Biomedical subjects

Shugo Suzuki

Publications and source records attributed to Shugo Suzuki.

At least 19 recordsLinked to original sources

PubMed2006

Prediction of carcinogenic potential by a toxicogenomic approach using rat hepatoma cells.

The long-term rodent bioassay is the standard method to predict the carcinogenic hazard of chemicals for humans. However, this assay is costly, and the results take at least two years to produce. In the present study, we conducted gene expression profiling of cultured cells exposed to carcinogenic chemicals with the aim of providing a basis for rapid and reliable prediction of carcinogenicity using microarray technology. We selected 39 chemicals, including 17 rat hepatocarcinogens and eight compounds demonstrating carcinogenicity in organs other than the liver. The remaining 14 were non-carcinogens. When rat hepatoma cells (MH1C1) were treated with the chemicals for 3 days at a non-toxic dose, analysis of gene expression changes with our in-house microarray allowed a set of genes to be identified differentiating hepatocarcinogens from non-carcinogens, and all carcinogens from non-carcinogens, by statistical methods. Moreover, optimization of the two gene sets for classification with an SVM and LOO-CV resulted in selection of 39 genes. The highest predictivity was achieved with 207 genes for differentiation between non-hepatocarcinogens and non-carcinogens. The overlap between the two selected gene sets encompassed 26 genes. This gene set contained significant genes for prediction of carcinogenicity, with a concordance of 84.6% by LOO-CV SVM. Using nine external samples, correct prediction of carcinogenicity by SVM was 88.9%. These results indicate that short-term bioassay systems for carcinogenicity using gene expression profiling in hepatoma cells have great promise.

Animals↗

PubMed2006

Expression of prothymosin alpha is correlated with development and progression in human prostate cancers.

BACKGROUND: Our previous study clearly demonstrated that decreased expression of prothymosin alpha (PTMA) was associated with inhibition of rat prostate carcinogenesis by isoflavones. The purpose of the present investigation was to provide a better understanding of the role of PTMA in human prostate cancers. METHODS AND RESULTS: PTMA expression in 68 prostate cancer cases and in prostate cancer cell lines was examined by immunohistochemistry and immunoblotting, and its levels were increased with progression from normal epithelium, through prostatic intraepithelial neoplasia (PIN) to carcinomas, correlating with the Gleason's pattern. All cell lines studied (LNCaP, 22Rv1, DU145, and PC3) showed high PTMA expression compared with prostate epithelial cells (PrEC). Knockdown of PTMA expression in PC3 cells by RNAi resulted in the inhibition of both cell growth and invasion in vitro. CONCLUSIONS: The present study clearly demonstrated that PTMA expression is intimately involved in the differentiation and progression of human prostate cancers, and could be a target for therapy and diagnostic purposes.

Autopsy↗

PubMed2006

Differences between latent and clinical prostate carcinomas: lower cell proliferation activity in latent cases.

BACKGROUND: Biological significance of prostate latent cancers as early phase of clinical cancers has been controversial. The characterization of the latent cancer may be important to investigate differences between latent and clinical prostate cancers. METHODS: Latent cancers of the prostate, discovered at autopsy in men with no prior treatment for prostate disease and clinical prostate cancers, were compared for cell proliferation activities with parameters such as markers Ag-nucleolar organizer regions (AgNOR), topoisomerase II-alpha, and Ki-67. We also immunohistochemically studied alpha-methylacyl-CoA racemase (AMACR) expression that was recently identified as a possible positive marker of the prostate cancers. We analyzed 50 latent cancers and 50 clinical cancers, and samples were analyzed with Gleason grades or tumor volume. RESULTS: In the latent cancers, Gleason grades 1-4 were observed, but in the clinical cancers Gleason grades 2-5 were recognized. Cell proliferation activities were significantly lower in the latent cancers in Gleason grade 3, and similar results were obtained but without statistical significance in Gleason grades 2 and 4. When analysis was performed according to the tumor size, it was shown that the growth activities of the tumor of the clinical cancer were higher than the latent cancer. CONCLUSIONS: These results indicate that proliferation activities of the latent cancers were lower than the clinical cancers at the same Gleason grades. The data also suggest that latent cancers are just of preclinical stage and there is a possibility to progress to clinical ones by changing life style and longer life expectancy.

Antigens, Neoplasm↗

PubMed2006

Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by leuprorelin, a luteinizing hormone-releasing hormone agonist.

