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Biomedical subjects

Y Maehara

Publications and source records attributed to Y Maehara.

At least 19 recordsLinked to original sources
PubMed2001

A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma.

Scirrhous carcinoma of the stomach is characterized by rapid growth with a vast fibrous stroma, high invasiveness, and substantially a poor prognosis. Little is known of the molecular pathogenesis of this disease. Members of the emerging family of the CCN gene (for connective tissue growth factor, cysteine-rich 61, nephroblastoma overexpressed) encode cysteine-rich secreted proteins with roles in human fibrotic disorders and cancer progression. Using targeted differential displays, we identified a novel variant of the CCN family member WISP1 (Wnt-induced secreted protein 1), named WISP1v, as overexpressed in scirrhous gastric carcinomas. Predicted protein of the WISP1v completely lacks a module of Von Willebrand type C that is thought to participate in protein complex formation. Ectopic expression revealed WISP1v to be a secreted oncoprotein inducing a striking cellular transformation and rapid piling-up growth. It is noteworthy that WISP1v transfectants enhanced the invasive phenotype of co-cultured gastric carcinoma cells, while wild-type WISP1 had no such potential. These findings suggest that CCN protein WISP1v is involved in the aggressive progression of scirrhous gastric carcinoma.

3T3 Cells↗
PubMed2001

Loss of motility-related protein 1 (MRP1/CD9) and integrin alpha3 expression in endometrial cancers.

BACKGROUND: MRP1/CD9 and integrin alpha3 have played crucial roles in cell adhesion, motility, and signaling events. The loss of MRP1/CD9 and integrin alpha3 has been involved in tumor growth and metastasis of cancer cells. The aim of the current study was to clarify the clinical significance of MRP1/CD9 and integrin alpha3 in endometrial cancer. METHODS: The expression of MRP1/CD9 and integrin alpha3 from the same tissue sample were examined immunohistochemically in 15 patients with normal endometrium and in 56 patients with uterine endometrioid adenocarcinoma. Disease-free survival curves were estimated using the Kaplan-Meier method and analyzed by the log-rank test between the positive and reduced expression statuses of both MRP1/CD9 and integrin alpha3. These expressions and clinicopathologic variables were analyzed univariately and multivariately. RESULTS: In normal endometrium, MRP/CD9 was expressed at the cell membrane of cell contact sites, and the expression of integrin alpha3 was detected also at the cell membrane of cell contact sites and at borders of stromal tissues. In patients with endometrioid adenocarcinoma, 17 cases showed reduced expression of MRP1/CD9, and 20 cases had reduced expression of integrin alpha3. Fourteen cases indicated a reduced expression of both MRP1/CD9 and integrin alpha3. Each reduced expression of MRP1/CD9 or integrin alpha3 was significantly correlated with histologic grade and metastasis. Multivariate analysis using the Cox regression model disclosed that age at surgery, metastasis, and expression status of MRP1/CD9 were significant prognostic factors for disease-free survival. CONCLUSIONS: These findings suggested that the analysis for the expression statuses of MRP1/CD9 and integrin alpha3 may provide important information on the clinical behavior of endometrial cancer.

Antigens, CD↗
PubMed2001

The instability within: problems in current analyses of microsatellite instability.

Microsatellite instability is regarded as one of the phenotypes of defective DNA mismatch repair and, consequently, as a marker of high risk for cancer. Despite numerous studies, the reported rates for positive microsatellite instability differ widely in each human malignancy. These discrepancies may relate to problems in the methods used. To establish a methodology for an accurate microsatellite instability analysis, technical requirements for a precise assay and biological conditions required for positive microsatellite instability were discussed. First, to describe microsatellite changes in detail, a sensitive detection system with linear detection characteristics and electrophoresis with standardised migration and minimised migration errors are considered to be necessary. Therefore, systems using fluorescent labelling and laser scanning are recommended. For reproducible polymerase chain reactions, it is essential to control the terminal deoxynucleotidyl transferase activity in Taq polymerase. Second, as a biological condition for positive microsatellite instability, feasible selection and combination of microsatellite markers, mutations in specific DNA mismatch repair genes and existence of monoclonal populations enriched sufficiently in a sample are essential. Finally, one possible diagnostic criterion for positive microsatellite instability is proposed, that is the existence of one of the patterns shown in the panel (see Fig. 6) at one or more loci in a set of more than five microsatellite markers.

