※一部利用できない機能があります
| 1.
論文 |
論文
|
Mukaida, Naofumi ; Nakamoto, Yasunari ; 向田, 直史 ; 中本, 安成
概要:
金沢大学がん進展制御研究所<br />Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen
…
presenting cells (APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma (HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC. © The Author(s) 2018.<br />Supported by (in part) Research Programs on the Innovative Development and Application for New Drugs for Hepatitis B (No. 17fk0310116h0001) from the Japan Agency for Medical Research and Development (AMED) and Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University.
続きを見る
|
||||
| 2.
論文 |
論文
|
Mukaida, Naofumi ; Tanabe, Yamato ; Baba, Tomohisa ; 向田, 直史 ; 馬場, 智久
概要:
金沢大学がん進展制御研究所<br />All blood lineage cells are generated from hematopoietic stem cells (HSCs), which reside in bone marr
…
ow after birth. HSCs self-renew, proliferate, and differentiate into mature progeny under the control of local microenvironments including hematopoietic niche, which can deliver regulatory signals in the form of bound or secreted molecules and from physical cues such as oxygen tension and shear stress. Among these mediators, accumulating evidence indicates the potential involvement of several chemokines, particularly CXCL12, in the interaction between HSCs and bone marrow microenvironments. Fusion between breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog (ABL)-1 gene gives rise to BCR-ABL protein with a constitutive tyrosine kinase activity and transforms HSCs and/or hematopoietic progenitor cells (HPCs) into disease-propagating leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). LSCs can self-renew, proliferate, and differentiate under the influence of the signals delivered by bone marrow microenvironments including niche, as HSCs can. Thus, the interaction with bone marrow microenvironments is indispensable for the initiation, maintenance, and progression of CML. Moreover, the crosstalk between LSCs and bone marrow microenvironments can contribute to some instances of therapeutic resistance. Furthermore, evidence is accumulating to indicate the important roles of bone marrow microenvironment-derived chemokines. Hence, we will herein discuss the roles of chemokines in CML with a focus on bone marrow microenvironments. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.
続きを見る
|
||||
| 3.
論文 |
論文
|
Iida, Noriho ; Nakamoto, Yasunari ; Baba, Tomohisa ; Nakagawa, Hidetoshi ; Mizukoshi, Eishiro ; Naito, Makoto ; Mukaida, Naofumi ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />Several chemokines are used for immunotherapy against cancers because they can attract immune cells
…
such as dendritic and cytotoxic T cells to augment immune responses. Radiofrequency ablation (RFA) is used to locally eliminate cancers such as hepatocellular carcinoma (HCC), renal cell carcinoma, and lung cancer. Because HCC often recurs even after an eradicative treatment with RFA, additional immunotherapy is necessary. We treated tumor-bearing mice by administering ECI301, an active variant of CC chemokine ligand 3, after RFA. Mice were injected s.c. with BNL 1ME A.7R.1, a murine hepatoma cell line, in the bilateral flank. After the tumor became palpable, RFA was done on the tumor of one flank with or without ECI301. RFA alone eliminated the treated ipsilateral tumors and retarded the growth of contralateral non-RFA-treated tumors accompanied by massive T-cell infiltration. Injection of ECI301 augmented RFA-induced antitumor effect against non-RFA-treated tumors when administered to wild-type or CCR5-deficient but not CCR1-deficient mice. ECI301 also increased CCR1-expressing CD11c+ cells in peripheral blood and RFA-treated tumors after RFA. Deficiency of CCR1 impairs accumulation of CD11c+, CD4+, and CD8+ cells in RFA-treated tumors. Furthermore, in IFN-ã-enzyme-linked immunospot assay, ECI301 augmented tumor-specific responses after RFA whereas deficiency of CCR1 abolished this augmentation. Thus, we proved that ECI301 further augments RFA-induced antitumor immune responses in a CCR1-dependent manner. ©2010 AACR.
続きを見る
|
||||
| 4.
論文 |
論文
|
Nakamoto, Yasunari ; Mizukoshi, Eishiro ; Kitahara, Masaaki ; Arihara, Fumitaka ; Sakai, Yoshio ; Kakinoki, Kaheita ; Fujita, Yui ; Marukawa, Yohei ; Arai, Kuniaki ; Yamashita, Tatsuya ; Mukaida, Naofumi ; Matsushima, Kouji ; Matsui, Osamu ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates
…
remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0.1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 106 of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0.046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology.
続きを見る
|
||||
| 5.
論文 |
論文
|
Kakinoki, Kaheita ; Nakamoto, Yasunari ; Kagaya, Takashi ; Tsuchiyama, Tomoya ; Sakai, Yoshio ; Nakahama, Tohru ; Mukaida, Naofumi ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, largely as a result of i
…
ntrahepatic metastasis. Using a mouse model of intrahepatic metastasis, we investigated whether chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) could potentiate the antitumor effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system.Methods: Mouse hepatoma cells infected with recombinant adenovirus vectors expressing HSV-tk, CCL2/MCP-1 and LacZ at multiplicities of infection of Ad-tk/Ad-MCP1 = 3/0.03 (T/MLow), 3/3 (T/MHigh) and Ad-tk/Ad-LacZ = 3/3 (T/L) were injected into BALB/c mice.Results: Intrahepatic tumor growth was significantly lower in T/MLow mice. By contrast, no tumor suppression was observed in T/MHigh mice. The tumor-specific cytolytic activities of splenocytes from T/MLow and T/MHigh mice were comparable. Immunohistochemical analysis of liver tissues showed similar infiltration by Mac-1+ and T cells in these animals, whereas the proportions of classical activated (M1) monocytes/macrophages were significantly higher in T/MLow mice. In addition, interleukin-12 production was elevated in these tissues. Vascular endothelial growth factor-A expression and CD31+ microvessels were increased in T/MHigh mice.Conclusions: Collectively, these results demonstrate that an adequate amount of CCL2/MCP-1, together with the HSV-tk/GCV system, may induce T helper 1-polarized antitumor effects without inducing tumor angiogenesis in the microenvironment of intrahepatic HCC progression. © 2010 John Wiley & Sons, Ltd.
続きを見る
|
||||
| 6.
