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Biomedical subjects

Y Ueyama

Publications and source records attributed to Y Ueyama.

At least 37 records · Page 2Linked to original sources
PubMed2001

Gene expression of angiogenesis related factors in glioma.

Angiogenesis plays an important role in growth and proliferation of cancer. Various angiogenic and angiostatic factors regulate angiogenesis. In this study, we examined gene expression of the angiopoietin family including angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2) in 39 gliomas and 5 glioma-xenografts by RT-PCR. Ang1 and Ang2 genes were expressed in 54%, and 77% of gliomas, respectively. The expression of Ang1 was significantly correlated with the expression of Ang2. Both Ang1 and Ang2 were shown to be expressed in the glioma cells. Ang2 gene expression was correlated with VEGF gene expression. Angiopoietin molecules may synergistically cooperate in growth and vascularization in glioma.

Angiopoietin-1↗
PubMed2001

Interleukin 10 expression is correlated with thrombospondin expression and decreased vascular involvement in colon cancer.

Interleukin 10 (IL-10) is an immuno-suppressive cytokine produced by T-lymphocytes, and a regulatory molecule for angiogenesis in various cancers. We examined IL-10 gene expression in 53 colon cancer patients who underwent surgical resection. IL-10 gene expression was correlated with TSP1 and TSP2 gene expression (P=0.0049, P=0.0285). Colon cancer with IL-10 gene expression (19/53) showed significantly decreased venous involvement (P=0.0433). The mean vessel counts in the colon cancers with IL-10 gene expression were significantly lower than those without IL-10 gene expression (P<0.001). These results suggested that IL-10 stimulates angiostatic factor gene expression, and results in suppression of venous involvement.

Adenocarcinoma↗
PubMed2001

Interleukin-10 expression is correlated with growth fraction in human non-small cell lung cancer xenografts.

We examined IL-10 and IL-10 receptor (IL-10R) gene expression in 44 xenografts of human non-small cell lung cancer (NSCLC) by reverse transcription-polymerase chain reaction (RT-PCR) assay with human-specific primers. IL-10 gene expression was detected in 10 (22.7%) of 44 xenografts (0/11 adenocarcinomas, 6/19 squamous cell carcinomas, 4/14 large cell carcinomas) and IL-10R expression in 8 (18.2%) xenografts. The IL-10-positive xenografts immunohistochemically showed significantly increased growth fractions of neoplastic cells (471.0 +/- 112.2) relative to IL-10-negative xenografts (208.4 +/- 96.3) (p=0.009, Mann-Whitney U test), and showed significantly increased vascular number (p=0.008, Mann-Whitney U test). These results suggested that IL-10 expression is correlated with growth features in human NSCLC.

Animals↗
PubMed2001

Interleukin-10 relieves the inhibitory effects of interferon-gamma on normal human lung fibroblasts.

Interleukin-10 (IL-10) is an important cytokine that suppresses the production of cytokines and chemokines by immune cells. IL-10 has been suggested to be involved in chronic inflammatory responses including the remodeling process in the lung. We investigated the effects of IL-10 on proliferation, extracellular matrix and cytokine production in normal human lung fibroblasts (NHLF). Human IL-10 (hIL-10) complementary DNA (cDNA) was transfected into NHLF using an adenoviral vector. No significant changes were observed in proliferation, fibronectin or procollagen type I production in the NHLF transfected with hIL-10 cDNA. Interferon (IFN)-gamma significantly inhibited cell proliferation and extracellular matrix production in a dose-dependent manner. Transfection of hIL-10 cDNA significantly relieved the suppressive effects of IFN-gamma in NHLF. Transforming growth factor (TGF)-beta production was not significantly affected by either transfection of hIL-10 cDNA or the addition of IFN-gamma. The relief of the suppressive function of IFN-gamma by IL-10 suggested that IL-10 is indirectly involved in the remodeling process in the lung interstitium.

Adenoviridae↗
PubMed2001

Significant correlation between interleukin 10 expression and vascularization through angiopoietin/TIE2 networks in non-small cell lung cancer.

