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Biomedical subjects

Masayuki Imamura

Publications and source records attributed to Masayuki Imamura.

At least 73 records · Page 4Linked to original sources
PubMed2004

The prognostic relevance of fascin expression in human gastric carcinoma.

OBJECTIVE: Fascin, an actin-bundling protein that is found in membrane ruffles, microspikes, and stress fibers, induces membrane protrusions and increases cell motility in various transformed cells. The expression of fascin in epithelial neoplasms has been described only recently, and its role in gastric cancer is still unknown. METHODS: Paraffin sections of gastric carcinoma from 214 patients were immunohistochemically investigated using monoclonal antifascin antibody. Staining more than 5% of tumor cells was recorded as positive immunoreactivity. RESULTS: Overall, fascin immunoreactivity was detected in 54 out of a total of 214 patients (25%). 26 patients were classified as 1+ (5-25% immunoreactive tumor cells) and 28 were 2+ (>25%). In these patients, 7 tumors showed high (>75%) fascin immunoreactivity. Increased immunoreactivity of fascin was sometimes seen at the edge of the tumor. Fascin immunoreactivity was increased according to the extent of primary tumor (p = 0.026). Fascin expression was correlated with age (p = 0.005), serosal invasion (p = 0.013), positive lymph node metastasis (p = 0.006), histopathological grading (p = 0.019), TNM stage (p = 0.003) and recurrence (p = 0.006); however, it was not correlated with distant metastasis (p = 0.108), Lauren's type (p = 0.205), or R classification (p = 0.056). Among 166 patients with T1, T2, T3 or T4, those with fascin-positive tumors had a significantly poorer prognosis than those with fascin-negative tumors (p = 0.029). Multivariate analysis showed that fascin expression was not an independent poor prognostic factor. CONCLUSION: Our findings suggest that the immunohistochemical detection of fascin could provide useful information as one of the prognostic factors in gastric cancer patients.

Actins↗
PubMed2004

CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer.

The stromal cell-derived factor-1 (SDF-1)/CXCR4 system is implicated in various instances of cell migration in mammals, including the migration of lymphocytes and the formation of metastases. We have recently synthesized a potent novel CXCR4 antagonist, TN14003. The purpose of this study was to investigate the role of SDF-1/CXCR4 axis in the pancreatic cancer metastasis via cell migration and invasion, and the inhibitory effect of TN14003 on pancreatic cancer cell metastasis. The expression of CXCR4 was detected in six pancreatic cancer cell lines by Western blotting and immunocytochemistry. In migration and invasion assays, SDF-1 stimulated both migration and invasion of cancer cells in a dose-dependent manner. The maximal effect of SDF-1 was observed at 100 ng/ml. SDF-1-induced migration and invasion of cancer cells were completely blocked by 100 nM TN14003. The stimulatory effect of SDF-1 on cancer migration and the inhibitory effect of TN14003 were mediated via the alteration in phosphorylation of mitogen-activated protein kinases. Treatment of cancer cells with 100 ng/ml SDF-1 resulted in a significant increase of actin polymerization, which was reduced by 100 nM TN14003. SDF-1 enhanced cancer cell adhesion to laminin, which was not reversed by TN14003. Taken together, SDF-1/CXCR4 axis is involved in pancreatic cancer metastasis through migration and invasion. The small molecule antagonists against CXCR4 such as TN14003 might be an effective anti-metastatic agent for pancreatic cancer.

Actins↗
PubMed2004

Combination of alpha-fetoprotein mRNA-based detection of hematogenously disseminating hepatocellular carcinoma cells and analysis of cancer cell membrane fluidity is more accurate in screening patients at risk of postoperative recurrence.

We developed an mRNA-based, highly specific and sensitive method to detect hepatocellular carcinoma cells present in blood. However, the reason for some patients being positive for blood analysis and negative for recurrence has yet to be found. We recently established a method to measure membrane fluidity of hepatocellular carcinoma cells, and used it to analyze the actual membrane fluidity of human hepatocellular carcinoma cells. We found that patients with carcinoma cells with lower membrane fluidity less frequently developed recurrence. The analysis of both membrane fluidity and alpha-fetoprotein mRNA thus greatly increased the accuracy of the prediction of postoperative recurrence.