DNA Repair↗
PubMed2001

Prognostic significance of natural killer cell activity in patients with gastric carcinoma: a multivariate analysis.

OBJECTIVE: Natural cytotoxicity, mediated by natural killer (NK) cells, has been believed to play an important role in inhibiting experimental tumor metastasis, and diminished NK cell activities leads to a high incidence of tumor occurrence. Despite convincing evidence from experimental studies, the role of NK cells in the immunological surveillance against cancer in human is poorly defined. METHODS: The present study was based on a retrospective analysis of data on 156 patients with gastric cancer, who were surgically treated in the Department of Surgery II, Kyushu University Hospital from 1993 to 1996. All patients were examined for NK cell activity based on a peripheral blood sampling done preoperatively. RESULTS: Significant association between NK cell activity and clinicopathological parameters including tumor size, lymphatic involvement, vascular involvement, and lymph node metastases was evident. When comparing the two groups according to NK cell activity, tumors with low NK cell activity tend to have lymphatic involvement. The 5-yr survival rates were 94.6% and 72.3% for those with NK cell activity > 25% lysis and < or = 25% lysis, respectively, the value being statistically significant (p < 0.05). The independent risk factors for prognosis examined by logistic regression analysis were lymphatic involvement. NK cell activity, depth of tumor invasion, and lymph node dissection. CONCLUSIONS: These current data showed that NK cell activity may be related to tumor volume and dissemination. Measurement of preoperative NK cell activity may be pertinent for the prognosis of patients with gastric cancer and for follow-up clinical management.

Cytotoxicity, Immunologic↗
PubMed2001

Overexpression of vascular endothelial growth factor C is related to lymphogenous metastasis in early gastric carcinoma.

Vascular endothelial growth factor C (VEGF-C) is considered to be potentially lymphangiogenic and can selectively induce hyperplasia of the lymphatic vasculature. In this study, we clarified the clinicopathological features of early gastric carcinoma (EGC) that has metastasized to the lymph nodes, as well as the correlation between lymphogenous metastases in EGC and the expression of VEGF-C and VEGF. We selected 35 cases of lymph node metastasis-positive [n(+)] EGC and 70 cases of lymph node metastasis-negative [n(-)] EGC for the present study. The expression of VEGF and VEGF-C was investigated with immunohistochemical staining using monoclonal antibodies against VEGF and VEGF-C. Clinicopathologically, there were significant differences in median size (4.1 +/- 2.4 vs. 2.4 +/- 1.7 cm), lymphatic invasion (54 vs. 4%) and venous invasion (23 vs. 3%) between n(+) EGC and n(-) EGC. Immunohistochemically, the incidence of positive expression of VEGF-C in lymphatic invasion-positive EGC (36%) was significantly higher than that in lymphatic invasion-negative EGC (14%). The incidence of positive expression of VEGF-C in n(+) or venous invasion-positive EGC tended to be higher than that in n(-) or venous invasion-negative EGC. In conclusion, lymphatic invasion was significantly increased in VEGF-C-positive EGC.

Aged↗
PubMed2001

Tumor growth patterns and biological characteristics of early gastric carcinoma.