The effects of leuprorelin acetate, a luteinizing hormone-releasing hormone agonist (LHRH-A), on prostate carcinogenesis in probasin/SV40 Tag transgenic rat was investigated. Fifteen weeks after administration of 0.28 and 2.8 mg/kg leuprorelin, prostate weights and serum testosterone levels were significantly decreased compared to values for transgenic controls. Histopathological findings revealed that the incidence of prostatic adenocarcinomas was significantly reduced in ventral, dorsal and lateral lobes of the prostate, correlating with decreased expression of SV40 Tag oncoprotein as well as inhibition of DNA synthesis and proliferation of epithelial cells in neoplastic lesions of the ventral prostate. Microarray analysis further showed leuprorelin acetate to significantly inhibit testicular steroidogenesis, suppressing the expression of SV40 Tag oncoprotein and altering the expression of a large number of genes which might be involved in the inhibition of prostate cancer progression in this rat model.

Adenocarcinoma↗

PubMed2006

Pitfalls with MRI evaluation of prostate cancer detection: comparison of findings with histopathological assessment of retropubic radical prostatectomy specimens.

INTRODUCTION: To assess differences between MRI findings and histopathologically defined prostate cancer localization, we compared clinical results with mapping of radical prostatectomy specimens, and conducted a retrospective MRI cancer localization re-assessment by a urologist-technician after surgery. METHODS: We performed MRI for a total of 37 suspected prostate cancer patients. Subsequently, all underwent retropubic radical prostatectomy after prostate biopsy for confirmation of the diagnosis. All the specimens were studied histopathologically with serial sectioning using a whole organ approach. RESULTS: Of the 37 patients, 26 had positive MRI findings. All the surgical specimens contained cancerous lesions, and 23 had multiple foci. Twenty-four of the MRI-positive cases (92.3%) demonstrated coincidence of both MRI and histopathologically defined lesions. In the single focus cases, 78.6% (11/14) demonstrated exact coincidence, but in the multifocal cases there were no cases with exact coincidence of MRI and histopathological findings (0/23). CONCLUSION: MRI evaluation cannot be considered an effective diagnostic tool in itself for detection of prostate cancers because sensitivity is far from satisfactory, especially in multi-focal cases.

Aged↗

PubMed2005

Lack of prophylactic effect of incadronate on skeletal lesions associated with implants of prostate cancer.

OBJECTIVES: To evaluate prophylactic effects of bisphosphonate (BP) on skeletal lesions induced by prostate cancer (CaP). METHODS: Incadronate, a third-generation BP, was administered weekly for 4 weeks, with or without 4-week pre-administration, to rats whose calvaria had been inoculated with syngeneic CaP tissue. RESULTS: The transplanted CaP grew up and caused bone resorption with osteoblastic changes regardless of incadronate treatment. Although decrease in bone resorption accompanied by reduced number of osteoclasts was shown by incadronate administration, pre-administration had no additional inhibitory effect on bone destruction and Ki-67 labeling indices of CaP cells were not altered. CONCLUSIONS: These results indicate that application of BP alone is not sufficient to prevent skeletal lesions due to CaP in patients with high risk of bone metastases although it is useful in inhibition of cancer-induced bone resorption with osteoblastic changes.

Animals↗

PubMed2005

Lack of carcinogenicity of L-isoleucine in F344/DuCrj rats.

The carcinogenic potential of L-isoleucine, used as a food fortifier, was examined in both sexes of F344 rats. Groups of 50 female and 50 male animals were given diet containing L-isoleucine at concentrations of 0%, 2.5% or 5.0%. No treatment-related changes in the survival rate, general condition, body weight, food consumption, urinalysis, hematology or clinical chemistry data and organ weights were noted. Detailed histopathological examination revealed no treatment-related increase in the incidences of any non-neoplastic or neoplastic lesions. The results indicate that L-isoleucine is not carcinogenic in F344 rats of either sex.

Animals↗

PubMed2005

Lack of modification of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) rat hepatocarcinogenesis by caffeine, a CYP1A2 inducer, points to complex counteracting influences.

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), one of the most abundant carcinogenic heterocyclic amines in cooked foods, is speculated to be a human liver carcinogen. To test the hypothesis that it is metabolically activated by CYP1A2, we here investigated the effects of caffeine as a CYP1A2 inducer on MeIQx induced rat hepatocarcinogenesis in a medium-term liver bioassay system. Unexpectedly, no modifying effects of caffeine on MeIQx-induced hepatocarcinogenesis were evident, although up-regulation of CYP1A2 and NAT2 were detected. Therefore, mRNAs extracted from GST-P positive foci and the surrounding liver tissue in each group were analyzed to explore mechanisms in detail. The results suggest that suppression of syndecan-2 (Sdc2) and induction of cell cycle arrest through a p21-dependent pathway might have counter-acted any promotion effects of up-regulation of CYP1A2.

