Biomedical subjects

Ryoichi Oyasu

Publications and source records attributed to Ryoichi Oyasu.

6 recordsLinked to original sources

PubMed2006

Inactivation of AR activates HGF/c-Met system in human prostatic carcinoma cells.

Clinical studies with prostate cancer tissue indicate that alterations in androgen receptor (AR) or c-Met overexpression are associated with androgen-independent progression. We investigated the interaction between AR and c-Met signaling in human prostate cancer cells. Androgen withdrawal or AR-specific small interfering RNA significantly reduced the growth rate while each maneuver induced the expression of c-Met. Knockdown of both AR and c-Met expression markedly inhibited the cell growth. Furthermore, microarray analysis indicated that the activation of c-Met down-regulated the expression of DNA repair-related genes including 8-oxoguanine DNA glycosylase. Exogenous hepatocyte growth factor also induced the production of intracellular reactive oxygen species and resulted in the accumulation of DNA damages. These results suggested that the activation of c-Met signaling may lead to induction of spontaneous mutations or genomic instability, which may lead to the progression of androgen-independent state. Thus, c-Met signaling is utilized for survival and growth under the androgen-depleted condition.

Cell Line, Tumor↗

PubMed2006

Bladder reconstruction using a collagen patch prefabricated within the omentum.

OBJECTIVE: We present our experience with a novel bladder reconstruction model using a collagen sponge pre-embedded within the omentum. The aim of the study is to evaluate tissue regeneration of the reconstructed bladder and the effect of prefabricating the collagen patch within the omentum. MATERIALS AND METHODS: Twenty pigs were divided into three groups. For the prefabricated patch group (PFP; n=10), collagen sponge was inserted into the omentum. After 1 week, the pigs underwent a hemicystectomy and the sponge with an attached omental flap was brought to close the defect. For the non-prefabricated patch group (NPFP; n=6), pigs received hemicystectomy and closure with a collagen sponge without prefabricating in the omentum. Four other pigs received hemicystectomy alone as a control (C; n=4). All animals in the NPFP and C groups, and 7 of 10 in the PFP group were sacrificed at 4 or 8 weeks. Three other pigs in the PFP group were sacrificed at 12 weeks. Resected bladders were submitted to hematoxylin-eosin, and immunohistochemical staining. RESULTS: All animals except for two in the NPFP group survived. At the time of grafting, the collagen sponge was covered with thick omental methothelial layers, and neo-vascularization from the omentum was observed. At each time point, only slight adhesion was observed around the patch in the PFP group, while severe adhesion between the patch and the bowel was observed in the NPFP group, suggesting that prefabricated collagen sponge within the omentum prevented urine leakage from the bladder. Histologically, the patch was well vascularized, and the luminal surface was covered with urothelium at 4 weeks in both groups. However, in the PFP group, there was mild inflammation in the submucosa and in-growth of smooth muscle derived from the adjacent muscle layers was observed with time, whereas severe inflammation was observed and in-growth of smooth muscle was limited in the NPF group. CONCLUSIONS: Prefabricating of a collagen patch within the omentum stimulated early neo-vascularization before grafting, and this procedure appears to offer an advantage for bladder reconstruction over a non-prefabricated procedure in terms of prevention of urine leakage and inflammation, and favorable tissue regeneration.

Animals↗

PubMed2006

Chemopreventive effects of cyclooxygenase-2 inhibitor and epidermal growth factor-receptor kinase inhibitor on rat urinary bladder carcinogenesis.

OBJECTIVE: To examine the chemopreventive effects of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, and a selective epidermal growth factor (EGF)-receptor tyrosine kinase inhibitor, gefitinib (as a single agent) on a carcinogen-induced rodent bladder carcinogenesis model. MATERIALS AND METHODS: The study comprised 103 male Fisher-344 rats (8 weeks old); after initial carcinogen treatment for 8 weeks with 0.05%N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water, the rats were divided into five groups, i.e. group 1, control (vehicle only); group 2, gefitinib high-dose (15 mg/kg by gavage once daily); group 3, gefitinib low-dose (5 mg/kg); group 4, meloxicam high-dose (1.8 mg/kg by gavage once daily); and group 5, meloxicam low-dose (0.6 mg/kg). Twelve weeks later the rats were killed; after fixing the bladder in 10% formalin, the number and size of hyperplasia and carcinoma foci were recorded microscopically in sections stained with haematoxylin and eosin, submitted entirely as multiple strips. RESULTS: The incidence of carcinoma, confirmed microscopically, was: control 14/20 (70%); high-dose gefitinib, 7/20 (35%); low-dose gefitinib, 7/20 (35%); high-dose meloxicam 7/21 (33%); and low-dose meloxicam, 12/20 (60%). The mean numbers of carcinomas per bladder in groups 1-5 were 1.2, 0.5, 0.4, 0.5 and 1.1, respectively. The incidence and the mean number of carcinomas per bladder were significantly lower in the treatment groups (P < 0.05) than in the control group, except in the low-dose meloxicam group. There were no significant adverse effects. CONCLUSION: Both meloxicam and gefitinib have inhibitory effects on rat bladder carcinogenesis with no significant adverse effects. A combination of these drugs would be worth studying for their synergistic effects.