The expression of interleukin 10 (IL-10) is correlated with clinical prognosis in non-small cell lung cancer [NSCLC (H. Hatanaka et al., ANN: ONCOL:, 11: 815--819, 2000)]. However, the effects of IL-10 expression on vascularization in NSCLC are not apparent. We examined the gene expression of IL-10/IL-10 receptor and various angiogenic/angioinhibitory factors in 95 NSCLC samples to determine the correlation between IL-10 production and vascularization. Vascular endothelial growth factor, angiopoietin [Ang (Ang-1 and Ang-2)], thrombospondin, brain-specific angiogenesis inhibitor 1, vascular endothelial growth factor receptors (KDR and flt-1), and Ang receptor (TIE2) gene expression were evaluated by reverse transcription-PCR. The cellular localization of these factors and vascularity in the cancer stroma were examined immunohistochemically. Seventy-eight (82.1%) and 93 (97.9%) of these 95 NSCLCs were positive for IL-10 and IL-10 receptor, respectively. Ang-1, Ang-2, and TIE2 gene expression was seen in 76 (97.4%), 73 (93.6%), and 78 (100%) of 78 IL-10-positive NSCLCs, respectively, and was significantly correlated with IL-10 gene expression (P < 0.0088, <0.0008, and 0.0305, respectively; Fisher's exact method). The localizations of Ang-1, Ang-2, and TIE2 were confirmed within tumor cells immunohistochemically. Vascular number and measurement area were significantly higher in the IL-10-positive NSCLCs (33.500 +/- 9.299/microm(2) and 4.742 +/- 1.287%) as compared with IL-10-negative NSCLCs (10.611 +/- 2.839/microm(2) and 0.718 +/- 0.331%; Mann-Whitney U test, P = 0.0039). The IL-10 expression did not show any significant correlation with the expression of other factors. These results suggested that tumor-produced IL-10 promotes stromal vascularization through expression of Ang-1, Ang-2, and TIE2.

Angiogenesis Inhibitors↗
PubMed2000

Expression of a truncated epidermal growth factor receptor in oral squamous cell carcinomas.

Epidermal growth factor receptor (EGFR) frequently overexpresses in cancers, including oral squamous cell carcinomas (OSCC). We previously identified a truncated EGFR (tEGFR) in human oral keratinocytes. In this study, we evaluated the prognostic value of tEGFR in 45 cases of OSCC. tEGFR expression inversely correlated with EGFR expression (r=-0.83, P<0.01), decreased with T-stage progression and lymph-node metastasis (P<0.05). The EGFR/tEGFR ratio correlated with the lymph-node metastasis (P<0.05) and survival outcome (hazard ratio =3.601; P<0.05). These results suggest that tEGFR may play an important roles in oral carcinogenesis and that the EGFR/tEGFR ratio may be a prognostic factor for OSCC.

Adult↗
PubMed2000

Alterations of Rb, p16(INK4A) and cyclin D1 in the tumorigenesis of oral squamous cell carcinomas.

Immunohistochemical analysis of Rb, p16(INK4A) and cyclin D1 expression was performed on 78 oral squamous cell carcinoma (SCC), 46 leukoplakia, and 20 normal mucosa. Rb and p16(INK4A) expression were observed in all normal mucosa and most of leukoplakia. Lack of Rb and p16(INK4A) was observed in 56.4 and 67.9% of SCC, respectively. The overexpression of cyclin D1 was not observed in normal mucosa and was observed in 35.9% of SCC. A strong reciprocal relationship between Rb and p16(INK4A) expression was observed in oral SCC, and all these SCC cases have at least one of the alterations in the Rb pathway.

Carcinoma, Squamous Cell↗
PubMed2000

Apoptosis and p53 are associated with effect of preoperative radiation in oral squamous cell carcinomas.

This study was carried out to elucidate whether apoptosis and p53 can be used to stratify oral cancer patients into groups with a favorable or unfavorable response to preoperative radiation therapy. Thirty-two patients were evaluated. The apoptosis index was 1.7+/-0. 9% in the ineffective cases, and it was significantly lower than effective cases (3.2+/-1.2%). While 14 of 16 effective cases (86.7%) did not express p53, 13 of 16 ineffective cases (81.3%) overexpressed p53. These results suggest that mutated p53 in tumors is associated with a poor response to radiation which may be related to evasion of apoptosis in oral cancer.

Aged↗
PubMed2000

Ribozyme approach to downregulate vascular endothelial growth factor (VEGF) 189 expression in non-small cell lung cancer (NSCLC).