Acetyltransferases↗

PubMed2005

Linkage and microarray analyses of susceptibility genes in ACI/Seg rats: a model for prostate cancers in the aged.

ACI/Seg (ACI) rats develop prostate cancers spontaneously with aging, similar to humans. Here, to identify genes involved in prostate cancer susceptibility, we did linkage analysis and oligonucleotide microarray analysis. Linkage analysis was done using 118 effective rats, and prostate cancer susceptibility 1 (Pcs1), whose ACI allele dominantly induced prostate cancers, was mapped on chromosome 19 [logarithm of odds (LOD) score of 5.0]. PC resistance 1 (Pcr1), whose ACI allele dominantly and paradoxically suppressed the size of prostate cancers, was mapped on chromosome 2 (LOD score of 5.0). When linkage analysis was done in 51 rats with single or no macroscopic testicular tumors, which had larger prostates and higher testosterone levels than those with bilateral testicular tumors, Pcs2 and Pcr2 were mapped on chromosomes 20 and 1, respectively. By oligonucleotide microarray analysis with 8,800 probe sets and confirmation by quantitative reverse transcription-PCR, only two genes within these four loci were found to be differentially expressed >1.8-fold. Membrane metalloendopeptidase (Mme), known to inhibit androgen-independent growth of prostate cancers, on Pcr1 was expressed 2.0- to 5.5-fold higher in the ACI prostate, in accordance with its paradoxical effect. Cdkn1a on Pcs2 was expressed 1.5- to 4.5-fold lower in the ACI prostate. Additionally, genes responsible for testicular tumors and unilateral renal agenesis were mapped on chromosomes 11 and 14, respectively. These results showed that prostate cancer susceptibility of ACI rats involves at least four loci, and suggested Mme and Cdkn1a as candidates for Pcr1 and Pcs2.

Animals↗

PubMed2005

Downregulation of apoptosis revealed by laser microdissection and cDNA microarray analysis of related genes in rat liver preneoplastic lesions.

Regulation of cell proliferation and apoptosis plays a key role in tumor development. To elucidate mechanisms underlying hepatocarcinogenesis, patterns of gene expression, including apoptosis-related genes, were compared between glutathione S-transferase placental form (GST-P)-positive preneoplastic foci and surrounding tissue in the rat. Lesions were induced with a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg bw) and then 100 ppm 2-acetylaminofluorene (2-AAF)-containing diet combined with two-thirds partial hepatectomy. Frozen sections of the livers were applied for immunohistochemical staining of GST-P, and both positive foci and surrounding negative areas were harvested by laser microdissection. Total RNAs were extracted and amplified with T7 polymerase to allow gene expression analysis by cDNA microarray assays. In the GST-P-positive foci, altered levels were observed for many genes, mostly related to metabolism or catalysis, with increased expression of testosterone-repressive prostate message-2 (TRPM-2), which is reported to act as a protective factor against apoptosis, and decreased expression of thymus-expressed acidic protein (TEAP), which is considered to promote apoptosis. The results indicate that rat liver preneoplastic lesions might be protected against apoptosis and that the approach adopted is useful for clarification of mechanisms underlying hepatocarcinogenesis.

Alkylating Agents↗

PubMed2005

Kinetics of marked development of lung metastasis of rat prostatic carcinomas transplanted in syngeneic rats.

In order to investigate how and when metastases develop under experimental conditions, kinetics of the size and the number of lung metastasis lesions in F344 rats were examined after syngeneic transplantation of rat prostate carcinomas induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB). Cell proliferation of the subcutaneous tumor and lung metastatic lesions was evaluated along with the expression of VEGF-A splicing variants and endostatin, serum VEGF levels and vascular density in the tumor. Several pieces of tumor tissue were introduced subcutaneously into two different sites on the dorsal side of F344 rats through a 14G needle. Average body weight of recipient rats markedly decreased despite only a gradual increase in tumor volume. The absolute total number of metastatic lesions in rats (n=5) were 2, 10, 19 and 194 at weeks 7.5, 9, 11 and 13, respectively, and a notable increase was observed at week 13. Similarly, the mitotic index of lung metastatic lesions increased remarkably at week 9 while the mitotic index and apoptotic index of transplanted tumors did not change throughout the experimental period. Expression of VEGF-A121, A164, A188 and endostatin, serum VEGF levels and vascular density did not correlate with the spread of lung lesions. In conclusion, both the number and the size of metastatic lesions increased at the same time after a notable increase in cell proliferation. Factors other than VEGF or endostatin may be involved in the mechanism of explosive lung metastasis spread.

