PubMed Health⌕ Search

Biomedical subjects

Shinji Tanaka

Publications and source records attributed to Shinji Tanaka.

At least 91 records · Page 5Linked to original sources
PubMed2004

Mucin phenotype and background mucosa of intramucosal differentiated-type adenocarcinoma of the stomach.

OBJECTIVES: Gastric carcinomas have been divided into differentiated (intestinal) and undifferentiated (diffuse) types. Recently, classification studies based on mucin expression have revealed that some differentiated-type carcinomas are of a gastric phenotype. In this study, we investigated the clinicopathological features of differentiated-type adenocarcinomas and evaluated the background mucosa of the stomach based on mucin expression by the tumors. METHODS: Seventy-six intramucosal differentiated-type adenocarcinomas of the stomach were evaluated macroscopically and histologically. The mucin expression of tumor cells was examined by immunohistochemical staining with monoclonal antibodies against human gastric mucin (45M1), class III mucin (HIK1083), small intestinal mucinous antigen (SIMA-4D3), and MUC2 (Ccp58). Tumors were classified by phenotype as gastric (G-type), intestinal (I-type), mixed (M-type), or null (N-type). Not only the clinicopathological features but also the background mucosa of the stomach of G-type and I-type carcinomas were compared histologically and serologically. RESULTS: Seventeen tumors (22.4%) were classified as G-type, 31 (40.8%) as I-type, 22 (28.9%) as M-type, and 6 (7.9%) as N-type. The frequencies of elevated type tumors and papillary adenocarcinomas and the ratio of moderately/well-differentiated adenocarcinomas were higher in G-type than in I-type carcinomas. The scores for glandular atrophy and intestinal metaplasia were higher and the scores for chronic inflammation, polymorphonuclear neutrophil activity, and the density of Helicobacter pylori were lower in G-type than in I-type tumors. The serum level of pepsinogen I and the pepsinogen I/II ratio were significantly lower in G-type than in I-type tumors. CONCLUSIONS: G-type carcinoma is the predominant phenotype of papillary adenocarcinoma. The background mucosa of G-type carcinoma is associated with glandular atrophy and intestinal metaplasia, whereas that of I-type carcinoma is associated with active and chronic inflammation induced by H. pylori infection.

Adenocarcinoma↗
PubMed2004

cDNA microarray analysis in hepatocyte differentiation in Huh 7 cells.

The risk of xenozoonosis infections poses the greatest obstacle against the clinical application of a hybrid artificial liver support system (HALSS). Primary human hepatocytes are an ideal source for HALSS, but the shortage of human livers available for hepatocyte isolation limits this modality. To resolve this issue, we previously demonstrated the upregulation of hepatocyte-specific function by spheroid formation in polyurethane foam and by culturing with the histone deacetylase inhibitor, trichostatin A (TSA), in a human hepatoma cell line (Huh 7). In this article we analyze the gene expression profile using cDNA microarray (1281 genes) in spheroid formation or culturing with TSA in Huh 7 to determine the target genes in hepatocyte differentiation. In both the spheroid formation and in the culture with TSA, the Oct-3/4 transcription factor was upregulated more thantwofold, while the early growth response-1 (EGR-1) transactivator was downregulated less than 0.5-fold. These results indicate that expressions of Oct-3/4 and EGR-1 may be key factors in the induction of hepatocyte differentiation in Huh 7.

Cell Culture Techniques↗
PubMed2004

Expression of human telomerase reverse transcriptase mRNA in esophageal cancers and precancerous lesions.

Telomerase activity confers immortality to cells through stabilization of chromosomes and contributes to the development of most human cancers. Human telomerase reverse transcriptase (hTERT) is a catalytic subunit of telomerase. Expression of hTERT mRNA has been reported to be correlated with telomerase activity. The purpose of this study was to investigate localization of hTERT mRNA in human esophageal precancerous and cancerous lesions by in situ mRNA hybridization with avidin-biotin staining. Ki-67 immunoreactivity was also examined. We analyzed 51 squamous cell carcinomas, 9 dysplasias and 60 normal mucosae. The integrity of mRNA in each sample was verified with a poly-d(T)20 probe. Seventy-eight samples (65%), including 35 carcinomas, 4 dysplasias and 39 normal mucosae, contained intact mRNA. At the single-cell level, hTERT was expressed at high levels in both the cytoplasm and nucleus. In all cases, the majority of cancer and dysplastic cells showed high levels of hTERT expression. In all 39 normal mucosae, basal cells expressed hTERT mRNA, and this was also observed in infiltrating lymphocytes. The distribution of cells expressing hTERT was similar to that of Ki-67-positive cells. These results suggest that overexpression of hTERT mRNA may be correlated with proliferative activity reflected by Ki-67 immunoreactivity and is an early event in carcinogenesis of the esophagus.