The aim of this study was to further clarify the role of the cell-associated isoform of vascular endothelial growth factor (VEGF189) on tumour growth and vascularity. Five isoforms of VEGF have been identified with different biological activities. VEGF121, VEGF145, VEGF165, VEGF189, VEGF206 are generated by alternative splicing. We used a hammerhead-type ribozyme (V189Rz) to suppress VEGF189 mRNA. The V189Rz specifically cleaved exon 6 of VEGF189 mRNA, but showed no activity against the VEGF121 or VEGF165 isoforms. The V189Rz was introduced into the human non-small cell lung cancer (NSCLC) cell line (OZ-6/VR). The expression level of VEGF189 mRNA was decreased in the OZ-6/VR cells, while VEGF121 and 165 expression was unaltered. The OZ-6/VR cells xenotransplanted into nude mice showed markedly reduced vascularisation and growth, whereas the cell line did not show any decreased growth under tissue culture conditions. The OZ-6/VR cells (1 x 10(5) cells/mouse) formed no tumours, whereas the parental OZ-6 cells formed large tumours within 8 weeks. The specific suppression of VEGF189 by the ribozyme decreased vascularity and xenotransplantability of the lung cancer cell line. Thus, the cell-associated isoform of VEGF, VEGF189, might have a key role in stromal vascularisation and the growth of NSCLC xenografts in vivo.

Animals↗
PubMed2000

Clinical implications of interleukin (IL)-10 induced by non-small-cell lung cancer.

BACKGROUND: The type 2 cytokine interleukin (IL)-10 has been reported to inhibit the antitumour activity of the regional immunity against various neoplasms. Certain lung cancers produce IL-10, but the clinical significance of IL-10 expression is not well understood. PATIENTS AND METHODS: We examined IL-10 and IL-10 receptor (IL-10R) mRNA expression in 82 non-small-cell lung cancers (NSCLC) by reverse transcription-polymerase chain reaction (RT-PCR) assay. Immunohistochemistry (IHC) and enzyme immunoassay (EIA) were applied to evaluate the cellular localisation and the serum levels of IL-10. RESULTS: RT-PCR assay revealed IL-10 mRNA expression in 68 (83%) of 82 NSCLC surgical specimens (40 of 50 adenocarcinomas, 22 of 26 squamous cell carcinomas, 5 of 5 large-cell carcinomas, 1 of 1 adenosquamous-cell carcinoma). RT-PCR assay also revealed IL-10R mRNA expression in 79 cases of NSCLC (96.1%). IL-10 expression was confirmed within tumour cells by IHC. EIA showed no significant serum IL-10 elevation in the 12 NSCLC positive for IL-10 mRNA expression (0-2.99 pg/ml). The NSCLC patients with IL-10 production showed significantly poorer prognosis than those without IL-10 production (P < 0.05, Kaplan Meier, log-rank test). CONCLUSIONS: These results suggested that the cytoplasmic IL-10 correlated to clinical prognosis, and that IL-10 expression is a prognostic factor for NSCLC.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

Adenovirus-mediated anti-K-ras ribozyme induces apoptosis and growth suppression of human pancreatic carcinoma.

Human pancreatic cancer is a lethal malignancy, and the lesions show a very high incidence of point mutations of the K-ras oncogene. These alterations can be used as potential targets for specific ribozyme (Rz)-mediated growth suppression of the cancer cells. We designed an anti-K-ras Rz against mutant K-ras gene transcripts (codon 12, GGT to GTT) and generated a recombinant adenovirus (rAd) to express the Rz (rAd/anti-K-ras Rz). More than 95% of Capan-1 human pancreatic cells were infected with rAd/anti-K-ras Rz when treated with the virus at 200 plaque-forming units/cell. The virus, rAd/anti-K-ras Rz, significantly suppressed mutant K-ras gene expression and inhibited the growth of Capan-1 cells. At 3 days postinfection, we observed maximum growth suppression of the cells, characteristic morphological changes of apoptosis such as nuclear condensation and oligonucleosomal DNA fragmentation, and suppression of bcl-2 oncoprotein. These changes were not found in control virus-infected cells. Our results indicated that the virus rAd/anti-K-ras Rz specifically down-regulated the K-ras/bcl-2 pathway and induced apoptotic changes in Capan-1 pancreatic carcinoma cells. High-efficiency adenovirus-mediated delivery of anti-K-ras Rz could become a significant gene therapy strategy against human pancreatic cancer.

Adenoviridae↗
PubMed2000

Arsenic trioxide (As2O3)-induced apoptosis and differentiation in retinoic acid-resistant acute promyelocytic leukemia model in hGM-CSF-producing transgenic SCID mice.

