Biomedical subjects

Tetsuji Tanaka

Publications and source records attributed to Tetsuji Tanaka.

34 records · Page 2Linked to original sources

PubMed2004

Phase II study of irinotecan combined with mitomycin-C for advanced or recurrent squamous cell carcinoma of the uterine cervix: the JGOG study.

OBJECTIVES: The efficacy and toxicity of combined therapy with irinotecan (CPT-11) plus mitomycin-C (MMC) were evaluated in patients with advanced or recurrent squamous cell carcinoma (SCC) of the uterine cervix. METHODS: CPT-11 (100 mg/m(2)) was administered on days 1, 8, and 15 by intravenous (iv) infusion over 90 min, while MMC (10 mg/m(2) iv) was given on day 1. This regimen was repeated every 28 days and at least two courses were given. RESULTS: Among 51 eligible patients (median age: 52 years; range: 25-72 years), 2 showed complete response (CR) and 24 showed PR, for an overall response rate (ORR) of 51.0% (95% confidence interval: 36.6-65.3%). In patients without prior chemotherapy, the ORR was 54.8% (38.7-70.2%). Twenty-five patients (Ib2:3, IIb:17, and IIIb:5) received this regimen as neoadjuvant chemotherapy and their ORR was 76% (54.9-90.6%). Twenty-two patients were able to undergo radical surgery after NAC. The major toxicity was neutropenia, which was grade 3-4 in 59% of the patients. Grade 3-4 thrombocytopenia and anemia were also seen in 26% of the patients each. The most common nonhematologic toxicity was diarrhea (grade 3-4 in 12%). CONCLUSION: CPT-11 combined with MMC can be effective against advanced or recurrent SCC of the uterine cervix.

Adult↗

PubMed2004

Deletion of the kinase domain in death-associated protein kinase attenuates tubular cell apoptosis in renal ischemia-reperfusion injury.

Death-associated protein kinase (DAPK) is a calcium/calmodulin-dependent serine/threonine kinase localized to renal tubular epithelial cells. To elucidate the contribution of DAPK activity to apoptosis in renal ischemia-reperfusion (IR) injury, wild-type (WT) mice and DAPK-mutant mice, which express a DAPK deletion mutant that lacks a portion of the kinase domain, were subjected to renal pedicle clamping and reperfusion. After IR, DAPK activity was elevated in WT kidneys but not in mutant kidneys (1785.7 +/- 54.1 pmol/min/mg versus 160.7 +/- 60.6 pmol/min/mg). Furthermore, there were more TUNEL-positive nuclei and activated caspase 3-positive cells in WT kidneys than in mutant kidneys after IR (24.0 +/- 5.9 nuclei or 9.4 +/- 0.6 cells per high-power field [HPF] versus 6.3 +/- 2.2 nuclei or 4.4 +/- 0.7 cells/HPF at 40 h after ischemia). In addition, the increase in p53-positive tubule cells after IR was greater in WT kidney than in mutant kidneys (9.9 +/- 1.4 cells/HPF versus 0.8 +/- 0.4 cells/HPF), which is consistent with the theory that DAPK activity stabilizes p53 protein. Finally, serum creatinine levels after IR were higher in WT mice than in mutant mice (2.54 +/- 0.34 mg/dl versus 0.87 +/- 0.24 mg/dl at 40 h after ischemia). Thus, these results indicate that deletion of the kinase domain from DAPK molecule can attenuate tubular cell apoptosis and renal dysfunction after IR injury.

Animals↗

PubMed2004

Reduced expression of death-associated protein kinase in human uterine and ovarian carcinoma cells.