Carcinoma, Squamous Cell↗
PubMed2004

Angiogenic switch occurs during the precancerous stage of human esophageal squamous cell carcinoma.

We previously reported that vascular endothelial growth factor (VEGF) expression correlates with vessel density in human esophageal squamous cell carcinomas. However, tumor angiogenesis is not controlled simply by the presence of VEGF, and is likely regulated by several angiogenic factors produced by tumor and host cells. The goal of the present study was to determine the angiogenic profile of precancerous and cancerous lesions of the esophagus. Expression of mRNAs for VEGF, platelet derived endothelial cell growth factor (PD-ECGF), basic fibroblast growth factor (bFGF), and interleukin (IL)-8 was examined in six esophageal carcinoma cell lines and fresh biopsy specimens from 16 patients with invasive esophageal carcinoma by RT-PCR. Immunohistochemical analyses with antibodies against VEGF, PD-ECGF, bFGF, and IL-8 were performed on archival specimens of 60 normal esophageal mucosa, 11 dysplasias and 49 carcinomas of the esophagus. Microvessels were stained with anti-CD34 antibody and quantified by counting the number of vessels in a x200 field in the most vascularized areas of the tumor. Esophageal carcinoma cell lines and tumor tissues expressed mRNAs for one or more these angiogenic factors at various levels. An initial increase in vessel density and enhanced expression of PD-ECGF and VEGF were observed in dysplastic epithelium. Vessel density was significantly higher in more advanced lesions. bFGF and IL-8 were not expressed in dysplasias and mucosal carcinomas, but expression was increased in late stage squamous cell carcinoma. These findings suggest that the angiogenic switch is a very early event in the development of invasive carcinoma. Several different angiogenic factors produced by tumor cells and host cells may regulate angiogenesis during different steps of esophageal carcinogenesis.

Base Sequence↗
PubMed2004

Clinical significance of angiopoietin-2 expression at the deepest invasive tumor site of advanced colorectal carcinoma.

Angiopoietin (Ang)-2 and vascular endothelial growth factor (VEGF) are thought to be critical regulators in tumor angiogenesis. We investigated the clinical significance of Ang-2 expression at the deepest invasive tumor site under the influence of VEGF expression in relation to angiogenesis, invasive/metastatic potential, and prognosis of advanced colorectal carcinoma (CRC). One hundred and fifty-two patients who underwent surgical resection for advanced CRC were enrolled in this study. Ang-2 and VEGF expression were examined immunohistochemically. Tumor microvessel density (MVD) was examined by immunohistochemical staining against CD34. Ang-2 and VEGF were expressed at the deepest invasive tumor site in 90 (59.2%) and 64 (42.1%) of 152 lesions, respectively. Patients with Ang-2 expression at the deepest invasive tumor site showed significantly (p<0.01) more frequent poorly histologic grade (71.9%), lymphatic involvement (65.9%), venous involvement (69.1%), lymph node metastasis (75.0%), liver metastasis (80.0%) and advanced disease (Dukes' stage C, 70.2%; stage D, 80.0%) than patients without Ang-2 expression. MVD was not significantly up-regulated by Ang-2 expression alone at the deepest invasive tumor site but was significantly up-regulated by VEGF expression at the deepest invasive tumor site under the positive-Ang-2 condition. In patients treated by curative surgery, patients with tumors showing both positive-Ang-2 and positive-VEGF condition at the deepest invasive tumor site had significantly poorer prognoses than patients with tumors under other conditions. Multivariate analysis with logistic regression for 5-year survival in cases of curative surgery showed that lymph node metastasis, VEGF expression and Ang-2 expression were significant factors to predict poor prognosis. Our results suggest that Ang-2 expression in collaboration with VEGF expression at the deepest invasive tumor site may result in tumor angiogenesis and that these angiogenic factors at the deepest invasive tumor site may be correlated with invasive/malignant potential and prognosis of advanced CRC.

Adenocarcinoma↗
PubMed2004

Frequent loss of heterozygosity on chromosome 10p14-p15 in esophageal dysplasia and squamous cell carcinoma.