Carcinoma, Hepatocellular↗
PubMed2004

[Analysis of microsatellite instability and p53 LOH in advanced colorectal cancers--first report of the No. 3 protocol].

In order to establish the most appropriate protocol of adjuvant chemotherapy for colorectal cancers, several cooperative studies have been undertaken by the Kinki Cooperative Study Group of Chemotherapy for Colorectal Carcinoma (KCSGCCC). In the No. 3 protocol of KCSGCCC, several cancer-associated molecular markers were analyzed to investigate a possible correlation with chemosensitivity and/or patient's prognosis. Here, we report the preliminary results of the analysis of microsatellite instability (MSI) and p53 LOH in 559 cases of Stage II, III colorectal cancer. The MSI was detected in 51 cases (9%) and was shown to have a significant correlation with right-sided localization and histology (poorly differentiated, mucinous). p53 LOH was positive in 225 cases (40%) and was shown to have a significant correlation with left-sided localization and histology (well to moderately differentiated). These results might support the concept of 2 distinct pathways of colorectal carcinogenesis, e.g., RER pathway and LOH pathway.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Involvement of TSLC1 in progression of esophageal squamous cell carcinoma.

Frequent allelic losses of 11q23 in esophageal squamous cell carcinoma (ESCC) have been reported previously, but no tumor suppressor genes in this region have been identified in ESCC. TSLC1 was identified on chromosome 11q23.2 as a tumor suppressor gene in non-small cell lung cancer by functional complementation of a lung adenocarcinoma cell line. The purpose of this study is to evaluate the role of TSLC1 in ESCC. Loss of TSLC1 expression was observed by reverse transcription-PCR in 75% of the cell lines (27 of 36) and 50% of the primary tumors from ESCC patients (28 of 56). In a clinicopathological analysis, loss of TSLC1 expression correlated significantly with depth of invasion (pT) and status of metastasis (pM; P = 0.012 and 0.036, respectively). Patients with tumors lacking TSLC1 expression tended to have a poorer prognosis than those with tumors expressing TSLC1. (P = 0.079). Moreover, TSLC1 expression was an independent prognostic factor in a multivariate analysis (P = 0.049). Methylation analyses revealed that TSLC1 expression or loss correlated with the promoter methylation status, as determined by bisulfite sequencing, and that TSLC1 expression could be restored by a demethylating agent in certain cell lines. The growth of TSLC1-transfected ESCC cells was significantly suppressed both in vitro and in vivo (P < 0.01), possibly by a G(1) cell cycle arrest. TSLC1 expression also suppressed motility and invasion of ESCC cells in vitro significantly (P < 0.01). These findings suggest that loss of TSLC1 expression has an important role in tumor growth, cell motility, and invasion and is associated with aggressive tumor behavior in ESCC.

Aged↗
PubMed2003

Identification of ZASC1 encoding a Krüppel-like zinc finger protein as a novel target for 3q26 amplification in esophageal squamous cell carcinomas.

Among the transcription factors that direct proliferation, differentiation, and death of cells, several Krüppel-like zinc finger molecules such as GLI1 and ZNF147 can become oncogenic when the genes encoding them are overexpressed by the DNA amplification mechanism. Here, we report the discovery of a novel member of this class, ZASC1, from a recently reported critical region of 3q26 amplification frequently observed in various squamous cell carcinomas, including esophageal squamous cell carcinomas (ESCs). The deduced 485-amino acid protein product of ZASC1 contained a putative nuclear localization signal; the exogenously transfected ZASC1 was translocated into cell nuclei. ZASC1 was frequently coamplified and subsequently overexpressed with PIK3CA in our panel of ESC cell lines and primary tumors. In patients with ESC, a higher mRNA expression level of ZASC1 appeared to be associated with shorter overall survival, and a multivariate analysis demonstrated that ZASC1 mRNA expression was an independent prognosticator. In addition, exogenous expression of ZASC1 promoted the growth of ESC cells, whereas down-regulation of ZASC1 expression by means of an antisense oligonucleotide suppressed the growth of ESC cells. Taken together, our results suggest that ZASC1 might be involved in the pathogenesis of ESC as one of the targets for 3q26 amplification, alone or in concert with other targets.

Aged↗
PubMed2003

Dihydropyrimidine dehydrogenase and thymidylate synthase activities in hepatocellular carcinomas and in diseased livers.