Animals↗

PubMed2004

Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis.

The induction of phase 2 detoxifying enzymes, such as UDP-glucuronosyltransferases (UGTs), in response to an array of naturally occurring and synthetic agents, such as oltipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiole-3-thione), provides an effective means of protection against a variety of carcinogens. Transcription factor Nrf2 is an essential regulator of the inducible expression of detoxifying enzyme genes by chemopreventive agents. In this study, we investigated in Nrf2-deficient mice the susceptibility to the urinary bladder-specific carcinogen N-nitrosobutyl(4-hydroxybutyl)amine (BBN) and the chemopreventive efficacy of oltipraz. The incidence of urinary bladder carcinoma by BBN was significantly higher in Nrf2-/- mice than in wild-type mice; invasive carcinoma was found in 24.0 and 38.5% of wild-type and Nrf2-/- mice, respectively. Oltipraz induced the phase 2 enzymes responsible for BBN detoxification in the liver and urinary bladder in an Nrf2-dependent manner. As expected, therefore, oltipraz decreased the incidence of urinary bladder carcinoma by BBN in wild-type mice but had little effect in Nrf2-/- mice. In wild-type mouse liver, oltipraz significantly induced BBN glucuronidation and decreased the urinary concentration of N-nitrosobutyl(3-carboxypropyl)amine, a proximate carcinogen of BBN. Importantly, BBN was found to suppress the expression of UGT1A specifically in the urinary bladder. This suppression was counteracted by oltipraz in wild-type mice but not in Nrf2-/- mice. These results show that Nrf2 and its downstream target genes are responsible for BBN detoxification. Furthermore, oltipraz prevents carcinogenesis by BBN by enhancing detoxification of this carcinogen in the liver and urinary bladder.

Animals↗

PubMed2004

Phenotypic switch from paracrine to autocrine role of hepatocyte growth factor in an androgen-independent human prostatic carcinoma cell line, CWR22R.

Support mechanisms involved in growth of androgen-independent prostate cancer are primarily unknown. Hepatocyte growth factor (HGF)/Met has been suggested to be one of them based primarily on immunohistochemical studies. We conducted a series of experiments to assess the role of the HGF/Met system in an androgen-dependent human prostate carcinoma, CWR22 and its androgen-independent derivative, CWR22R. We found that action of HGF changed from paracrine to autocrine in progression to androgen-independent state. CWR22 tumors did not express HGF but expressed Met, whereas prostate stromal cells expressed HGF at a high level. Growth of CWR22 was stimulated either by addition of HGF to the culture or by the presence of prostate stromal cells. On the other hand, CWR22R cells expressed both HGF and Met. Knockdown of Met expression by RNA interference method suppressed the growth of CWR22R cells. Our data suggest that HGF is intimately involved in growth of human prostate cancer and that progression from the androgen-dependent to the androgen-independent state is associated with an adaptive switch in support mechanism from paracrine to autocrine. Our data offer one mechanism to account for androgen-independent human cancer growth.

Androgens↗

PubMedDate not supplied

Immunohistochemical expression of hepatocyte growth factor and c-Met/HGF receptor in benign and malignant human prostate tissue.

Hepatocyte growth factor (HGF) has been proposed to be an autocrine/paracrine growth factor for carcinomas of various organs. We recently demonstrated that HGF produced by prostate-derived stromal cells was a paracrine growth factor that stimulated the growth of androgen-independent prostate cancer cells in vitro and in vivo. To assess possible involvement of HGF in prostate cancer, we examined the immunohistochemical expression and localization of HGF and c-Met/HGF receptor in benign and malignant human prostate tissues. In benign glands, columnar cells generally were negative for c-Met, but basal cells were stained uniformly at a high level. In high-grade prostatic intraepithelial neoplasia (PIN) and carcinoma, more than 50% of these foci were stained uniformly. There was no difference in the frequency of positively stained cells by Gleason score. The prostate stroma stained diffusely for HGF, and the staining intensity varied depending upon the amounts of smooth-muscle cells that were stained more intensely than the connective-tissue matrix. A great majority of benign columnar cells were negative for HGF whereas high-grade PIN and carcinoma foci stained focally for HGF. Hormonal ablation therapy prior to prostatectomy did not seem to alter the expression of HGF/c-Met in carcinoma cells. These results indicate that, as the degree of neoplasia progresses, epithelial cells begin to express c-Met protein, that PIN and carcinoma may have developed a c-Met-HGF paracrine loop with the stroma, and that in some carcinoma foci an autocrine loop may operate with HGF expressed by carcinoma cells themselves.

Cell Line, Tumor↗