High frequencies of loss of heterozygosity (LOH) on chromosome 10p14-p15 have been reported in various tumors, including glioma, pulmonary carcinoid and cervical, hepatic and prostatic carcinomas. These findings suggest the presence of a tumor suppressor gene at the loci. However, analysis of LOH on chromosome 10p14-p15 in esophageal tumors has not been reported. Therefore, we examined LOH on chromosome 10p14-p15 in 88 esophageal squamous cell carcinomas (SCC) (35 superficial- and 53 advanced-types) and 44 dysplasias by microsatellite assay. Five oligonucleotide primer sets for microsatellite loci D10S191, D10S501, D10S559, D10S558 and D10S249 were used. In dysplasias, frequent LOH was detected with markers D10S191 (26%) and D10S249 (33%). In superficial esophageal SCCs, frequent LOH was detected with markers D10S191 (26%), D10S559 (50%), D10S558 (29%) and D10S249 (33%). In advanced esophageal SCCs, we found frequent LOH was detected with markers D10S191 (38%), D10S501 (25%) and D10S559 (30%). There were no significant correlations between LOH on chromosome 10p14-p15 and clinicopathologic features, including patient age, sex, tumor location, depth of invasion and lymph node metastasis. These data suggest that a putative tumor suppressor gene for esophageal carcinogenesis may be located on chromosome 10p14-p15 and that malfunction of this gene may be involved in the development but not progression of esophageal tumors.

Adult↗
PubMed2004

[Novel molecularly targeted peptides interfering the specific signal transduction of cancer metastasis].

Metastatic spread of tumor cells is one of the major risk factors affecting clinical prognosis. There are several sequential steps in this process including cell migration into the surrounding host tissue, infiltration and penetration into vessels for dissemination, attachment to capillary beds of distant organs, cell extravasation and subsequent growth in tissues. Some of the mechanisms involving normal cell migration observed during development are believed to be closely associated with the properties of tumor cell invasion. Thus, the so-called 'cell migration genes' may be frequently utilized by cancer cells to allow for metastatic spread of disease. We have isolated one of the candidate genes homologous to a C. elegans cell migration gene, that overexpressed specially in clinical cancer tissues. Based on in vitro analysis of the signal transduction, a novel peptide interfering the signals provides an attractive target for therapeutic intervention against the cancer invasion and metastasis.

Animals↗
PubMed2004

[Differential diagnosis of GERD].

It was widely accepted that the prevalence of GERD is lower in Oriental countries compared to Western countries. But the incidence of GERD has recently increased in Japan. The most commonly recognized manifestation of GERD is heartburn or a substernal burning sensation in the chest. Most patients with reflux esophagitis complain of typical symptoms such as heartburn, regurgitation or dysphagia. However, some patients complain of atypical symptoms such as hoarse voice, chronic cough, adult-onset asthma or vocal cord polyps. It is not always easy to diagnose atypical symptomatic patients as GERD. If patients who complain of these atypical symptoms have not improved with common medical treatment, GERD should be the consideration in its differential diagnosis.

Asthma↗
PubMed2004

Muscle-targeted interleukin-12 gene therapy of orthotopic hepatocellular carcinoma in mice using in vivo electrosonoporation.

We developed a new potent nonviral gene transfer method into mouse muscles in vivo named "electrosonoporation." We tried in this report to treat murine orthotopic hepatocellular carcinoma (HCC) by muscle-targeted mouse interleukin-12 (mIL-12) gene transfer using in vivo electrosonoporation. I.m. administration of the mIL-12 gene with electrosonoporation elevated serum IL-12 and IFN-gamma and significantly prolonged the survival periods with both growth inhibition of orthotopic HCC and inhibition of spontaneous lung metastasis. The IL-12 gene therapy reduced the number of microvessels and induced more Mac-1-positive cells into HCC. These results show that muscle-targeted mIL-12 gene therapy for orthotopic HCC using in vivo electrosonoporation is very efficient and is thus promising for further clinical trial.

Animals↗
PubMed2004

Digital image analysis and stereology of angiogenesis in polypoid and nonpolypoid colorectal adenomas.

OBJECTIVE: To evaluate 3-dimensional parameters and bidimensional microvascular quantification in the different morphologic presentations of colorectal adenomas. STUDY DESIGN: A study was carried out, including 102 neoplastic colorectal lesions obtained by endoscopy or surgical resection. For the analysis of angiogenesis, immunohistochemistry, digital image analysis, microvascular quantification and stereology were used. RESULTS: Microvascular quantification, volume and microvascular length estimate rose gradually with high grade dysplasia as compared to the low grade ones (P < .001). There was no significant difference in angiogenesis between polypoid and nonpolypoid colorectal adenomas in terms of quantification and microvascular length estimate. CONCLUSION: The use of digital image analysis and stereology added greater objectivity and effectiveness to angiogenic evaluation because they allowed accurate segmentation of hypervascular areas, representation of the characteristic 3-dimensional morphology of the vascular supply and identification of differences in microvascularization in the developmental stages of colorectal cancer. However, no significant relation could be found between macroscopic type and angiogenesis, suggesting that angiogenesis may contribute little to morphogenesis of colorectal adenomas.