BACKGROUND/PURPOSE: Dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are key enzymes for predicting the efficacy of 5-FU in the treatment of malignant tumors. However, 5-FU is not commonly commonly chosen for chemotherapeutic treatment of hepatocellular carcinoma (HCC) in practice. The aim of this study was to determine the activities of both DPD and TS in HCCs and corresponding liver parenchyma and to assess the correlation between the activities of these enzymes and clinicopathological features. The possibility of using 5-FU as a first-choice chemotherapeutic agent for HCC was also evaluated. METHODS: The study material comprised 33 pairs of hepatocellular carcinoma and noncancerous liver samples. The DPD and TS activities were quantified by a radiometric enzymatic assay and a 5-fluoro-2'-deoxyuridine-5'- monophosphate (FdUMP) ligand-binding assay, respectively. RESULTS: Pathologically invasive HCCs tended to show higher DPD activity and lower TS activity with some exceptions. DPD activity was lower in the HCCs regardless of their clinical features than in the noncancerous liver parenchyma, whereas TS activity was generally lower in HCCs except for those with certain clinical features. HCCs with multiple nodules showed lower DPD activity and those with a diameter of more than 5 cm showed lower TS activity. In the noncancerous liver parenchyma, a gradual decrease in DPD activity and an increase in TS activity were associated with the age of the patient, liver damage and z-factor. Of 30 HCC samples, 10 exhibited comparatively low DPD and TS activity, and these could be considered 5-FU-sensitive HCC. CONCLUSIONS: DPD and TS activity may be affected by the clinicopathological status in both the HCC and the corresponding liver parenchyma. However, further investigation is necessary. Some HCC patients may be good candidates for 5-FU-based chemotherapy based on measurements of tumor levels of DPD and TS.

Adult↗
PubMed2003

Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma.

PURPOSE: CC chemokine receptor 7 (CCR7) plays a critical role in the migration of activated dendritic cells to regional lymph nodes. Recent studies have shown that CCR7 is involved in metastasis in some malignant diseases. The role of CCR7 in esophageal squamous cell carcinoma (SCC) has not yet been clarified. EXPERIMENTAL DESIGN: We performed reverse transcription-PCR analysis for CCR7 in 20 esophageal SCC cell lines and immunohistochemical analysis of 96 esophageal SCC samples. We then performed a cell migration assay, F-actin polymerization, and a phagokinetic assay on esophageal SCC cell lines in the presence of CCL21, a ligand of CCR7. RESULTS: CCR7 mRNA was detected in 9 of 20 esophageal SCC cell lines. Immunoreactive CCR7 was found mainly in esophageal cancer cells. High CCR7 expression was significantly correlated with esophageal SCC lymphatic permeation, lymph node metastasis, tumor depth, and tumor-node-metastasis stage and was associated with poor survival. In vitro studies demonstrated that CCL21 significantly increased the cell migration ability of esophageal SCC cell lines, and pseudopodia formation was induced by CCL21 stimulation. Furthermore, CCL21 markedly enhanced the motility of esophageal carcinoma cell lines by the phagokinetic assay. CONCLUSIONS: The results suggested that the CCR7/CCL21 receptor ligand system may play a role in the lymph node metastasis of esophageal SCC.

Aged↗
PubMed2003

Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma.

Many cancers are resistant to Fas-mediated apoptosis despite the expression of Fas. To investigate the mechanisms by which Fas signals are attenuated, we focused on decoy receptor 3 (DcR3). DcR3 is a soluble receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily and overexpresses in some forms of cancers. Exogenous DcR3 inhibits Fas-mediated apoptosis in Fas-sensitive Jurkat cells. In our study, we examined the expression and function of DcR3 in pancreatic cancers. TaqMan RT-PCR showed that DcR3 mRNA was highly expressed in pancreatic cancer cell lines (71%) and tissues (67%). Its expression significantly correlated with cancer invasion to veins. Western blotting showed that the DcR3 protein was produced and secreted in 4 of 6 cell lines. The protein expressions were compatible with the mRNA expression. Five of 7 pancreatic cancer cell lines became sensitive to agonistic anti-Fas antibody (CH-11) to various extents, without Fas upregulation, when exposed to CH-11 for 48 hr after pretreatment with IFNgamma. Four of 7 pancreatic cancer cell lines were inhibited from growing, compared to control cells, when cocultured with membrane-bounded Fas ligand (mFasL) transfected lymphomas for 48 hr after pretreatment with IFNgamma. DcR3 reduced this growth inhibition when added exogenously. Regression analysis showed that the DcR3 expression significantly correlated with the sensitivity to mFasL, and not to CH-11. These results suggest that DcR3 is highly expressed in many pancreatic cancers and endogenous DcR3 blocks the growth inhibition signals mediated by mFasL. DcR3 can be a candidate target molecule for the therapeutic intervention.