論文 |
論文
|
Wada, Takashi ; Tomosugi, Naohisa I. ; Naito, Takero ; Yokoyama, Hitoshi ; Kobayashi, Kenichi ; Harada, Akihisa ; Mukaida, Naofumi ; Matsushima, Kouji
概要:
Glomerular infiltration by neutrophils is a hallmark of acute glomerulonephritis. The pathophysiological role of interle
…
ukin 8 (IL-8), a potent neutrophil chemotactic cytokine (chemokine), was explored in an animal model of acute immune complex-mediated glomerulonephritis by administering a neutralizing antibody against IL-8. Repeated injection of bovine serum albumin (BSA) into rabbits caused the deposition of immune complexes consisting of BSA and rabbit IgG in glomeruli. Histological analyses revealed a small but significant number of neutrophils in glomeruli and the fusion of epithelial cell foot processes. Concomitantly, urinary levels of protein and albumin increased markedly (3.20 ± 0.97 and 1.39 ± 0.53 mg/h, respectively) compared with those of untreated animals (0.77 ± 0.21 and 0.01 ± 0.01 mg/h, respectively). Anti-IL-8 antibody treatment decreased the number of neutrophils in glomeruli by 40% and dramatically prevented the fusion of epithelial cell foot process. Furthermore, treatment with anti-IL-8 antibody completely normalized the urinary levels of protein and albumin (0.89 ± 0.15 and 0.02 ± 0.01 mg/h, respectively). These results indicated that IL-8 participated in the impairment of renal functions in experimental acute immune complex-mediated glomerulonephritis through activating as well as recruiting neutrophils.
続きを見る
|
||||
| 7.
論文 |
論文
|
Marukawa, Yohei ; Nakamoto, Yasunari ; Kakinoki, Kaheita ; Tsuchiyama, Tomoya ; Iida, Noriho ; Kagaya, Takashi ; Sakai, Yoshio ; Naito, Makoto ; Mukaida, Naofumi ; Kaneko, Shuichi
概要:
Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system combined with monoc
…
yte chemoattractant protein-1 (MCP-1) provides significant antitumor efficacy. The current study was designed to evaluate the antitumor immunity of a newly developed membrane-bound form of MCP-1 (mMCP-1) in an immunocompetent mouse model of hepatocellular carcinoma (HCC). A recombinant adenovirus vector (rAd) harboring the human MCP-1 gene and the membrane-spanning domain of the CX3CL1 gene was used. Large amounts of MCP-1 protein were expressed and accumulated on the tumor cell surface. The growth of subcutaneous tumors was markedly suppressed when tumors were treated with mMCP-1, as compared with soluble MCP-1, in combination with the HSV-tk/GCV system (P<0.01). The numbers of Mac-1-, CD4-and CD8a-positive cells were significantly higher in tumor tissues (P<0.05), and tumor necrosis factor (TNF) mRNA expression levels with mMCP-1 were almost five-fold higher than those with soluble MCP-1. These results indicate that the delivery of the mMCP-1 gene greatly enhanced antitumor effects following the apoptotic stimuli by promoting the recruitment and activation of macrophages and T lymphocytes, suggesting a novel strategy of immune-based gene therapy in the treatment of patients with HCC. © 2012 Macmillan Publishers Limited All rights reserved.
続きを見る
|
||||
| 8.
論文 |
論文
|
Kitahara, Masaaki ; Mizukoshi, Eishiro ; Nakamoto, Yasunari ; Mukaida, Naofumi ; Matsushima, Kouji ; Kaneko, Shuichi
概要:
Background & aims Immunotherapy using dendritic cells (DCs) is a promising cancer therapy. The success of this therapy d
…
epends on the function of induced DCs. However, there has been no consensus on optimal conditions for DC preparation in vitro for immunotherapy of hepatocellular carcinoma (HCC) patients. To address relevant issues, we evaluated the procedures to induce DCs that efficiently function in hepatitis C virus (HCV)-related HCC. Methods We studied immunological data from 14 HCC patients. The DC preparation and the surface markers were assessed by flow cytometric analysis. Four different additional activation stimuli (Method I, medium alone; Method II, with OK-432; Method III, with IL-1β + IL-6 + TNF-α; Method IV, with IL-1β + IL-6 + TNF-α + PGE2) were tested and the functions of DCs were confirmed by examination of the ability of phagocytosis, cytokine production and allogeneic mixed lymphocyte reaction (MLR). Results The numbers of DCs induced and their cytokine production ability were not different between healthy controls and HCC patients. T-cell stimulatory activity of DCs in MLR was significantly lower in HCC patients than in healthy controls. The maturation of DCs with OK-432 boosted production of cytokines and chemokines, such as IL-2, IL-12p70, IFN-γ, TNF-α, IL-13 and MIP1α, and restored T-cell stimulatory activity of DCs in MLR. Conclusions The clinically approved compound OK-432 is a candidate for highly immunocompetent DC preparation and may be considered as a key drug for immunotherapy of HCV-related HCC patients. © 2014 Published by Elsevier B.V.
続きを見る
|
||||
| 9.
論文 |
論文
|
Marukawa, Yohei ; Nakamoto, Yasunari ; Kakinoki, Kaheita ; Tsuchiyama, Tomoya ; Iida, Noriho ; Kagaya, Takashi ; Sakai, Yoshio ; Naito, Makoto ; Mukaida, Naofumi ; Kaneko, Shuichi
概要:
Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system combined with monocyte chemoattractant protein-1 (MCP-1) provides significant antitumor efficacy. The current study was designed to
…
evaluate the antitumor immunity of a newly developed membrane-bound form of MCP-1 (mMCP-1) in an immunocompetent mouse model of hepatocellular carcinoma (HCC). A recombinant adenovirus vector (rAd) harboring the human MCP-1 gene and the membrane-spanning domain of the CX3CL1 gene was used. Large amounts of MCP-1 protein were expressed and accumulated on the tumor cell surface. The growth of subcutaneous tumors was markedly suppressed when tumors were treated with mMCP-1, as compared with soluble MCP-1, in combination with the HSV-tk/GCV system (P<0.01). The numbers of Mac-1-, CD4- and CD8a-positive cells were significantly higher in tumor tissues (P<0.05), and tumor necrosis factor (TNF) mRNA expression levels with mMCP-1 were almost five-fold higher than those with soluble MCP-1. These results indicate that the delivery of the mMCP-1 gene greatly enhanced antitumor effects following the apoptotic stimuli by promoting the recruitment and activation of macrophages and T lymphocytes, suggesting a novel strategy of immune-based gene therapy in the treatment of patients with HCC.Cancer Gene Therapy advance online publication, 9 March 2012; doi:10.1038/cgt.2012.3.