Gastric cancer is a major malignant disease. The development of new diagnostic techniques and mass screening have led to increased detection rates of patients with early-stage gastric cancer in Japan. However, after curative resection of early gastric cancer, there are various types of recurrences, and residual occult disease and distant micrometastasis precede death. The growth and metastatic potential of cancer cells are closely related to the postoperative outcome, and patients at risk for cancer-related death after surgery have to be closely monitored to prevent tumor recurrence. The biological behavior of cancer cells should be determined in patients with early gastric cancer and with a less favorable prognosis to detect potential early recurrences in the liver. Two types of growth patterns have been found in early gastric cancer: the superficially spreading (Super) type and the penetrating (Pen) type, and the clinicopathological and biological characteristics of each type have been extensively determined. A subtype of the Pen-type gastric cancer, which is progressing expansively with complete destruction of the muscularis mucosae (Pen A type) has a less favorable prognosis due to early recurrences in the liver. These clinical cancer types are closely related to chromosomal instability in DNA aneuploidy and p53 overexpression, and vascular endothelial growth factor activation induced tumor angiogenesis, vascular invasion and hematogenous metastasis. Thus, patients with Pen-A-type cancer showing expansive tumor growth had a poorer postoperative outcome and a hematogenous-related recurrence of the cancer. Antiangiogenic approaches in a postoperative setting may prove to be effective in preventing tumor recurrence and improving the prognosis for these patients.

Adenocarcinoma↗
PubMed2001

Genetic alterations in the human Tcf-4 gene in Japanese patients with sporadic gastrointestinal cancers with microsatellite instability.

Disruption of the APC/beta-catenin/Tcf pathway has been proposed as an important step in the development of cancer. The Tcf-4 transcription factor gene was reported to be one of the targets of microsatellite instability (MSI) in colorectal cancers in with MSI. We carried out a sequencing analysis of the Tcf-4 gene in 41 Japanese patients with gastrointestinal tumors with MSI as well as in cancer cell lines. Three of 21 (14.3%) colorectal tumors with MSI contained a mutant Tcf-4 gene encoding 1-bp deletion in an (A)9 repeat, leading to carboxyl terminal truncation of Tcf-4 protein. No Tcf-4 mutations were detected in 20 gastric tumors with MSI, or in gastric cancer cell lines. Additionally, we found a novel transcript of the Tcf-4 gene which contained a segment of 73 bp in front of the (A)9 repeat of the Tcf-4 coding sequence. Sequencing analysis revealed that the inserted fragment was 60% homologous to that of exon IXA of the Tcf-1 gene. It is of interest that this insertion resulted in truncation of Tcf-4, similar to the 1-bp deletion in the (A)9 repeat. Therefore, in part of the Japanese colorectal tumors with MSI, frameshift mutations in Tcf-4 may be of functional significance. Functional alterations in the Tcf-4 signaling network in gastrointestinal tumorigenesis require further investigations.

Adenocarcinoma↗
PubMed2001

Features of microsatellite instability in colorectal cancer: comparison between colon and rectum.

In one third of colorectal cancer patients, tumours occur in the rectum. Unique aetiologies may underlie the increased carcinogenesis in this region of the colorectum. Microsatellite instability (MSI) was analysed in specimens obtained from 121 colorectal carcinoma patients, using five dinucleotide markers and a new fluorescent system. The incidence of microsatellite alterations in the proximal colon, the distal colon and the rectum was 44.4% (16/36), 37.2% (16/43) and 23.8% (10/42), respectively. Patterns of microsatellite alterations could be classified into two subtypes, one showing relatively small changes within 6 bases (type A) and the other exhibiting drastic changes over 8 bases (type B). All the changes observed in tumours in the rectum were type A, and no type B mutation was noted. There was a close correlation between type B mutations and high-frequency MSI (> or =2 markers), MSI-H, and between type A mutations and low-frequency MSI (1 marker), MSI-L. The type B/MSI-H phenotype significantly correlated with the proximal localisation of tumours. In the rectum, there was no tumour with the type B/MSI-H phenotype. These findings suggest that cancers occurring in the colon and the rectum have a differential molecular background for carcinogenesis.

Adenocarcinoma↗
PubMed2001

A prospective multicenter trial to determine the incidence of transient neurologic symptoms after spinal anesthesia with phenylephrine added to 0.5% tetracaine.