Recent clinical studies in China and USA showed that arsenic trioxide (As2O3) is an effective treatment of acute promyelocytic leukemia (APL) patients refractory to all-trans retinoic acid (RA). We here investigate the effects of As2O3 on RA-resistant APL in vivo and in vitro using our RA-resistant APL model system. As2O3 can induce inhibition of cellular growth of both RA-sensitive NB4 and RA-resistant UF-1 APL cells via induction of apoptosis in vitro. The expression of BCL-2 protein decreased in a dose- and time-dependent manner in NB4 cells. Interestingly, the levels of BCL-2 protein were not modulated by As2O3, but it did upregulate BAX protein in UF-1 cells. UF-1 cells (1x10(7)) were transplanted into hGM-CSF-producing transgenic SCID mice and successfully formed subcutaneous tumors. After 40 days of implantation, mice were treated with As2O3, all-trans RA and PBS for 21 days. In all-trans RA- and PBS-treated mice, tumors grew rapidly, with a 4.5-fold increase in volume at day 21 compared to the initial size. In marked contrast, tumor size was decreased to half of the initial size by the treatment of As2O3, which resulted in cells with the typical appearance of apoptosis. Interestingly, one of the As2O3-treated mice showed mature granulocytes in the diminished tumor, suggesting that As2O3 had dual effects on RA-resistant APL cells in vivo: both inducing apoptosis and differentiation of the leukemic cells. We conclude that our RA-resistant APL model will be useful for evaluating novel therapeutic approaches to patients with RA-resistant APL, and for further investigation of the metabolism of As2O3 in vivo.

Animals↗
PubMed2000

Histologic and cell kinetic studies of hair loss and subsequent recovery process of human scalp hair follicles grafted onto severe combined immunodeficient mice.

To establish a model for studying human scalp hair, individually isolated hair follicles were grafted onto back skin of severe combined immunodeficient mice. Histologic changes and cell kinetics in the hair loss and subsequent recovery process were investigated. In the dystrophic stage (from day 7 to 30), all the hair shafts became dystrophic and were shed. Thickening and corrugation of vitreous membrane, apoptosis, and regression of the lower part were observed in the grafted hair follicles. 5-bromo-2'-deoxy-uridine-labeled cells were not detected in the lower end of the follicles, and keratin 19-positive cells appeared there. At the end of this stage their lower part was maximally retracted, secondary germ remained beneath the bulge, and the vitreous membrane disappeared. In the regeneration stage (from day 30 to 50), the same histologic findings as those at the end of the dystrophic stage were observed. The keratin 19-positive cells in the secondary germ, however, were replaced with keratin 19-negative and 5-bromo-2'-deoxy-uridine-labeled cells. Then, differentiation into an inner root sheath and a hair shaft began, and apoptosis was terminated. In the stable growth stage (from day 40 to at least 150), the grafted follicles were immunohistochemically and light microscopically identical with the normal anagen hair follicles except for the presence of melanin incontinence. These findings suggest that the grafted hair follicles entered into dystrophic catagen, subsequently dystrophic telogen, then returned to normal anagen follicles, and that stem cells or their close progeny in the secondary germ play an important part in the recovery process.

Animals↗
PubMed2000

Ribozyme-mediated inactivation of mutant K-ras oncogene in a colon cancer cell line.

Mutation of c-K-ras oncogene is an important step in progression of colon cancer. We used a hammerhead ribozyme (KrasRz) against mutated K-ras gene transcripts (codon 12, GTT) to inactivate mutant K-ras function in the colon cancer cell line SW480, harbouring a mutant K-ras gene. The beta-actin promoter-driven KrasRz sequence (pHbeta/KrasRz) was introduced into these cells (SW480/KrasRz), and we evaluated its effects on growth of the colon cancer. The gene expression of angiogenesis-related molecules (vascular endothelial growth factor and thrombospondin) was also estimated in SW480/KrasRz. KrasRz specifically and efficiently cleaved the mutant K-ras mRNA but not wild-type mRNA in vitro. SW480/KrasRz showed decreased growth rate under tissue culture conditions (P< 0.01, Dunnett's test). The xenotransplantability of SW480/KrasRz (XeSW480/KrasRz) was significantly decreased in nude mice (P< 0.05, Fisher's exact test). Tumour volume of the xenografts XeSW480/KrasRz was significantly smaller than that of XeSW480/DisKrasRz (P< 0.01, Dunnett's test). Gene expression of VEGF was suppressed in SW480/KrasRz, while TSP1 gene expression was enhanced. The SW480/KrasRz cells showed apoptosis-related features including nuclear condensation and DNA fragmentation. These results suggested that the hammerhead ribozyme-mediated inactivation of the mutated K-ras mRNA induced growth suppression, apoptosis and alteration of angiogenic factor expression.

Animals↗
PubMed2000

Identification of hepatic tamoxifen-DNA adducts in mice: alpha-(N(2)-deoxyguanosinyl)tamoxifen and alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide.