続きを見る
|
||||
| 10.
論文 |
論文
|
Yang, Xiaoqin ; Lu, Peirong ; Fujii, Chifumi ; Nakamoto, Yasunari ; Gao, Ji Liang ; Kaneko, Shuichi ; Murphy, Philip M. ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />We previously observed that a chemokine, macrophage inflammatory protein-1 α/CCL3, and its receptor
…
, CCR1, were aberrantly expressed in human hepatocellular carcinoma (HCC) tissues. Here, we show that CCL3 and CCR1 are also expressed in 2 different models of this cancer; N-nitrosodiethylamine (DEN)-induced HCC and HCC induced by hepatitis B virus surface (HBs) antigen-primed splenocyte transfer to myelo-ablated syngeneic HBs antigen transgenic mice. At 10 months after DEN treatment, foci number and sizes were remarkably reduced in CCR1- and CCL3-deficient mice, compared with those of wild-type (WT) mice, although tumor incidence were marginally, but significantly, higher in CCR1- and CCL3-deficient mice than in WT mice. Of note is that tumor angiogenesis was also markedly diminished in CCL3- and CCR1-deficient mice, with a concomitant reduction in the number of intratumoral Kupffer cells, a rich source of growth factors and matrix metalloproteinases (MMPs). Among growth factors and MMPs that we examined, only MMP9 and MMP13 gene expression was augmented progressively in liver of WT mice after DEN treatment. Moreover, MMP9, but not MMP13, gene expression was attenuated in CCR1- and CCL3-deficient mice, compared with that of WT mice. Furthermore, MMP9 was expressed mainly by mononuclear cells but not hepatoma cells, and MMP9-expressing cell numbers were decreased in CCR1- or CCL3-deficient mice, compared with WT mice. These observations suggest the contribution of the CCR1-CCL3 axis to HCC progression. © 2005 Wiley-Liss, Inc.
続きを見る
|
||||
| 11.
論文 |
論文
|
Fujii, Chifumi ; Nakamoto, Yasunari ; Lu, Peirong ; Tsuneyama, Koichi ; Popivanova, Boryana K. ; Kaneko, Shuichi ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />Most cases of human hepatocellular carcinoma develop after persistent chronic infection with human
…
hepatitis B virus or hepatitis C virus, and host responses are presumed to have major roles in this process. To recapitulate this process, we have developed the mouse model of hepatocellular carcinoma using hepatitis B virus surface antigen transgenic mice. To identify the genes associated with hepatocarcinogenesis in this model, we compared the gene expression patterns between pre-malignant lesions surrounded by hepatocellular carcinoma tissues and control liver tissues by using a fluorescent differential display analysis. Among the genes that were expressed differentially in the pre-malignant lesions, we focused on Pim-3, a member of a proto-oncogene Pim family, because its contribution to hepatocarcinogenesis remains unknown. Moreover, the unavailability of the nucleotide sequence of full-length human Pim-3 cDNA prompted us to clone it from the cDNA library constructed from a human hepatoma cell line, HepG2. The obtained 2,392 bp human Pim-3 cDNA encodes a predicted open reading frame consisting of 326 amino acids. Pim-3 mRNA was selectively expressed in human hepatoma cell lines, but not in normal liver tissues. Moreover, Pim-3 protein was detected in human hepatocellular carcinoma tissues and cell lines but not in normal hepatocytes. Furthermore, cell proliferation was attenuated and apoptosis was enhanced in human hepatoma cell lines by the ablation of Pim-3 gene with RNA interference. These observations suggest that aberrantly expressed Pim-3 can cause autonomous cell proliferation or prevent apoptosis in hepatoma cell lines. © 2004 Wiley-Liss, Inc.
続きを見る
|
||||
| 12.
論文 |
論文
|
Yang, Xiaoqin ; Lu, Peirong ; Ishida, Yuko ; Kuziel, William A. ; Fujii, Chifumi ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />The liver parenchyma is populated by hepatocytes and several nonparenchymal cell types, including K
…
upffer cells and hepatic stellate cells. Both Kupffer cells and hepatic stellate cells are responsive to the chemokine CCL2, but the precise roles of CCL2 and these cells in liver tumor formation remain undefined. Hence, we investigated the effects of the lack of the major CCL2 receptor, CCR2, on liver tumor formation induced by intraportal injection of the murine colon adenocarcinoma cell line, colon 26. Wild-type mice showed macroscopic tumor foci in the liver 10 days after injection of colon 26 cells. After 10 days, CCL2 proteins were detected predominantly in tumor cells, coincident with increased intratumoral macrophage and hepatic stellate cell numbers. Although tumor formation occurred at similar rates in wild-type and CCR2-deficient mice up to 10 days after tumor cell injection, the number and size of tumor foci were significantly attenuated in CCR2-deficient mice relative to wild-type mice thereafter. Moreover, neovascularization and matrix metalloproteinase 2 expression were diminished in CCR2-deficient mice with a concomitant reduction in the accumulation of macrophages and hepatic stellate cells. Furthermore, matrix metalloproteinase 2 was detected predominantly in hepatic stellate cells but not in macrophages. We provided the first definitive evidence that the absence of CCR2-mediated signals can reduce the trafficking of hepatic stellate cells, a main source of matrix metalloproteinase 2, and consequently can diminish neovascularization during liver tumor formation. © 2005 Wiley-Liss, Inc.
続きを見る
|
||||
| 13.
論文 |
論文
|
Popivanova, Boryana K. ; Kitamura, Kazuya ; Wu, Yu ; Kondo, Toshikazu ; Kagaya, Takashi ; Kaneko, Shuichi ; Oshima, Masanobu ; Fujii, Chifumi ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To un
…
derstand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-α expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-α, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-α as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-α may be useful in treating colon cancer in individuals with UC.
続きを見る
|
||||
| 14.