The expression of the death-associated protein kinase (DAPK) protein and promoter methylation in 11 human uterine and ovarian carcinoma cell lines originally established from histopathologically-different carcinoma tissues were examined to investigate the relationship between DAPK and carcinogenesis in female reproductive tissues. The 11 cell lines included three cervical carcinomas, three endometrial carcinomas and five ovarian carcinomas. Western blot analysis showed no detectable expression of DAPK protein in 4 cell lines (ME180, HOKUG, MCAS and OVK-18) while moderate levels of DAPK protein were readily detected in normal human endometrium, and normal murine uterus and ovary. Methylation-specific PCR of the 11 cell lines revealed that 5 carcinoma cell lines (ME180, HOKUG, MCAS, OVK-18 and HEC-1) expressed hypermethylated promoters in the DAPK genes, while DAPK promoters in the other 6 carcinoma cell lines remained unmethylated. These results indicate that DAPK protein expression is reduced or silenced in some human uterine and ovarian carcinoma cells by methylation of the DAPK gene promoter region. Therefore, reduced DAPK expression and methylation of the DAPK promoter may be involved in carcinogenesis of human uterine and ovarian tissues.

Animals↗

PubMed2004

Growth-inhibitory signals by activin A do not affect anticancer drug-sensitivity and acquired multi-drug-resistance in human ovarian endometrioid adenocarcinoma OVK-18 cells.

Using the human ovarian adenocarcinoma cell line, OVK-18, which is sensitive to activin A-mediated inhibition of growth and various anticancer drugs, we determined whether activin A altered the sensitivity of these cells to seven anticancer drugs. The relationship between the sensitivity to activin and the resistance to anticancer drugs was also investigated in OVK-18 parent cells and OVK-18-derived CDDP-resistant cells. Activin A inhibited proliferation of OVK-18 parent cells in a dose-dependent manner, although it did not affect the sensitivity of OVK-18 parent cells to the seven anticancer drugs, CDDP, CBDCA, adriamycin, paclitaxel, SN38, terarubicin and etoposide (VP16). Both the sensitivity to activin A-mediated inhibition of growth and the sensitivity to anticancer drug-induced apoptosis were reduced in CDDP-resistant cells, while their sensitivity to the seven anticancer drugs was not affected by activin A. Flow cytometric analysis revealed a significant reduction in type IIA activin receptor expression on the surface of CDDP-resistant cells. These results indicate that the activin A-induced intracellular signals inhibiting cell growth are independent of the inhibition caused by the seven anticancer drugs, and suggest that the reduced sensitivity of CDDP-resistant cells to activin A is derived in part from reduced activin receptor expression and not acquired drug-resistance.

Activins↗

PubMed2004

Deletion of the kinase domain in death-associated protein kinase attenuates renal tubular cell apoptosis in chronic obstructive uropathy.

Death-associated protein kinase (DAPK) is a Ca2+/calmodulin-dependent serine/threonine kinase that has been implicated as a positive mediator of apoptosis. However, little is known about the involvement of DAPK in the apoptosis associated with several pathological states, except for cancer. Here, DAPK-mutant mice were used in order to examine the role of DAPK in renal cell apoptosis in chronic obstructive uropathy (COU) created by unilateral ureteral ligation. These mice express mutant DAPK with a deletion of 74 amino acids from the catalytic kinase domain. Obstructed kidneys in wild-type and mutant mice were examined for both DAPK protein levels and renal cell apoptosis during the course of COU. Obstructed kidneys in wild-type and mutant mice showed a marked increase in the DAPK and mutant DAPK protein levels, respectively, at day 14 after ureteric ligation. The obstructed kidneys in DAPK-mutant mice displayed a significant attenuation of tubular cell apoptosis, compared with wild-type mice. In contrast, no significant difference in interstitial cell apoptosis was observed between the obstructed kidneys from wild-type and mutant mice. Thus, these results indicate that the part of the kinase domain deleted by the gene targeting is crucial for the execution of tubular cell apoptosis, but is not essential for interstitial cell apoptosis in a COU model in mice.

Animals↗

PubMed2004

Activin A inhibits growth-inhibitory signals by TGF-beta1 in differentiated human endometrial adenocarcinoma cells.