Adenoma↗
PubMed2004

Single nucleotide polymorphism in the hypoxia-inducible factor-1alpha gene in colorectal carcinoma.

Colorectal carcinoma is one of the most common malignancies in the world, and its incidence has increased in recent years. We have reported that expression of hypoxia-inducible factor (HIF)-1alpha correlates with expression of vascular endothelial growth factor (VEGF), tumor stage, lymphatic invasion, venous invasion, and liver metastasis. It has also been reported that a single nucleotide polymorphism (SNP) in exon 12 of HIF-1alpha gene is present in renal cell carcinoma and head and neck squamous cell carcinoma patients. We investigated the C1772T polymorphism in colorectal cancer patients and healthy control subjects to clarify the mechanism of HIF-1alpha activation in colorectal carcinoma. The exon 12 genotype was not associated with sex or age. The distribution of HIF-1alpha genotypes in controls was 89 C/C (89%), 11 C/T (11%), and 0 T/T (0%). The distribution of HIF-1alpha genotypes in colorectal cancer patients was 100 C/C (100%), 0 C/T (0%), and 0 T/T (0%). The difference in genotype distribution between patients and control subjects was significant (p<0.0005). These results suggest that the C1772T polymorphism in HIF-1alpha is not involved in progression or metastasis of colorectal carcinoma.

Adenocarcinoma↗
PubMed2004

Effects of aged garlic extract (AGE) on colorectal adenomas: a double-blinded study.

Aged garlic extract (AGE) is a material that has the possibility of a cancer-preventive effect according to epidemiologic and animal studies. In order to confirm the effects of AGE on colorectal adenomas, we conducted a double-blinded randomized study using high-AGE (AGE 2.4 ml/day) and low-AGE (AGE 0.16 ml/day) doses 1 groups. Fifty-one patients who were diagnosed as having colorectal adenomas by colonoscopy were randomly assigned to the high-AGE and low-AGE groups. The number and size of adenomas before intake (0 month) and 6 and 12 months after intake were measured using colonoscopy. In 37 patients chosen as efficacy evaluated subjects, 47.4% (9/19) in the high-AGE and 66.7% (12/18) in the low-AGE group had at least one new adenoma for the first and second interval (0 to 12 months after intake), and its relative risk was 0.71. The decrease rate of at least one adenoma was 50.0% (7/14) in the high-AGE group for the second interval (6 to 12 months after intake), whereas there was no decrease in subjects in the low-AGE group (p=0.02). The difference from the base-line for total size of adenomas increased in the low-AGE group, whereas an increase in the high-AGE group was suppressed for the second interval (p=0.04). The difference from the base-line for the total size of adenomas in subjects who had adenomas on the base-line increased in the low-AGE group and decreased in the high-AGE group for the second interval (p=0.03). The results of this study suggest the possibility of preventive and therapeutic effects of AGE on colorectal adenomas, though it is necessary to investigate these in larger-scale and longer-term trials.

Adenoma↗
PubMed2003

Helicobacter pylori infection influences expression of genes related to angiogenesis and invasion in human gastric carcinoma cells.

Infection with Helicobacter pylori (H. pylori) is considered a risk factor for gastric carcinoma. The purpose of this study was to clarify whether H. pylori infection plays a role in progression of gastric carcinoma. We examined the expression of genes encoding angiogenic factors and proteases by human gastric carcinoma cell lines (MKN-1 and TMK-1) co-cultured with or without H. pylori by cDNA microarray analysis. Co-culture with H. pylori increased expression of mRNAs encoding interleukin (IL)-8, vascular endothelial growth factor (VEGF), angiogenin, urokinase-type plasminogen activator (uPA), and metalloproteinase (MMP)-9 by gastric carcinoma cells. Up-regulation of these genes at the mRNA and protein levels was confirmed by Northern blot analysis, semi-quantitative RT-PCR analysis, and ELISA. In vitro angiogenic and collagenase activities of conditioned medium from the gastric carcinoma cells were also stimulated by co-culture with H. pylori. These results indicate that H. pylori infection may regulate angiogenesis and invasion of human gastric carcinoma.

Adenocarcinoma↗
PubMed2003

Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features.