論文 |
論文
|
Lu, Peirong ; Li, Longbiao ; Wu, Yu Ying ; Mukaida, Naofumi ; Zhang, Xueguang Guang
概要:
金沢大学がん研究所がん病態制御<br />Purpose: To evaluate the roles of CCL3 and its specific chemokine receptors, CCR1 and CCR5, in alka
…
li-induced corneal neovascularization (CNV). Methods: Chemical denudation of corneal and limbal epithelium was performed on wild-type (WT) BALB/c mice and CCL3-, CCR1-, and CCR5-deficienct (knockout [KO]) counterparts. Two weeks after injury CNV was quantified by immunostaining with anti-CD31. Angiogenic factor expression and leukocyte accumulation in the early phase after injury were quantified by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical analysis, respectively. Results: Alkali injury augmented the intraocular mRNA expression of CCL3 and its receptors, CCR1 and CCR5, together with a transient infiltration of F4/80 positive macrophages and Gr-1 positive neutrophils. Compared with WT mice, CCL3-KO and CCR5-KO mice but not CCR1-KO mice exhibited reduced CNV two weeks after injury both macroscopically and microscopically as evidenced by CD31 positive areas. Concomitantly, the infiltration of F4/80 positive macrophages but not Gr-1 positive neutrophils was significantly attenuated in CCL3-KO mice compared with WT mice. Intracorneal infiltration of CCR5 expressing cells was significantly impaired in CCL3-KO mice compared with WT mice. Alkali injury induced a massive increase in the intraocular mRNA expression of a potent angiogenic factor, vascular endothelial growth factor (VEGF), in WT mice whereas these increments were severely retarded in CCL3-KO mice. Moreover, CCL3 enhanced VEGF expression by murine peritoneal macrophages at both the mRNA and the protein level. Furthermore, topical CCL3 application restored CNV, which was macroscopically and microscopically reduced in CCL3-KO mice after two weeks to levels similar to those found in WT mice. Conclusions: In alkali-induced CNV, CCL3 induced macrophages to infiltrate and produce VEGF by binding to CCR5 but not to CCR1 and eventually promoted angiogenesis. © 2008 Molecular Vision.
続きを見る
|
||||
| 15.
論文 |
論文
|
Popivanova, Boryana Konstantinova ; Kostadinova, Feodora Ivanova ; Furuichi, Kengo ; Shamekh, Mohamed M. ; Kondo, Toshikazu ; Wada, Takashi ; Egashira, Kensuke ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />Accumulating evidence indicates the crucial contribution of chronic inflammation to various types o
…
f carcinogenesis, including colon carcinoma associated with ulcerative colitis and asbestosis-induced malignant mesothelioma. Ulcerative colitis-associated colon carcinogenesis can be recapitulated in mice by azoxymethane administration followed by repetitive dextran sulfate sodium ingestion. In the course of this carcinogenesis process, the expression of a macrophage-tropic chemokine, CCL2, was enhanced together with intracolonic massive infiltration of macrophages, which were a major source of cyclooxygenase (COX)-2, a crucial mediator of colon carcinogenesis. Mice deficient in CCL2-specific receptor, CCR2, exhibited less macrophage infiltration and lower tumor numbers with attenuated COX-2 expression. Moreover, CCL2 antagonists decreased intracolonic macrophage infiltration and COX-2 expression, attenuated neovascularization, and eventually reduced the numbers and size of colon tumors, even when given after multiple colon tumors have developed. These observations identify CCL2 as a crucial mediator of the initiation and progression of chronic colitis-associated colon carcinogenesis and suggest that targeting CCL2 may be useful in treating colon cancers, particularly those associated with chronic inflammation. ©2009 American Association for Cancer Research.
続きを見る
|
||||
| 16.
論文 |
論文
|
Wu, Yu ; Wang, Ying Ying ; Nakamoto, Yasunari ; Li, Ying-Yi ; Baba, Tomohisa ; Kaneko, Shuichi ; Fujii, Chifumi ; Mukaida, Naofumi
概要:
金沢大学がん研究所<br />Pim-3, a proto-oncogene with serine/threonine kinase activity, was enhanced in hepatocellular carcinoma (
…
HCC) tissues. To address the roles of Pim-3 in HCC development, we prepared transgenic mice that express human Pim-3 selectively in liver. The mice were born at a Mendelian ratio, were fertile and did not exhibit any apparent pathological changes in the liver until 1 year after birth. Pim-3-transgenic mouse-derived hepatocytes exhibited accelerated cell cycle progression. The administration of a potent hepatocarcinogen, diethylnitrosamine (DEN), induced accelerated proliferation of liver cells in Pim-3 transgenic mice in the early phase, compared with that observed for wild-type mice. Treatment with DEN induced lipid droplet accumulation with increased proliferating cell numbers 6 months after the treatment. Eventually, wild-type mice developed HCC with a frequency of 40% until 10 month after the treatment. Lipid accumulation was accelerated in Pim-3 transgenic mice with higher proliferating cell numbers, compared with that observed for wild-type mice. Pim-3 transgenic mice developed HCC with a higher incidence (80%) and a heavier burden, together with enhanced intratumoral CD31-positive vascular areas, compared with that observed for wild-type mice. These observations indicate that Pim-3 alone cannot cause, but can accelerate HCC development when induced by a hepatocarcinogen, such as DEN. © 2010 Macmillan Publishers Limited. All rights reserved.
続きを見る
|
||||
| 17.
論文 |
論文
|
Popivanova, Boryana Konstantinova ; Li, Ying-Yi ; Zheng, Huachuan ; Omura, Kenji ; Fujii, Chifumi ; Tsuneyama, Koichi ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />We previously observed that Pim-3 with serine/threonine kinase activity, was aberrantly expressed i
…
n malignant lesions of endoderm-derived organs, liver and pancreas. Because Pim-3 protein was not detected in normal colon mucosal tissues, we evaluated Pim-3 expression in malignant lesions of human colon, another endoderm-derived organ. Pim-3 was detected immunohistochemically in well-differentiated (43/68 cases) and moderately differentiated (23/41 cases) but not poorly differentiated colon adenocarcinomas (0/5 cases). Moreover, Pim-3 proteins were detected in adenoma (35/40 cases) and normal mucosa (26/111 cases), which are adjacent to adenocarcinoma. Pim-3 was constitutively expressed in SW480 cells and the transfection with Pim-3 short hairpin RNA promoted apoptosis. In the same cell line, a pro-apoptotic molecule, Bad, was phosphorylated at Ser112 and Ser 136 sites of phosphorylation that are representative of its inactive form. Ser112 but not Ser136 phosphorylation in this cell line was abrogated by Pim-3 knockdown. Furthermore, in human colon cancer tissues, Pim-3 co-localized with Bad in all cases (9/9) and with phospho-Ser112 Bad in most cases (6/9). These observations suggest that Pim-3 can inactivate Bad by phosphorylating its Ser112 in human colon cancer cells and thus may prevent apoptosis and promote progression of human colon cancer. © 2007 Japanese Cancer Association.