The addition of vasoconstrictors for spinal anesthesia is controversial, since an increase in the incidence of transient neurologic symptoms (TNS) has been reported. A multicenter, randomized, double-blind study was conducted to assess the effectiveness of spinal anesthesia with phenylephrine in addition to tetracaine as well as the incidence of neurological complications. We studied 64 patients with comparable demographic characteristics who were scheduled for elective surgery for a lower limb, or a gynecological or urological procedure. The patients were allocated randomly into 2 groups. Group P (n = 34) received 0.5% tetracaine in 10% glucose with 0.025% phenylephrine, while group C (n = 30) received 0.5% tetracaine in 10% glucose. Our results showed that only 2 patients (6.7%) in group C experienced TNS, and their symptoms disappeared within 72 hr after anesthesia, while none of the patients (0%) in group P complained of symptoms. The incidence of TNS was thus not significantly different between the two groups. Six hours after the sensory block, group P patients demonstrated sensory disturbance, with the median spinal dermatome corresponding to the L1 segment. Moreover, systolic blood pressure in group P was significantly higher than that in group C, 5 min, 15 min, and 20 min after injection. The incidence of TNS in the present study does not seem to be greater after surgery with spinal anesthesia using 0.5% hyperbaric tetracaine and 0.5 mg phenylephrine than without phenylephrine. Randomized, double-blind, cross-over trials with a larger sample size would be required in the future to obtain more reliable results.

Anesthesia, Spinal↗
PubMed2001

Lung cancer with p53 expression and a solitary metastasis to the stomach: a case report.

Lung cancer with a solitary metastasis to the stomach occurred in a 65-year-old man, surgically treated for gastric metastasis was followed by pulmonary resection. The gastric metastasis accompanied by upper gastrointestinal hemorrhage. After total gastrectomy to control this hemorrhage, a left lower lobectomy with a partial resection of the lingular segment and combined resection of the chest wall were done. Histopathological features of both the primary tumor in the left lower lobe and the gastric tumor were poorly differentiated adenocarcinoma, and showed the same immunoreactivities of p53 protein, carcinoembryonic antigen and keratin. These results indicate that the gastric tumor was a metastasis originated from the lung cancer.

Adenocarcinoma↗
PubMed2001

Nuclear expression of the Y-box binding protein, YB-1, as a novel marker of disease progression in non-small cell lung cancer.

Transcription factor Y-box binding protein 1 (YB-1) that binds to the inverted CCAAT box is involved not only in transcription of various genes but also in cell proliferation and DNA repair. We determined whether localization of YB-1 in either the nucleus or cytoplasm could serve as a prognostic marker for patients with non-small cell lung cancer (NSCLC). In 196 NSCLC patients, expression of YB-1 protein in the nucleus or cytoplasm was immunohistochemically evaluated. Of the 196 tumors examined, 88 (44.9%) were positive for YB-1 expression in the nucleus. Nuclear YB-1 expression significantly correlated with T factor, lymph node metastasis, and stage of the disease. Patients with a nuclear YB-1 tumor had a poorer prognosis than did those with a cytoplasmic YB-1 tumor in all of the NSCLC patients (P = 0.0494) and in patients with squamous cell carcinoma (P = 0.0313) but not in patients with adenocarcinomas. Nuclear localization of the YB-1 protein may prove to be an important factor of disease progression for patients with NSCLC, in particular, in cases of squamous cell carcinoma.