PURPOSE: Amplification of the MYCN proto-oncogene is strongly correlated with poor outcome in neuroblastoma (NB), although deregulated MYCN is a potent inducer of apoptosis. BIN1 (2q14) encodes multiple isoforms of a Myc-interacting adaptor protein that has features of a tumor suppressor, including the ability to inhibit Myc-mediated cell transformation and to promote apoptosis. We hypothesized that BIN1 may function as a suppressor gene in NB, because Bin1 is highly expressed in neural tissues and binds the Myc Box motifs that are conserved in MycN. EXPERMENTAL DESIGN: Expression of MYCN, total BIN1, and BIN1 isoforms were determined in 56 primary NBs using the real-time PCR. Expression was correlated with biological and genetic features. To determine the functional significance of BIN1 expression we ectopically expressed BIN1 isoforms in NB cell lines with and without MYCN amplification, and assessed clonogenic growth. RESULTS: Four predominant BIN1 isoforms resulting from alternative splicing of exon 12A (a neural tissue-specific exon) and exon 13 (a Myc-binding domain encoding exon) were variably expressed in the 56 primary NBs. Expression of BIN1 was lower in: NBs with MYCN amplification (n = 10) compared with those without, P < 0.03; in International Neuroblastoma Risk Group high-risk NB (n = 19) compared with low- or intermediate-risk NB, P < 0.01; and in metastatic NB (n = 21) compared with localized NB, P < 0.06. BIN1 inactivation by deletion or genomic rearrangement was identified infrequently. Forced expression of BIN1 isoforms containing the Myc-binding domain (with or without exon 12A) inhibited colony formation in NB cell lines with MYCN amplification (P < 0.01) but not in those without. Forced expression of BIN1 isoforms with a MBD deletion did not inhibit colony formation in any cell line assessed. CONCLUSIONS: These data support that reduced BIN1 expression contributes to the malignant phenotype of childhood NB. As we reported previously, BIN1 may function to circumvent MycN-mediated apoptosis in NBs with MYCN amplification.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Blocking of alpha 5 integrin stimulates production of TGF-beta and PAI-1 by human mesangial cells.

Expression of integrin, which mediates cell-matrix interaction, is affected by several cytokines, in particular by transforming growth factor-beta (TGF-beta). However, it is unknown whether, in an opposite way, a specific integrin is involved in cytokine synthesis. We tested this hypothesis. Function-blocking anti-alpha 5 integrin (fibronectin receptor) antibody increased TGF-beta secretion in growth-arrested human mesangial cells (2.3-fold) compared with control IgG or anti-alpha v beta 3 integrin (receptor for several matrix proteins) antibody. It also increased the secretion of plasminogen activator inhibitor-1 (PAI-1), a protein associated with matrix increase, by 3.2-fold. The increase in PAI-1 secretion induced by anti-alpha 5 integrin antibody was not abrogated by anti-TGF-beta neutralizing antibody. These results indicate that function-blocking of anti-alpha 5 integrin stimulates TGF-beta as well as PAI-1 production, suggesting that alpha 5 integrin is involved in fibrotic process. Function-modulation of a specific integrin thus appears to play a role in glomerular remodeling.

Antibodies↗
PubMed2003

Expression of hypoxia-inducible factor-1alpha is associated with tumor vascularization in human colorectal carcinoma.

HIF-1 is reported to transactivate expression of VEGF, which is an important angiogenic factor. To determine whether HIF-1alpha plays a role in angiogenesis through its regulation of VEGF, we examined expression of HIF-1alpha and its relation to clinicopathologic features, VEGF expression and prognosis of patients with colorectal carcinoma. Expression of HIF-1alpha and VEGF was examined in 4 colorectal carcinoma cell lines (COLO320DM, COLO201, DLD-1, WiDr) and 149 colorectal carcinoma tissues (10 fresh specimens, 139 archival, paraffin-embedded specimens). HIF-1alpha protein levels were increased by hypoxia in 3 of 4 colorectal carcinoma cell lines (COLO201, DLD-1, WiDr), and VEGF mRNA levels were also increased by hypoxia in the same cell lines. In 8 of 10 patients with colorectal cancer, expression of HIF-1alpha and VEGF was increased in tumor tissues compared to corresponding normal mucosa. Of 139 archival specimens of colorectal carcinoma, 81 (58.3%) expressed HIF-1alpha protein at a high level. HIF-1alpha expression was correlated with tumor invasion, tumor stage, lymphatic invasion, venous invasion and liver metastasis. Moreover, HIF-1alpha expression was correlated significantly with VEGF expression and microvessel density. Although there was a tendency for poorer prognosis in patients with high HIF-1alpha-expressing tumors, this correlation was not statistically significant. These findings suggest that HIF-1alpha may play a role in angiogenesis and tumor progression via regulation of VEGF in human colorectal carcinoma.

Adenocarcinoma↗