続きを見る
|
||||
| 18.
論文 |
論文
|
Mukaida, Naofumi ; Wang, Ying-Ying ; Li, Ying-Yi
概要:
Pim-3 is a member of the Provirus integrating site Moloney murine leukemia virus (Pim) family, which belongs to the Ca2+
…
/calmodulin-dependent protein kinase (CaMK) group and exhibits serine/threonine kinase activity. Similar to other members of the Pim family (i.e. Pim-1 and Pim-2), Pim-3 can prevent apoptosis and promote cell survival and protein translation, thereby enhancing cell proliferation of normal and malignant cells. Pim-3 is expressed in vital organs, such as the heart, lung, and brain. However, minimal phenotypic changes in Pim-3-deficient mice suggest that Pim-3 may be physiologically dispensable. Pim-3 expression is enhanced in several cancer tissues, particularly those of endoderm-derived organs, including the liver, pancreas, colon, and stomach. The development of hepatocellular carcinoma is accelerated in mice expressing the Pim-3 gene selectively in the liver only when these mice are treated with a hepatocarcinogen, indicating that Pim-3 can act as a promoter but not as an initiator. Moreover, inhibition of Pim-3 expression can retard in vitro cell proliferation of hepatocellular, pancreatic, and colon carcinoma cell lines by promoting cell apoptosis. Furthermore, a Pim-3 kinase inhibitor has been reported to inhibit cell proliferation in an in vivo xenograft model using a human pancreatic cancer cell line without inducing any major adverse effects. Thus, Pim-3 kinase may be a candidate molecule for the development of molecular targeting drugs against cancer. © 2011 Japanese Cancer Association.
続きを見る
|
||||
| 19.
論文 |
論文
|
Mukaida, Naofumi ; Sasakki, So-ichiro ; Popivanova, Boryana K.
概要:
The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evi
…
dence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development of colon cancer. Moreover, intratumoral infiltration of inflammatory cells suggests the involvement of inflammatory responses also in other forms of sporadic as well as heritable colon cancer. Inflammatory responses and tumorigenesis activate similar sets of transcription factors such as NF-κB, Stat3, and hypoxia inducible factor and eventually enhances the expression of inflammatory cytokines including tumor necrosis factor (TNF) and chemokines. The expression of TNF and chemokines is aberrantly expressed in a mouse model of colitis-associated carcinogenesis as well as in inflammatory bowel disease and colon cancer in humans. Here, after summarizing the presumed actions of TNF and chemokines in tumor biology, we will discuss the potential roles of TNF and chemokines in chronic inflammation-associated colon cancer in mice. © 2011 by the authors; licensee MDPI, Basel, Switzerland.
続きを見る
|
||||
| 20.
論文 |
論文
|
Mukaida, Naofumi ; Baba, Tomohisa
概要:
Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking.
…
Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression. © 2011 Elsevier Inc. All rights reserved.
続きを見る
|
||||
| 21.
論文 |
論文
|
Wang, Wei ; Li, Qi ; Takeuchi, Shinji ; Yamada, Tadaaki ; Koizumi, Hitomi ; Nakamura, Takahiro ; Matsumoto, Kunio ; Mukaida, Naofumi ; Nishioka, Yasuhiko ; Sone, Saburo ; Nakagawa, Takayuki ; Uenaka, Toshimitsu ; Yano, Seiji
概要:
PURPOSE: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant lung cancer cells by activating Met and the
…
downstream PI3K/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. EXPERIMENTAL DESIGN: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR-mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion, and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into SCID mice and the therapeutic effects of E7050 plus gefitinib were assayed. RESULTS: E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. CONCLUSIONS: A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.
続きを見る
|
||||
| 22.
論文 |
論文
|
Wang, Ying-Ying ; Taniguchi, Tsuyoshi ; Baba, Tomohisa ; Li, Ying-Yi ; Ishibashi, Hiroyuki ; Mukaida, Naofumi
概要:
Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in malignant lesions, but not in
…
normal tissues, of endoderm-derived organs, including the pancreas, liver, colon, and stomach. Furthermore, the development of hepatocellular carcinoma is accelerated in mice expressing Pim-3 transgene selectively in the liver when these mice are treated with a hepatocarcinogen. These observations suggest that a chemical targeting Pim-3 kinase may be a novel type of anticancer drug. In the present study, we screened low molecular weight chemicals and observed that the phenanthrene derivative T26 potently inhibited Pim-3 and Pim-1, but only weakly inhibited Pim-2. Moreover, T26 markedly inhibited the in vitro growth of human pancreatic cancer cell lines by inducing apoptosis and G 2/M arrest. The growth inhibitory effects of T26 were reversed by overexpression of Pim-3 cDNA in human pancreatic cancer cells, indicating that T26 acts primarily on Pim-3. Furthermore, T26 inhibited the growth of a human pancreatic cancer cell line in nude mice without causing apparent adverse effects when it was administered after tumor formation was evident. These observations imply that the chemical and its related compounds may be effective for the treatment of cancers in which there is aberrant Pim-3 expression. © 2011 Japanese Cancer Association.
続きを見る
|
||||
| 23.
論文 |
論文
|
Baba, Tomohisa ; Badr, M.E.S. ; Tomaru, Utano ; Ishizu, Akihiro ; Mukaida, Naofumi
概要:
Immune surveillance system can detect more efficiently secretory tumor-specific antigens, which are superior as a target
…
for cancer immunotherapy. On the contrary, immune tolerance can be induced in the thymus when a tumor antigen is massively secreted into circulation. Thus, the secretion of tumor-specific antigen may have contradictory roles in tumor immunity in a context-dependent manner. However, it remains elusive on the precise cellular mechanism of intrathymic immune tolerance against tumor antigens. We previously demonstrated that a minor thymic conventional dendritic cell (cDC) subset, CD8α -Sirpα + cDCs, but not the major subset, CD8α +Sirpα - cDCs can selectively capture blood-borne antigens and crucially contribute to the self-tolerance. In the present study, we further demonstrated that Sirpα + cDCs can capture a blood-borne antigen leaking inside the interlobular vascular-rich regions (IVRs). Blood-borne antigen selectively captured by Sirpα + cDCs can induce antigen-specific Treg generation or negative selection, depending on the immunogenicity of the presented antigen. Furthermore, CCR2 expression by thymic Sirpα + cDCs and abundant expression of its ligands, particularly, CCL2 by tumor-bearing mice prompted us to examine the function of thymic Sirpα + cDCs in tumor-bearing mice. Interestingly, tumor-bearing mice deposited CCL2 inside IVRs in the thymus. Moreover, tumor formation induced the accumulation of Sirpα + cDCs in IVRs under the control of CCR2-CCL2 axis and enhanced their capacity to take up antigens, resulting in the shift from Treg differentiation to negative selection. Finally, intrathymic negative selection similarly ensued in CCR2-competent mice once the tumor-specific antigen was secreted into bloodstream. Thus, we demonstrated that thymic Sirpα + cDCs crucially contribute to this novel process of intrathymic tumor immune tolerance. © 2012 Baba et al.