Animals↗

PubMed2005

Influence of atrazine administration and reduction of calorie intake on prostate carcinogenesis in probasin/SV40 T antigen transgenic rats.

Atrazine, which has been used worldwide as a pesticide, is now known to exert endocrine disrupting (antiandrogenic) effects in mammals. In this study, modifying effects of dietary feeding of 500 and 1000 p.p.m. atrazine on the development of androgen-dependent prostate cancer were investigated using male probasin/SV40 T antigen transgenic (TG) rats. As administration of atrazine has now been identified as causing a decrease in bodyweight, a dietary-restricted TG rat group was also included in order to elucidate the influence of reduction of calorie intake per se on the development of prostate cancer. At week 13, almost the entire lobes of the prostate were occupied with tumor lesions, with no clear intergroup differences in the incidences and multiplicities. Therefore, morphometrical assessment ratios of the prostate epithelial area to the whole prostate tissue area were evaluated. The ratio in the lateral lobe of the 1000 p.p.m. atrazine-treated group was significantly decreased, and there was a tendency to decrease in the ratios in the dorsal lobe of the atrazine-treated groups. However, dietary restriction itself without atrazine treatment caused the same reduction to a similar or greater extent. Testosterone levels were not affected by atrazine administration or dietary restriction. Our results indicate that the observed atrazine-related suppression of prostate carcinogenesis was probably caused by the decrease in calorie intake, rather than by atrazine-related endocrine disruption.

Adenocarcinoma↗

PubMed2004

p-Nonylphenol pretreatment during the late neonatal period has no effect on 3,2'-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in male F344 rats.

The modifying effects of late neonatal administration of p-nonylphenol (NP), a suspected xenoestrogen, on 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced prostatic carcinogenesis were investigated in male F344 rats. Three-week-old rats received 25, 250 or 2000 ppm of NP in the diet for 3 weeks prior to DMAB treatment and were sacrificed at 67 weeks of age for histopathological assessment of lesions and Ki-67 immunohistochemical analysis of cell cycle kinetics. Dietary administration of NP during the sexually immature period had no effects on maturation of male sex organs. Incidence, multiplicity and areas of neoplastic lesions in the prostate and seminal vesicles, and Ki-67 labeling indices in normal-looking epithelium were not significantly different among the experimental groups. These results indicate that late neonatal treatment with NP has no modulating effects on DMAB-induced rat prostatic carcinogenesis.

Aminobiphenyl Compounds↗

PubMed2004

Expression of myelencephalon-specific protease in transient middle cerebral artery occlusion model of rat brain.

Myelencephalon-specific protease (MSP) is one of the serine proteases and is expressed in the central nervous system of rats. Its function and alternation in brain injury have not yet been clarified. In this study, we investigated the expression of MSP after transient middle cerebral artery occlusion (MCAO) using in situ hybridization and immunohistochemistry. In situ localization of MSP mRNA demonstrated a higher level in the corpus callosum and around the ischemic area from 12 h to 14 days after MCA reperfusion, with the peak of expression coming 3 days after reperfusion in both regions. Immunohistochemically, the expression of protein was found 1 day after reperfusion in the same brain region that was observed for mRNA. The peak was 7 days after reperfusion in both regions. Micro-autoradiography, immunostaining and double immunohistochemical labeling revealed the expression of MSP to be located mainly in the oligodendrocytes. The present results indicate that MSP may be related to the turnover of the myelin-associated proteins and the extracellular matrix proteins after transient MCAO. The activation of MSP may play a role in remodeling processes such as neurite outgrowth and remyelination.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed2004

Reactive angioendotheliomatosis of the intestine.