Although human endometrial adenocarcinoma tissues express high levels of activin A, the pathophysiological functions of endometrial activin A remain unclear. Human endometrial cancer cells express both activin receptor and TGF-beta receptor, and TGF-beta1 utilizes the same intracellular signaling molecules as activin A. Using three differentiated human endometrial adenocarcinoma cell lines, we investigated whether there are interactions between TGF-beta1- and activin A-mediated signaling. Flow cytometric analysis revealed cell surface expression of two types of TGF-beta receptor subunits and four types of activin receptor subunits. TGF-beta1 inhibited cell proliferation in three endometrial adenocarcinoma cell lines. Activin A did not affect the growth of the three endometrial cell lines, and pre-incubation with activin A dose-dependently reduced TGF-beta1-mediated inhibition of cell growth. These results suggest that in endometrial adenocarcinoma cells, the intracellular signals underlying TGF-beta1-mediated inhibition of growth can themselves be inhibited by activin A. Therefore, the increased expression of activin A may be involved in carcinogenesis by reducing TGF-beta-mediated signals inhibiting cell growth in human endometrial adenocarcinoma tissues.

Activins↗

PubMed2003

Granulated metrial gland cells in the murine uterus: localization, kinetics, and the functional role in angiogenesis during pregnancy.

Granulated metrial gland (GMG) cells are a major immune cell population in the murine pregnant uterus, and contribute to the maintenance of pregnancy by functioning as uterus-specific natural killer (NK) cells. In order to reveal their kinetics, activation, and functional roles in pregnancy, we conducted quantitative and immunohistochemical analyses in normal and immuno-modulator-treated mice. Under a light microscope, GMG cells were identified by red cytoplasmic granules in periodic-acid-Schiff (PAS)-stained sections. They progressively increased in number and size with the peak at day 12-14 of pregnancy in the decidua and metrial gland. New vessel formation was most prominent around day 8, and the total vascular area reached the peak at day 13. GMG cells were often located near the blood vessels, and expressed vascular endothelial growth factor (VEGF), suggesting their possible inducing role in angiogenesis during the development of decidua/metrial gland. While blood vessels in the non-pregnant uterus were negative for vascular cell adhesion molecule (VCAM)-1, those in the pregnant one were positive. Treatment with neutralizing antibody against VCAM-1, however, did not decrease the number of GMG cells. On the other hand, mitosis of GMG cells was frequently observed. These data suggest that the increment of GMG cells during pregnancy may largely result from local proliferation in the uterus rather than an increased influx of precursor cells. Although we attempted to induce in vivo activation of GMG cells by administration of interleukin-12 (IL-12) or alpha-galactosylceramide, a potent activator for natural killer-T (NK-T) cells, the number of GMG cells did not appreciably increase. The present study has demonstrated that GMG cells locally proliferate in the pregnant uterus, not being related to VCAM-1 expression by the uterine vasculature or systemic activation of NK cells and NK-T cells, and seem to be involved in angiogenesis in the pregnant uterus through VEGF production.

Animals↗

PubMed2003

Leukemia inhibitory factor regulates cell survival of normal human endometrial stromal cells.

Leukemia inhibitory factor (LIF) is produced locally in decidual tissues, but its direct effects on endometrial stromal cells have not been well characterized. In this study, we examined the direct effects of LIF on normal human endometrial stromal cells using an in vitro decidualization assay system with 8-Br-cAMP, a decidualization inducer. We found no effects of LIF on cell viability and prolactin secretion of unstimulated endometrial stromal cells. LIF dose-dependently enhanced cell viability, but not prolactin secretion of 8-Br-cAMP-stimulated cells. LIF dose-dependently enhanced the viability of stromal cells co-stimulated with 8-Br-cAMP and LIF without any significant effect on PRL secretion from the cells. Further, the extracellular matrix did not affect these stimulatory effects of LIF on cell viability of 8-Br-cAMP-stimulated endometrial stromal cells. These results indicate that LIF enhances the cell viability of PRL-non-secreting 8-Br-cAMP-stimulated stromal cells, and that the cell survival signals generated by LIF are independent of those generated by the extracellular matrix. LIF produced locally in decidual tissues may enhance cell viability in certain activated endometrial stromal cells in an autocrine or paracrine manner, and possibly protect against cell damage during embryo implantation and trophoblastic invasion.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2003

Regulation of the cellular subpopulation ratios of normal human endometrial stromal cells by macrophage colony-stimulating factor.