Tamoxifen-DNA adducts detected in the liver of mice treated with tamoxifen have not yet been identified. In the present study a new type of tamoxifen-DNA adduct, four stereoisomers of alpha-(N:(2)-deoxyguanosinyl)tamoxifen N:-oxide 3'-monophosphate (dG(3'P)-N:(2)-TAM N:-oxide) were prepared as standard DNA adducts by reacting 2'-deoxyguanosine 3'-monophosphate with trans-alpha-acetoxytamoxifen N:-oxide in addition to four stereoisomers of alpha-(N:(2)-deoxyguano- sinyl)tamoxifen 3'-monophosphate (dG(3'P)-N:(2)-TAM) that was reported previously. Liquid chromatography-electrospray ionization-mass spectrometry of the reaction products gave the most abundant ion at m/z 731 ([M - H](-)), which corresponded to dG(3'P)-N:(2)-TAM N:-oxide. The modified products digested by alkaline phosphatase corresponded to the isomers of dG-N:(2)-TAM N:-oxide whose structures were identified previously by mass spectrometry and nuclear magnetic resonance. Using these standard markers, we analyzed the hepatic DNA adducts of female DBA/2 mice treated with tamoxifen at a dosage of 120 mg/kg/day for 7 days by (32)P-post-labeling coupled with an HPLC/radioactive detector. Mixtures of eight isomers of dG(3'P)-N:(2)-TAM and dG(3'P)-N:(2)-TAM N-oxide were separated into six peaks, since each of the cis epimers were not separated under the present HPLC conditions. Nine adducts were detected in all liver samples of mice. An epimer of trans-dG(3'P)-N:(2)-TAM was detected as the principal DNA adduct at a level of 29.0 adducts/10(8) nucleotides, which accounted for 53.3% of the total tamoxifen-DNA adducts. Lesser amounts of cis-dG(3'P)-N:(2)-TAM (2.8%) were also observed. An epimer of the trans-dG(3'P)-N:(2)-TAM N:-oxide (3.9 adducts/10(8) nucleotides) was detected as the third biggest adduct (7.2% of the total). The cis-dG(3'P)-N:(2)-TAM N:-oxide (0.4 adducts/10(8) nucleotides) accounted for 0.7% of the total. Thus, dG(3'P)-N:(2)-TAM and dG(3'P)-N:(2)-TAM N:-oxide were identified in tamoxifen-treated mouse liver.

Animals↗
PubMed2000

Acinar-islet cell tumor of the pancreas: report of a malignant pancreatic composite tumor.

An unusual case of malignant pancreatic composite tumor with both components of acinar cell tumor (ACT) and islet cell tumor (ICT) was investigated histologically, immunohistochemically, and ultrastructurally. The pancreatic tumor with central cyst formation was found on computerized tomographic examination of a 72-year-old man reporting appetite and weight loss. The ACT component was present in the original pancreatic region and the ICT region was adjacent to the ACT. ACT was immunohistochemically positive for pancreatic amylase, whereas ICT had argyrophil tumor cells immunohistochemically positive for chromogranin A. There were several tumor cell nests positive for both pancreatic amylase (acinar differentiation) and chromogranin A (islet differentiation). We speculated that ICT may have arisen from the de-differentiated tumor cells in the ACT after the occurrence of ACT.

Aged↗
PubMed2000

Association of preoperative radiation effect with tumor angiogenesis and vascular endothelial growth factor in oral squamous cell carcinoma.

This study examined the relationship between tumor angiogenesis and the radiation-induced response, evaluated based on pathological changes, in oral squamous cell carcinoma patients treated with preoperative radiation therapy. Forty-one cases of squamous cell carcinoma treated with preoperative radiation therapy were investigated. Tumor angiogenesis was assessed by scoring the intratumor microvessel density (IMVD). Expression of vascular endothelial growth factor (VEGF) was also evaluated before and after preoperative radiotherapy. There was no correlation between IMVD in the specimens before therapy and the pathological response to radiation therapy. However, radiation therapy decreased IMVD in the specimens after therapy. A significant association was observed between VEGF expression and resistance to radiation therapy: only 4 of the 21 patients whose tumors exhibited a high level (2 + or 3 + ) of VEGF staining experienced a major (3 + or 4 + ) pathological response to radiation therapy. Furthermore, an increasing level of VEGF expression after radiation therapy was observed in non-effective (0 to 2 + ) response cases. These results suggest that VEGF expression and the induction of this protein are related to radiosensitivity and could be used to predict the effects of preoperative radiation therapy on oral squamous cell carcinoma.

Adult↗