続きを見る
|
||||
| 24.
論文 |
論文
|
Mukaida, Naofumi
概要:
Evaluation of: Iida N, Dzutsev A, Stewart CA et al. Commensal bacteria control cancer response to therapy by modulating
…
the tumor microenvironment. Science 342, 967-970 (2013). Intestinal microbiota is essential for host physiological processes, including the maintenance of epithelial barrier and immune functions. However, paradoxically, the intestinal microbiota can promote various types of experimental carcinogenesis. The paper under evaluation demonstrates that disruption of the microbiota impairs the response of tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy in a context-dependent manner. Thus, intestinal microbiota may have a great impact on the tumor response to chemotherapy and/or immunotherapy. © 2014 Future Medicine Ltd.
続きを見る
|
||||
| 25.
論文 |
論文
|
Popivanova, Boryana K. ; Kostadinova, Feodora I. ; Mukaida, Naofumi
概要:
Azoxymethane (AOM) administration followed by repetitive dextran sulfate sodium (DSS) ingestion causes chronic colonic inflammation with macrophage infiltration and enhanced expression of a macrophage-tropic chemokine, CCL2, in wild-type
…
(WT) mice. These mice eventually develop multiple colon tumors. In contrast, mice deficient in CCR2, a specific receptor for CCL2, exhibited less macrophage infiltration and attenuated tumor formation. WT mice transplanted with CCR2-deficient bone marrow developed fewer tumors after AOM and DSS treatment than either WT or CCR2-deficient mice transplanted with WT bone marrow. Furthermore, when injected to WT mice with multiple colon tumors, a CCL2 antagonist expression vector attenuated macrophage and granulocyte infiltration, and eventually reduced the numbers and sizes of tumors. These results implied the crucial involvement of the CCL2-CCR2 interactions in the development and progression of colon carcinoma associated with chronic inflammation.
続きを見る
|
||||
| 26.
論文 |
論文
|
Naito, Tatsushi ; Baba, Tomohisa ; Takeda, Kazuyoshi ; Sasaki, Soichiro ; Nakamoto, Yasunari ; Mukaida, Naofumi
概要:
Cancer chemotherapy regimens, particularly those employing high-dose cytotoxic drugs such as cyclophosphamide (CTX), hav
…
e been considered to be immune suppressive. However, we observed that a single administration of high-dose CTX abolished tumors arising from subcutaneous injection of a mouse hepatoma cell line and subsequently induced specific tumor immunity. Depletion of T cells, specifically CD4+ T cells, abrogated the CTX-mediated tumor regression. CTX treatment induced the rapid recruitment of CD4+ T cells into the tumors, and these recruited cells initiated expression of LAMP1/CD107a, a cytotoxic granule molecule, and granzyme B in the absence of antigen presentation at draining lymph nodes and proliferation in the tumor tissues. Moreover, CTX enhanced the expression of a CC chemokine, CCL3, in tumor tissues, and CTX-mediated tumor regression was attenuated in mice deficient in CCR5, the receptor for this chemokine. Consistently, less CTX-induced accumulation of intratumoral LAMP1/CD107a-expressing CD4+ T cells was observed in mice receiving splenocytes derived from CCR5-deficient mice than in those receiving splenocytes derived from WT mice. Thus, CTX induces the expression of CCL3, which induces the intratumoral migration of CD4+ T cells expressing cytotoxic molecules, leading to tumor eradication and subsequent specific tumor immunity. © 2015 Elsevier Ireland Ltd.<br />12 months Embargo
続きを見る
|
||||
| 27.
論文 |
論文
|
Mukaida, Naofumi ; Sasaki, So-ichiro ; Baba, Tomohisa
概要:
Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells includ
…
ing granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous cells present in cancer tissues, such as macrophages, lymphocytes, fibroblasts, and endothelial cells. The capacity of chemokines to regulate both cancerous and noncancerous cells highlights their crucial roles in cancer development and progression. Here, we will discuss the roles of chemokines in carcinogenesis and the possibility of chemokine targeting therapy for the treatment of cancer. © 2014 Naofumi Mukaida et al.
続きを見る
|
||||
| 28.
論文 |
論文
|
Sasaki, Soichiro ; Baba, Tomohisa ; Shinagawa, Kei ; Matsushima, Kouji ; Mukaida, Naofumi
概要:
Patients with inflammatory bowel diseases often develop colon carcinoma. Combined treatment of azoxymethane (AOM) and de
…
xtran sulfate sodium (DSS) recapitulates colitis-associated cancer in mice. AOM/DSS-induced tumor formation was reduced in CCL3- or its specific receptor, CCR5-deficient mice despite the presence of a massive infiltration of inflammatory cells. However, AOM/DSS-induced type I collagen-positive fibroblast accumulation in the colon was reduced in CCL3- or CCR5-deficient mice. This was associated with depressed expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which is expressed mainly by fibroblasts. Moreover in vitro, CCL3 induced fibroblasts to proliferate and to enhance HB-EGF expression. Furthermore, CCR5 blockade reduced tumor formation together with reduced fibroblast accumulation and HB-EGF expression, even when administered after the development of multiple colon tumors. Thus, CCL3-CCR5-mediated fibroblast accumulation may be required, in addition to leukocyte infiltration, to induce full-blown colitis-associated carcinogenesis. Our studies shed light on a therapeutic potential of CCR5 antagonist for patients with colitis-associated cancer. What's new? Inflammation of the bowel can lead to cancer, in some cases. By learning how one leads to the other, researchers hope to find a way to stave off this progression. Previously, it's been observed that these cancers have a lot of chemokine CCL3 hanging around. In this paper, the authors replicated these colitis-induced cancers in mice and investigated what CCL3 was doing. They learned that CCL3 and its receptor, CCR5, gather up cancer-associated fibroblasts, which promote transformation and tumor growth. Leukocyte infiltration wasn't enough, they found; without CCL3 and CCL5 bringing in fibroblasts, the tumor development slowed. © 2014 UICC.