Normal human endometrial stromal cells (ESCs) stimulated with 8-Br-cAMP secrete significantly large amounts of PRL and granulocyte colony-stimulating factor (G-CSF), whereas unstimulated stromal cells secreted little. However, there is no relation between PRL and G-CSF levels secreted from the stimulated cells, which suggests that PRL-secreting stromal cells may not completely coincide with the G-CSF-producing stromal cells. Recently we found that macrophage colony-stimulating factor (M-CSF) inhibits 8-Br-cAMP-induced decidualization, differentiation to prolactin (PRL)-secreting cells, by suppressing viable decidualizing cells. Therefore, we investigated the effects of M-CSF on G-CSF secretion from normal human endometrial stromal cells using an in vitro decidualization activity assay. M-CSF did not show any significant effects on viable cell numbers of unstimulated ESCs, while M-CSF dose-dependently enhanced G-CSF release from the non-decidualized stromal cells. A high concentration of M-CSF strongly suppressed the viable cell numbers and PRL secretion of stromal cells co-stimulated with 8-Br-cAMP and M-CSF, although G-CSF release from the co-stimulated stromal cells was not affected by M-CSF. Moreover, M-CSF did not affect viable cell numbers, PRL secretion or G-CSF secretion of 8-Br-cAMP-stimulated cells. These results indicate that M-CSF enhances G-CSF secretion from 8-Br-cAMP-unstimulated human endometrial stromal cells but not from 8-Br-cAMP-stimulated stromal cells, thus suggesting that there exists a functional subpopulation of G-CSF-secreting stromal cells that are different from the predecidualized ESCs that differentiate into PRL-secreting ESCs under stimuli with 8-Br-cAMP. Hence, M-CSF may autoregulate functional cellular subpopulations of human endometrial stromal cells in an autocrine or a paracrine manner.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2003

Oncostatin M inhibits decidualization of normal human endometrial stromal cells.

It is well known that oncostatin M binds and activates leukemia inhibitory factor-specific receptors while leukemia inhibitory factor cannot bind oncostatin M-specific receptors. In this study, the differential effects of oncostatin M and leukemia inhibitory factor on cell survival and decidualization of normal human endometrial stromal cells were investigated by using 8-Br-cAMP-induced decidualization assay. Oncostatin M did not affect the viable cell numbers or the prolactin release of unstimulated stromal cells. However, oncostatin M dose-dependently suppressed prolactin releases from 8-Br-cAMP-stimulating stromal cells but enhanced their viable cell numbers. Although oncostatin M significantly enhanced viable cell numbers of 8-Br-cAMP-stimulated stromal cells, it did not affect prolactin secretion from 8-Br-cAMP-induced decidualized cells. Leukemia inhibitory factor significantly enhanced viable cell numbers of 8-Br-cAMP-stimulating cells in a dose-dependent manner as did oncostatin M, while leukemia inhibitory factor did not show any significant suppression of PRL secretion from 8-Br-cAMP-stimulating cells. These results indicate that oncostatin M inhibits the 8-Br-cAMP-induced decidualization process via oncostatin M-specific receptors and that oncostatin M and leukemia inhibitory factor enhance cell survival of 8-Br-cAMP-stimulated prolactin-non-secreting stromal cells mainly via leukemia inhibitory factor receptors. Thus, oncostatin M may autoregulate human endometrial stromal cell survival and decidualization in a paracrine manner.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2003

Fas antigen (CD95) mediates cell survival signals to regulate functional cellular subpopulations in normal human endometrial stromal cells.