Adenocarcinoma↗
PubMed2000

Diminished expression of ING1 mRNA and the correlation with p53 expression in breast cancers.

p33(ING1) is a novel candidate tumor suppressor and its overexpression induces growth arrest or apoptosis in different cell lines. These functions of p33(ING1) depend largely on the activity of p53, and p53-dependent activation of the transcription from the p21/WAF1 promoter also requires p33(ING1). We examined the expression of ING1 mRNA in breast cancer cell lines and clinical breast cancer tissues, using quantitative RT-PCR and real time TaqMan technology. In breast cancer cell lines, ING1 mRNA was expressed at almost the same level. However, in a comparison between the cancer and matched normal tissues, a significant decrease in ING1 mRNA expression was found in 17 of 24 (70.8%) breast cancer tissues. We also examined the correlation between ING1 mRNA expression and p53 expression. There was a significant decrease of ING1 mRNA in nine of 15 tumors negative for p53 immunostaining, most of which were considered to have wild type p53. In these tumors, p53 may not function in case of a decreased expression of p33(ING1), and the lack of cell cycle regulation may correlate with the carcinogenesis and tumor progression.

Breast Neoplasms↗
PubMed2000

A phase II trial of a new 5-fluorouracil derivative, BOF-A2 (Emitefur), for patients with advanced gastric cancer.

The antineoplastic effects of BOF-A2 (Emitefur), a 5-fluorouracil (5-FU) derivative, in capsule form were assessed in patients with advanced gastric cancer, in a multicenter late phase II study and at 11 different hospitals. The patients were scheduled to receive a minimum of two courses of BOF-A2 orally, with each course of BOF-A2 consisting of 200 mg twice daily for 2 weeks followed by a withdrawal period of 2 weeks. Of the 24 patients entered into the study, the clinical response was able to be evaluated in 21 cases and the toxicity was determined in 23 cases. Eleven (45.8%) patients had been treated previously with other anticancer drugs. There was a 38.1% (8/21) response rate (95% confidence interval 17.3-58.9) with 1 (4.8%) complete response (CR) and 7 (33.3%) partial responses (PR), and these responses continued for over 4 months. In particular, the response rate for the primary lesion was 33.3% (3/9). No change (NC) in the disease was observed in 5 (23.8%) patients, and in 8 (38.1%) the disease progressed (PD). At the time of analysis, the median survival of the responders was 13 months, while that of the NC group was 7 months and that of the PD group was 2 months. The major adverse events consisted of gastrointestinal symptoms, myelosuppression, and skin symptoms, while toxicities of grade 3 or more occurred in 26.1% (6/23). These toxicities all resolved within 1-37 days after discontinuing the drug treatment. Based on the above findings, BOF-A2 is considered to be a promising anticancer drug for patients with advanced gastric cancer.

Administration, Oral↗
PubMed2000

Differential growth inhibition by 5-fluorouracil in human colorectal carcinoma cell lines.

The effects of 5-fluorouracil (5-FU) on cell growth were investigated using a primary culture of human fibroblasts, MRC-5, and three established human colon cancer cell lines, DLD-1, LoVo and SW620. Detailed flow cytometric analyses revealed differential growth inhibition among these cell lines including three modes of cell growth modulation: (a) loss or accumulation of S phase cells; (b) G2/M block; and (c) G1-S arrest. From analyses on the amount of 5-FU incorporated into cellular RNA and the activity of thymidylate synthase (TS), suppression of TS and depletion of dTTP, a possible consequence of the former, was considered to be the major action of 5-FU in these cells. Differences in the cellular responses to the nucleotide pool imbalance appeared to make the cell growth modulation diverse. Loss of S phase cells and G1-S phase arrest were evident in p53 wild-type cells, MRC-5 and LoVo. Cells proficient in DNA mismatch repair, SW620 and MRC-5, showed marked modulations in S-G2/M progression. These findings suggest that multiple factors, including p53 and DNA mismatch repair, participate in diverse cell growth modulations in cells treated with 5-FU. Cellular resistance to 5-FU correlated well with a loss of modulations in S-G2/M progression, rather than with a defect of G1-S arrest, which suggests the significance of DNA mismatch repair as a factor affecting the sensitivity of cells to 5-FU.

Antimetabolites, Antineoplastic↗
PubMed2000

Postoperative outcome and sites of recurrence in patients following curative resection of gastric cancer.

