes was transplanted on the surface of the spleen of both SCID mice and Balb/c mice suffering from ALF induced by 90% hepatectomy. RESULTS: When 100 microM V5 was utilized, ammonia-, lidocaine- and diazepam- metabolizing capacities and albumin production ability were significantly increased in V5-treated monkey hepatocytes. Such hepatocytes showed decreased Annexin V binding and increased the expression of anti-apoptotic and/or cytoprotective molecules, including Ku70, NF-kappaB, IKAP, hILP/XIAP, IkappaB, and CAS. Transplantation of the cloth containing the monkey hepatocytes significantly improved blood levels of glucose and ammonia and encephalopathy score and prolonged the survival of the mice with ALF. CONCLUSIONS: The present work clearly demonstrates the usefulness of V5 for maintaining the functions of monkey hepatocytes in tissue culture.

Ammonia↗