We present a case of reactive angioendotheliomatosis (RAE) of the colon, featuring intravascular proliferation of endothelial cells with histologic resemblance to glomeruloid hemangioma. A 19-year-old Japanese male with an anal fistula was diagnosed endoscopically with Crohn's disease. Six months later, he was hospitalized for fever and abdominal pain. Emergency resection of ileocecum and splenic flexure of the colon was undertaken to control massive intestinal hemorrhage, and in all parts of the resected colon, foci of many small vessels with intravascular proliferation of endothelial cells were noted throughout the layers. Moreover, solid proliferation of endothelial cells was seen in the submucosa at the base of open ulcers. Two small granulomas, compatible with Crohn's disease, were also evident in the muscle layer of the terminal ileum. No other hemangiomas or hemangioma-like structures were observed with CT scans, and the vascular lesions were histologically diagnosed as RAE. The pathogenesis of this disorder is unknown, and most cases occur in skin with systemic disease. The present case might thus be a first case of RAE of the intestine without cutaneous involvement. Whether there is a relation with coexistent enteritis suggestive of Crohn's disease needs to be clarified.

Adult↗

PubMed2003

Specific differences in gene expression profile revealed by cDNA microarray analysis of glutathione S-transferase placental form (GST-P) immunohistochemically positive rat liver foci and surrounding tissue.

Glutathione S-transferase placental form (GST-P), one of the glutathione S-transferases family of detoxification enzymes, is a very useful marker of rat liver pre-neoplastic lesions. We here investigated the gene expression profile in GST-P positive foci as compared with surrounding GST-P negative areas in the same liver of rats treated with diethylnitrosamine and then 2-acetylaminofluorene combined with partial hepatectomy. GST-P positive foci were harvested by laser microdissection and total RNAs were extracted to allow gene expression profiles to be assessed by cDNA microarray assays. Transaldolase, rat aflatoxin B1 aldehyde reductase and gamma-glutamylcysteine synthetase were found as up-regulated genes and regucalcin as a down-regulated gene, in line with findings for hepatocellular carcinomas. The results indicate that the approach adopted is useful for understanding mechanisms of hepatocarcinogenesis and identification of new markers for rat liver pre-neoplastic foci.

Animals↗

PubMed2003

Down-regulated expression of prostasin in high-grade or hormone-refractory human prostate cancers.

BACKGROUND: We previously conducted a search for genes which are differentially expressed in hormone-refractory prostate cancers using cDNA-representational difference analysis (RDA). The prostasin gene was isolated as one showing down-regulation in hormone-refractory cancers. In the present study, linkage to the stage in prostate neoplasia was examined. METHODS: Prostasin expressions in 54 prostate cancer cases were examined by mRNA in situ hybridization and immunohistochemistry as well as by northern blot analysis. RESULTS: Expression levels of prostasin in hormone-refractory cancers were approximately one-sixth of those in organ-confined cancers by northern blotting. Glandular components in benign prostatic hyperplasia and high-grade prostatic intraepithelial neoplasias tended to exhibit mild to moderate and relatively strong intensities, respectively. Expression levels of both prostasin mRNA and protein were inversely correlated with histological differentiation but not associated with clinical stage of human prostate cancer. Almost all cases of metastatic and hormone-refractory cancers demonstrated down-regulation of prostasin expression. CONCLUSIONS: These results suggest that prostasin cannot be regarded as a prognostic indicator for human prostate cancer although it may be a useful marker for tumor differentiation.

Adenocarcinoma↗

PubMed2003

High susceptibility of the ACI and spontaneously hypertensive rat (SHR) strains to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) prostate carcinogenesis.

Carcinogenic responses in the prostate to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were compared among seven rat strains (F344, ACI, Spontaneously Hypertensive Rat (SHR), Sprague-Dawley (SD), Wistar, Lewis and Brown Norway (BN)). Ten-week-old animals of each strain were given PhIP at 400 ppm in the diet for 20 weeks then maintained until week 54. The final survival rates were 92, 92, 83, 75, 67, 42 and 42%, respectively, and the SHR strain showed the highest sensitivity with regard to development of prostatic intraepithelial neoplasias (PINs) in the ventral prostate. With regard to the induction of adenocarcinomas of the ventral prostate, the ACI strain was most sensitive, whereas Lewis and F344 rats were relatively resistant. No adenocarcinomas were found in the dorsolateral or anterior prostate or seminal vesicles in any of the strains. The levels of serum testosterone and estrogen, PhIP-DNA adducts and cell kinetics did not correlate with the development of ventral prostatic lesions and thus other factors are presumably responsible for the variations in susceptibility. The present data indicate that ACI and SHR rats are appropriate strains for experimental investigation of PhIP-induced prostate carcinogenesis.

Adenocarcinoma↗