BACKGROUND: Recurrence occurs in a variety of forms and in different organs after 'curative resection' of gastric cancer. This study investigated the postoperative prognosis for each type of recurrence. METHODS: From 1969 to 1988, 939 patients with gastric cancer underwent curative resection; data on 130 of 207 patients who died with recurrence were analysed. Attention was focused on the site of recurrence and the postoperative outcome. RESULTS: Haematogenous recurrence was evident in 54 per cent (70 of 130 patients), peritoneal recurrence in 43 per cent (56 of 130), lymph node recurrence in 12 per cent (16 of 130) and local recurrence in 22 per cent (29 of 130). Thirty-three patients (25 per cent) had recurrences at multiple sites. Peritoneal and local recurrences were related to infiltrative growth, in contrast to haematogenous and lymphatic recurrences. There were no statistical differences in survival time among each type of recurrence and survival was not related to the number of sites of recurrence. Survival did not depend on factors of sex, age, tumour location, tumour size, depth of invasion, tissue differentiation, histological growth pattern, lymphatic and vascular involvement, lymph node metastasis and extent of lymph node dissection. CONCLUSION: The clinicopathological characteristics of gastric cancer determine the type of recurrence, although the clinical outcome is the same for each type of tumour and is not related to the number of sites of recurrence.

Humans↗
PubMed2000

Changes in E-cadherin associated with cytoplasmic molecules in well and poorly differentiated endometrial cancer.

E-cadherin function is thought to be impaired in epithelial cancer. To investigate the alterations in E-cadherin associated with cytoplasmic molecules including alpha-catenin, beta-catenin, gamma-catenin, p120CAS, and IQGAP1 in various endometrial cancers with different degree of differentiation, we examined the localization and expression of E-cadherin and cytoplasmic molecules in 30 cases of both well and poorly differentiated endometrioid adenocarcinomas, using immunofluorescence and immunoblotting techniques. E-cadherin and cytoplasmic molecules demonstrated linear staining at the cell boundaries in normal endometrium. In all 20 cases with well differentiated adenocarcinomas, alpha-catenin and IQGAP1 disappeared from the cell adhesive sites, but other cytoplasmic molecules were co-localized with E-cadherin along the cell boundaries. In all 10 cases with poorly differentiated adenocarcinomas, E-cadherin and cytoplasmic molecules accumulated as large aggregates along cell adhesive sites, and the localization of IQGAP1 differed from those of other cytoplasmic molecules. The expression of these molecules in all 20 cases with well differentiated adenocarcinomas decreased or was lost in Triton-insoluble fraction, in comparison with the findings for all cases with normal endometrium or poorly differentiated adenocarcinomas. These results suggested that each alteration in E-cadherin associated with cytoplasmic molecules may play a different role in E-cadherin dysfunction between well and poorly differentiated adenocarcinomas.

Adenocarcinoma↗
PubMed2000

Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues.

Vascular endothelial growth factor-C (VEGF-C) functions specifically to induce lymphangiogenesis. We examined the relationship between expression of VEGF-C and clinicopathological features in patients with colorectal cancer. The expression of VEGF-C in the 99 primary tumours and 18 metastatic lymph nodes from colorectal cancer patients was examined immunohistochemically. To verify VEGF-C mRNA expression, reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out. The expression of VEGF-C correlated with lymphatic involvement, lymph nodes metastasis, and depth of invasion. On the other hand, correlations were nil with regard to gender of the patients, histologic type, venous involvement, and liver metastasis. The expression of VEGF-C in metastatic lymph nodes was fairly consistent with this expression in the primary tumour. Survival time was shorter for VEGF-C positive groups than for VEGF-C negative ones, but with no statistically significant difference. RT-PCR findings revealed that the expression of VEGF-C mRNA correlated mostly with that of VEGF-C protein expression. VEGF-C may play an important role in lymphatic spread of colorectal cancer.

Adolescent↗