Fas antigen (CD95) is expressed on almost all types of human cells and is believed to mediate receptor-specific apoptotic signals. In human endometrial tissues, high Fas and Fas ligand expressions and Fas-mediated apoptosis in endometrial epithelial cells have been discussed in many reports but no study has examined Fas-mediated signals in endometrial stromal cells. In this study we investigated Fas expression and Fas-mediated signals of normal human endometrial stromal cells. Flow cytometric analysis revealed Fas antigen expression on the stromal cells and their Fas expression was enhanced by 8-Br-cAMP, a strong inducer of decidualization. Neither short-term nor long-term cultures with anti-Fas IgM affected proliferation or viability of the stromal cells. Anti-Fas IgM alone affected neither viable cell numbers nor PRL release of unstimulated stromal cells. However, anti-Fas IgM dose-dependently stimulated viable cell numbers of stromal cells co-stimulated with 8-Br-cAMP and anti-Fas IgM, whereas PRL secretion of the co-stimulated cells was not affected. Anti-Fas IgM dose-dependently stimulated viable cell numbers of 8-Br-cAMP-stimulated cells but did not affect PRL secretion of 8-Br-cAMP-induced decidualized cells. These results indicate that Fas antigen on human endometrial stromal cells cannot mediate receptor-specific apoptotic signals, and that Fas-mediated signals stimulate survival of 8-Br-cAMP-stimulated non-decidualized stromal cells. Thus, stimulation of Fas-antigen on the endometrial stromal cells enhances anti-apoptotic/survival signals in certain stromal cells, autoregulating functional cellular subpopulations of human endometrial stromal cells in a paracrine manner.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2003

Leptin inhibits decidualization and enhances cell viability of normal human endometrial stromal cells.

Recent reports have demonstrated that the peritoneal fluid and serum concentrations of leptin are increased in women with endometriosis. However, the pathophysiological roles of leptin in endometriosis have not been well characterized. In this study, we examined the direct effects of leptin on normal human endometrial stromal cells using an in vitro decidualization assay system with 8-Br-cAMP, a decidualization inducer. No effects of leptin on cell viability and prolactin secretion were found in unstimulated endometrial stromal cells. Leptin dose-dependently enhanced the viability of stromal cells co-stimulated with 8-Br-cAMP and leptin while PRL secretion from the cells was significantly inhibited in a dose-dependent manner. As for 8-Br-cAMP-stimulated cells, leptin significantly enhanced their cell viability in a dose-dependent manner but not their PRL secretion. These results indicate that leptin enhances the cell viability of PRL-non-secreting 8-Br-cAMP-stimulated stromal cells, and that it inhibits the decidualization process of endometrial stromal cells. Increased leptin in endometriotic patients might play an antiapoptotic role in some activated ESCs in the peritoneal cavity to stimulate endometrial cell implantation, and might cause infertility by inhibiting stromal decidualization.

Cell Survival↗

PubMed2003

Endometriotic patient serum enhances endometrial stromal cell proliferation and viability: a preliminary study.

Decreased numbers of eutopic endometrial apoptotic cells have been reported in endometriotic patients, indicating the possibility of antiapoptotic effects of their sera. In this preliminary study, we examined the effects of serum from 8 endometriotic patients on cell proliferation and viability of eutopic human endometrial stromal cells obtained from 3 non-endometriotic women. Endometrial stromal cell proliferation was stimulated in a dose-dependent manner by all sera examined, including those of healthy women. Compared with the sera from healthy women, all sera from 8 endometriotic patients significantly enhanced stromal cell proliferation, and 5 of the 8 sera significantly inhibited 8-Br-cAMP-activation-induced cell death in endometrial stromal cells. Considering these results, we suggest that the stromal cell growth and surviving factor(s) from the serum of most endometriotic patients have a higher activity, which may stimulate ectopic implantation and proliferation of endometrial stromal cells.

Cell Division↗

PubMed2003

Expression and function of activin receptors in human endometrial adenocarcinoma cells.