続きを見る
|
||||
| 29.
論文 |
論文
|
Li, Ying-Yi ; Mukaida, Naofumi
概要:
Pim-3 is a member of the provirus integration site for Moloney murine leukemia virus (Pim) family proteins that exhibit serine/threonine kinase activity. Similar to the other Pim kinases (Pim-1 and Pim-2), Pim-3 is involved in many
…
cellular processes, including cell proliferation, survival, and protein synthesis. Although Pim-3 is expressed in normal vital organs, it is overexpressed particularly in tumor tissues of endoderm-derived organs, including the liver, pancreas, and colon. Silencing of Pim-3 expression can retard in vitro cell proliferation of hepatocellular, pancreatic, and colon carcinoma cell lines by promoting cell apoptosis. Pim-3 lacks the regulatory domains similarly as Pim-1 and Pim-2 lack, and therefore, Pim-3 can exhibit its kinase activity once it is expressed. Pim-3 expression is regulated at transcriptional and post-transcriptional levels by transcription factors (e.g., Ets-1) and post-translational modifiers (e.g., translationally-controlled tumor protein), respectively. Pim-3 could promote growth and angiogenesis of human pancreatic cancer cells in vivo in an orthotopic nude mouse model. Furthermore, a Pim-3 kinase inhibitor inhibited cell proliferation when human pancreatic cancer cells were injected into nude mice, without inducing any major adverse effects. Thus, Pim-3 kinase may serve as a novel molecular target for developing targeting drugs against pancreatic and other types of cancer.
続きを見る
|
||||
| 30.
論文 |
論文
|
Naito, Tatsushi ; Baba, Tomohisa ; Takeda, Kazuyoshi ; Sasaki, Soichiro ; Nakamoto, Yasunari ; Mukaida, Naofumi
概要:
Cancer chemotherapy regimens, particularly those employing high-dose cytotoxic drugs such as cyclophosphamide (CTX), hav
…
e been considered to be immune suppressive. However, we observed that a single administration of high-dose CTX abolished tumors arising from subcutaneous injection of a mouse hepatoma cell line and subsequently induced specific tumor immunity. Depletion of T cells, specifically CD4+ T cells, abrogated the CTX-mediated tumor regression. CTX treatment induced the rapid recruitment of CD4+ T cells into the tumors, and these recruited cells initiated expression of LAMP1/CD107a, a cytotoxic granule molecule, and granzyme B in the absence of antigen presentation at draining lymph nodes and proliferation in the tumor tissues. Moreover, CTX enhanced the expression of a CC chemokine, CCL3, in tumor tissues, and CTX-mediated tumor regression was attenuated in mice deficient in CCR5, the receptor for this chemokine. Consistently, less CTX-induced accumulation of intratumoral LAMP1/CD107a-expressing CD4+ T cells was observed in mice receiving splenocytes derived from CCR5-deficient mice than in those receiving splenocytes derived from WT mice. Thus, CTX induces the expression of CCL3, which induces the intratumoral migration of CD4+ T cells expressing cytotoxic molecules, leading to tumor eradication and subsequent specific tumor immunity. © 2015 Elsevier Ireland Ltd.<br />Embargo Period 12 months
続きを見る
|
||||
| 31.
論文 |
論文
|
Song, Yao ; Baba, Tomohisa ; Li, Ying-Yi ; Furukawa, Kaoru ; Tanabe, Yamato ; Matsugo, Seiichi ; Sasaki, Soichiro ; Mukaida, Naofumi
概要:
mukaida@staff.kanazawa-u.ac.jp<br />Patients with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated wit
…
h metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization.
続きを見る
|
||||
| 32.
論文 |
論文
|
Tsuchiyama, Tomoya ; Nakamoto, Yasunari ; Sakai, Yoshio ; Mukaida, Naofumi ; Kaneko, Shuichi
概要:
skaneko@m-kanazawa.jp<br />Suicide gene therapy combined with chemokines provides significant antitumor efficacy. Coexpr
…
ession of suicide gene and monocyte chemoattractant protein-1 (MCP-1) increases antitumor effects in murine models of hepatocellular carcinoma (HCC) and colon cancer. However, it is unclear whether the doses administered achieved the maximum antitumor effects. We evaluated antitumor effects of various amounts of recombinant adenovirus vector (rAd) expressing MCP-1 in the presence of a suicide gene in a murine model of HCC. HCC cells were transplanted subcutaneously into BALB/c nude mice, and transduced with a fixed amount of Ad-tk harboring the suicide gene, HSV-tk, and various doses of Ad-MCP1 harboring MCP-1 (ratios of 1:1, 0.1:1, and 0.01:1 relative to Ad-tk). Growth of primary tumors was suppressed when treated with Ad-tk plus Ad-MCP1 (1:1 and 1:0.1) as compared with Ad-tk alone. The antitumor effects against tumor rechallenge tended to be high in the Ad-tk plus Ad-MCP1 group (1:0.1). The effects were dependent on production of Th1 type-cytokines. Delivery of an optimal amount of rAd expressing MCP-1 enhanced the antitumor effects of suicide gene therapy against HCC by M1 macrophage activation, suggesting that this is a plausible form of cancer gene therapy to prevent HCC progression and recurrence. © 2008 Japanese Cancer Association.
続きを見る
|
||||
| 33.
論文 |
論文
|
Mukaida, Naofumi
概要:
Chemokines are a family of structurally related cytokines with four cysteines at their well-conserved positions. Most ch
…
emokines are secreted proteins with a molecular weight about 10. kDa and their α helix structure at carboxyl-terminal portion is responsible for preferential binding to proteoglycans on the vascular endothelial cells and to extracellular matrix proteins. Chemokine receptors comprise a large branch of the rhodopsin family of cell-surface G-protein-coupled receptors with seven-transmembrane domains. Chemokines bind their corresponding receptors, thereby modulating the movement and functions of their target cells, particularly leukocyte trafficking, under physiological and pathological conditions. © 2014 Elsevier Inc. All rights reserved.<br />[Book Chapter]
続きを見る
|
||||
| 34.