Adenocarcinoma↗
PubMed2003

Neurotrophin receptor p75(NTR) characterizes human esophageal keratinocyte stem cells in vitro.

We report here that human esophageal keratinocyte stem cells are characterized by the expression of the low-affinity neurotrophin receptor p75(NTR) and differentially expressed cell adhesion molecules, the beta1 and beta4 integrins. The candidate stem cells could be fractionated from keratinocytes as a minor cell subset by means of immunocytochemical cell sorting based on the different levels of expression of these cell surface molecules. Flow cytometric analysis revealed that this minor cell subset retained a relatively slow-cycling phenotype in vitro. These cells expressed low levels of involucrin and cytokeratin 13, indicating that the p75(NTR)-positive cell subset is immature relative to the other predominant subpopulations coexpressing beta1 integrin at higher levels. The p75(NTR)-positive cell subset was crucial for achieving longevity and the greatest output of keratinocytes comprising all distinguishable subpopulations in vitro. This process was associated with self-renewal and self-amplification of the p75(NTR)-positive cell subset. These findings strongly implicate p75(NTR) as a stem cell marker, which will be valuable for prospectively investigating stem cell regulation in association with different biological processes including neoplastic transformation of regenerative epithelia.

Blotting, Western↗
PubMed2003

The impairment of hepatocytes and sinusoidal endothelial cells during cold preservation in rat fatty liver induced by alcohol and the beneficial effect of hepatocyte growth factor.

A fatty liver resulting from alcohol intake is often unattractive for grafting. In this study, we investigated the impairment of hepatocytes and sinusoidal endothelial cells (SECs) during cold preservation of alcohol-induced fatty liver and examined the efficacy of human recombinant hepatocyte growth factor (hrHGF). Rats were fed an alcohol diet. We performed histological examinations of the hepatocytes and observed the ultrastructural alteration of the SECs. Additionally, we measured hepatic transaminase and peroxidative lipids for hepatocellular injury and the hyaluronic acid uptake rate (HUR) to determine SEC injury. We added hrHGF to University of Wisconsin (UW) solution to assess the protective effect of the agent. Numerous fatty deposits were observed in ethanol-induced fatty livers. These grew with the duration of cold storage. Hepatic transaminases of the effluents increased during cold preservation in the livers of alcohol-treated rats. Additionally, peroxidative lipids in the effluents increased during cold preservation in the livers of alcohol-treated rats, whereas they were undetectable in non-alcohol-treated rat livers. The sinusoidal endothelium had severely deteriorated in the livers of alcohol-treated rats. Further, the HUR decreased with ethanol treatment and/or cold preservation. The addition of hrHGF suppressed the increase of hepatic transaminase in the effluent of cold-preserved alcohol-treated livers. Peroxidative lipids in the same effluents were undetectable. In fatty livers, both hepatocytes and SECs received severe damage during cold preservation. Furthermore, we demonstrated that hepatocellular injury was significantly inhibited by hrHGF.

Adenosine↗
PubMed2003

Diagnosis of pancreatic cancer using fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) --usefulness and limitations in "clinical reality".