Menstrual cycle-dependent expressions of activin A in normal human endometrial tissues have been reported. Expression of activin receptor mRNAs and increased activin A production were also observed in human endometrial adenocarcinoma tissues, suggesting that activin A might enhance cell proliferation and inhibit apoptotic signaling in endometrial cancer cells. In this study, we have examined the effects of activin A on cell proliferation, anticancer drug-induced apoptosis and Fas-mediated apoptosis in 3 differentiated human endometrial adenocarcinoma cell lines, namely HEC-1, HHUA and Ishikawa. Flow cytometric analyses revealed moderate expressions of all 4 types of activin receptor subunits on the cell surfaces of the 3 cell lines. The proliferations of the 3 endometrial cancer cells were completely unaffected by activin A, whereas it suppressed the cell proliferation of a human ovarian endometrioid adenocarcinoma cell line, OVK-18, in a dose-dependent manner. Moreover, activin A did not affect the apoptotic changes in the 3 endometrial adenocarcinoma cells treated with 4 different anticancer drugs, namely CDDP, paclitaxel, etoposide and SN38. The apoptotic changes in HHUA cells treated with anti-Fas IgM were also unaffected by activin A. These results indicate that the increased activin A production in human endometrial adenocarcinoma tissues in vivo may not stimulate carcinoma cell proliferation or inhibit apoptotic signaling in carcinoma cells. Insensitivity to the usual growth suppression signals induced by activin A might be one of the mechanisms of immortality of human endometrial adenocarcinoma cells.

Activin Receptors↗

PubMedDate not supplied

Cellular heterogeneity in long-term surviving cells isolated from eutopic endometrial, ovarian endometrioma and adenomyosis tissues.

Human endometrial tissues regenerate easily after menstruation and childbirth, suggesting the existence of endometrial stem-like cells that can survive and proliferate from a single cell over a long time. To clarify this hypothesis, limiting dilution cultures performed with eutopic endometrial, ovarian endometrioma and adenomyosis cells obtained from a patient, achieved cloning efficiencies of 13.0, 5.0, and 0.8%, respectively. These monoclonal cells survived for more than 24 months. More than 4 types of monoclonal cells were established from eutopic endometrial cells and microscopically were distinctly different from each other. Intraperitoneal injections of dispersed human eutopic endometrial cells did not cause any endometriosis-like lesions in scid mice, but those of endometrial tissue fragments did. IL-6, TNF-alpha, IL-1beta, M-CSF and HGF failed to enhance transplantation of dispersed endometrial cells to the mice. These results indicate that several types of eutopic endometrial cells survive long-term, and that simple regurgitation of eutopic endometrial stem-like cells may not induce peritoneal endometriosis.

Adult↗

PubMedDate not supplied

Death-associated protein kinase localization to human renal tubule cells, and increased expression of chronic obstructive uropathy in rats.

BACKGROUND: Death-associated protein kinase (DAP kinase) is a Ca2+/calmodulin-dependent serine/threonine kinase implicated as a positive apoptosis mediator. However, little is known about DAP kinase involvement with apoptosis in renal diseases. METHODS: In order to determine whether DAP kinase has a role in renal cell apoptosis in kidney diseases, we performed an immunohistochemical study using a monoclonal antibody to DAP kinase. Firstly, by examining the cellular distribution of DAP kinase in normal human renal tissues and cultured proximal tubule cells. We then used western blotting and immunohistochemical analysis to examine directly whether DAP kinase protein levels could be modulated in rat kidneys with chronic obstructive uropathy created by unilateral ureteric ligation. RESULTS: Immunohistochemistry of normal human kidney tissues showed that DAP kinase was exclusively localized in the cytoplasm of renal tubule cells. Expression analysis of DAP kinase using cultured cells confirmed DAP kinase mRNA and protein presence in human renal tubule cells. Immunocytochemical analysis directly visualized DAP kinase in the cytoplasm of the renal tubule cells in culture. Finally, DAP kinase was found up-regulated in renal tubule cells of rat kidneys with chronic obstructive uropathy. CONCLUSIONS: Our study demonstrates that DAP kinase is localized to renal tubule cells, implying a crucial role for DAP kinase in renal tubular cell apoptosis in progressive renal diseases.

Animals↗