The present review will provide an overview of the literature concerning the FDG PET diagnosis of pancreatic cancer and a summary from our experience of 231 cases of pancreatic lesions. FDG PET can effectively differentiate pancreatic cancer from benign lesion with high accuracy. Newly-developed PET scanners can detect small pancreatic cancers, up to 7 mm in diameter, by their high resolution, which could make a great contribution to the early detection of resectable and potentially curable pancreatic cancers. FDG PET is useful and cost-beneficial in the pre-operative staging of pancreatic cancer because an unexpected distant metastasis can be detected by whole-body PET in about 40% of the cases, which results in avoidance of unnecessary surgical procedures. FDG PET is also useful in evaluation of the treatment effect, monitoring after the operation and detection of recurrent pancreatic cancers. However, there are some drawbacks in PET diagnosis. A relatively wide overlap has been reported between semiquantitative uptake values obtained in cancers and those in inflammatory lesions. As for false-positive cases, active and chronic pancreatitis and autoimmune pancreatitis sometimes show high FDG accumulation and mimic pancreatic cancer with a shape of focal uptake. There were 8 false negative cases in the detection of pancreatic cancer by FDG PET, up to 33 mm in diameter, mainly because of their poor cellularity in cancer tissues. In addition, there are 19% of cancer cases with a decline in FDG uptake from 1 hr to 2 hr scan. FDG PET was recently applied to and was shown to be feasible in the differential diagnosis of cystic pancreatic lesions, such as intraductal papillary mucinous tumor of the pancreas. Further investigations are required to clarify the clinical value of FDG PET in predicting prognosis of the pancreatic patients.

Fluorodeoxyglucose F18↗
PubMed2003

Optimal scan time for evaluating pancreatic disease with positron emission tomography using F-18-fluorodeoxyglucose.

OBJECTIVE: Image interpretation in positron emission tomography (PET) using F-18-fluoro-2-deoxy-D-glucose (FDG) is usually performed for images obtained at 1 h postinjection (PI) of FDG, but it remains unknown whether this is the optimal time for imaging patients with pancreatic disease. The aim of this study was to assess the optimal scan time for FDG-PET for patients suspected of having pancreatic cancer. PATIENTS AND METHODS: Forty-four patients with suspected pancreatic cancer underwent FDG-PET scans at both 1 h and 2 h PI. Tracer uptake in the pancreatic lesions and possible liver metastasis was interpreted qualitatively, using a 5-point grading system (0 = normal, 1 = probably normal, 2 = equivocal, 3 = probably abnormal, and 4 = definitely abnormal) by 4 nuclear medicine physicians independently, who were blind to all clinical information. Detection performance with each image was compared using receiver operating characteristic (ROC) analysis. An average score of the 4 readers for each patient was also defined as consensus average index (CAI) and compared between the two images. RESULTS: ROC results indicated no significant differences in detection performance (Averaged areas under ROC curves of 1 h vs. 2 h were 0.92 vs. 0.90 for primary tumor, and 0.81 vs. 0.85 for liver metastases). There were no significant differences in CAIs between 1 h and 2 h PI images in interpreting primary tumor and positive liver metastases, but a significant difference was observed for cases without liver metastases (p < 0.05). CONCLUSIONS: The certainty of excluding liver metastases was increased when the 2h image was used, although ROC analysis did not establish a difference between 1 h and 2 h imaging for differentiating malignant and benign lesions in primary pancreatic cancer or its liver metastases.

False Positive Reactions↗
PubMed2003

Dendritic cells coinjected with tumor cells treated with an anticancer drug to induce tumor rejection.

PURPOSE: We examined whether bone marrow-derived dendritic cells (DCs) could induce antitumor immunity when a chemotherapeutic drug was added. METHODS: CT26 (a murine colon cancer cell line syngeneic with BALB/c) and CT26-bearing mice were treated with mitomycin C (MMC) intraperitoneally (i.p.). Next, mice immunized with a coinjection of DCs and MMC-treated CT26 (i.p.) were given an intradermal inoculation of CT26. Finally, CT26-bearing mice were treated with MMC (i.p.) with or without DCs, given peritumorally. RESULTS: Although the inoculated tumor was not rejected in the control mice, CT26 was rejected in 50% of the mice injected with MMC alone. Apoptosis was observed in the MMC-treated CT26 cells in vitro and in vivo. Immunization with DCs and apoptotic CT26 cells, but not with apoptotic CT26 alone, gave protection against tumor challenge in 7 of 13 mice. A significantly higher level of cytotoxic T-cell activity and interferon-gamma production was seen in the protected mice. When MMC (i.p.) treatment was followed by peritumoral DC injection in the CT26-bearing mice, remarkable therapeutic effects were observed. CONCLUSION: DCs can collaborate with chemotherapy-induced apoptotic tumor cells and elicit improved antitumor immunity, probably through the acquisition of tumor-associated antigens from apoptotic tumor cells.

Animals↗