論文 |
論文
|
Sasaki, Soichiro ; Baba, Tomohisa ; Nishimura, Tatsunori ; Hayakawa, Yoshihiro ; Hashimoto, Shin-ichi ; Goto, Noriko ; Mukaida, Naofumi
概要:
From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone up
…
on its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth factor (CTGF)/CCN2. Tumor cell-derived CCL4 could induce fibroblasts to express CTGF/CCN2, which could support 4T1.3 clone proliferation under hypoxic culture conditions. Thus, the CCL4-CCR5 axis can contribute to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in bone cavity. © 2016 Elsevier Ireland Ltd.<br />Embargo Period 12 months
続きを見る
|
||||
| 35.
論文 |
論文
|
Song, Yao ; Baba, Tomohisa ; Mukaida, Naofumi
概要:
Patients with pancreatic ductal adenocarcinoma (PDAC) commonly require chemotherapy because they frequently develop meta
…
static disease or locally advanced tumors. Gemcitabine, an analogue of cytosine arabinoside, is commonly used for PDAC treatment. We observed that gemcitabine induced senescence phenotypes characterized by enhanced senescence-associated β-galactosidase (SA β-Gal) staining and increased expression of senescence-associated molecules in two human pancreatic cancer cell lines, Miapaca-2 and Panc-1, which exhibit resistance to gemcitabine but not L3.pl cells with a high sensitivity to gemcitabine. Gemcitabine-induced cell senescence can be inhibited by reactive oxygen species inhibitor, N-acetyl cysteine. Although gemcitabine also enhanced CXCL8 expression, anti-CXCL8 antibody failed to reduce gemcitabine-induced increases in SA β-Gal-positive cell numbers. These observations would indicate that cell senescence can proceed independently of CXCL8 expression, a characteristic feature of senescence-associated secretion phenotype. © 2016 Elsevier Inc.<br />Embargo Priod 12 months
続きを見る
|
||||
| 36.
論文 |
論文
|
Mukaida, Naofumi ; Sasaki, So-ichiro
概要:
Tumor microenvironments have a crucial role in cancer initiation and progression, and share many molecular and pathologi
…
cal features with wound healing process. Unless treated, tumors, however, do not heal in contrast to wounds that heal within a limited time framework. Wounds heal in coordination of a myriad of types of cells, particularly endothelial cells, leukocytes, and fibroblasts. Similar sets of cells also contribute to cancer initiation and progression, and as a consequence, anti-cancer treatment strategies have been proposed and tested by targeting endothelial cells and/or leukocytes. Compared with endothelial cells and leukocytes, less attention has been paid to the roles of cancer-associated fibroblasts (CAFs), fibroblasts present in tumor tissues, because their heterogeneity hinders the elucidation on them at cellular and molecular levels. Here, we will discuss the origin of CAFs and their crucial roles in cancer initiation and progression, and the possibility to develop a novel type of anti-cancer treatment by manipulating the migration and functions of CAFs. © 2016 Baishideng Publishing Group Inc. All rights reserved.
続きを見る
|
||||
| 37.
論文 |
論文
|
Fujii, Hiroshi ; Baba, Tomohisa ; Ishida, Yuko ; Kondo, Toshikazu ; Yamagishi, Masakazu ; Kawano, Mitsuhiro ; Mukaida, Naofumi
概要:
金沢大学がん研究所<br />Objective The pathogenesis of rheumatoid arthritis (RA) involves cytokines and chemokines. Given the role
…
of intraarticular macrophage infiltration in RA, this study was undertaken to address the pathogenic role of CCR2, a chemokine receptor that is abundantly expressed by macrophages, in Il1rn-deficient mice, a mouse model of RA. Methods Il1rn-deficient and Il1rn and Ccr2-double-deficient mice were subjected to clinical assessment of arthritis and histologic examination. Bone mineral density was measured with computed tomography. The types of cells infiltrating joints were determined by immunohistochemical analysis and flow cytometric analysis. Osteoclasts in joints were quantified after tartrate-resistant acid phosphatase staining. Cytokine and chemokine levels were measured by enzyme-linked immunosorbent assay and multiplex suspension array assay. The expression patterns of chemokines and osteoclastogenic factors were determined by double-color immunofluorescence analysis. Anti-mouse CXCR2 antibody was injected into Il1rn and Ccr2-double-deficient mice for blocking experiments. Results Ablation of the Ccr2 gene actually exacerbated arthritis and intraarticular osteoclastogenesis, while it enhanced intraarticular neutrophil but not macrophage accumulation in Il1rn-deficient mice. Infiltrated neutrophils expressed the osteoclastogenic factors RANKL and ADAM-8, thereby augmenting intraarticular osteoclastogenesis in Il1rn and Ccr2-double-deficient mice. Moreover, the double-deficient mice exhibited enhanced expression of the neutrophilic chemokines keratinocyte chemoattractant and macrophage inflammatory protein 2 (MIP-2), compared with Il1rn-deficient mice. Finally, neutralizing antibodies to CXCR2, the receptor for keratinocyte chemoattractant and MIP-2, dramatically attenuated arthritis in Il1rn and Ccr2-double-deficient mice. Conclusion Our findings indicate that CCR2-mediated signals can modulate arthritis in Il1rn-deficient mice by negatively regulating neutrophil infiltration. © 2011 by the American College of Rheumatology.
続きを見る
|
||||
| 38.
論文 |
論文
|
Iida, Noriho ; Nakamoto, Yasunari ; Baba, Tomohisa ; Kakinoki, Kaheita ; Li, Ying-Yi ; Wu, Yu ; Matsushita, Kouji ; Kaneko, Shuichi ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />The first step in the generation of tumor immunity is the migration of dendritic cells (DCs) to the
…
apoptotic tumor, which is presumed to be mediated by various chemokines. To clarify the roles of chemokines, we induced apoptosis using suicide gene therapy and investigated the immune responses following tumor apoptosis. We injected mice with a murine hepatoma cell line, BNL 1ME A.7R.1 (BNL), transfected with HSV-thymidine kinase (tk) gene and then treated the animals with ganciclovir (GCV). GCV treatment induced massive tumor cell apoptosis accompanied with intratumoral DC infiltration. Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Moreover, tumor apoptosis increased the numbers of DCs migrating into the draining lymph nodes and eventually generated a specific cytotoxic cell population against BNL cells. Although GCV completely eradicated HSV-tk-transfected BNL cells in CCR1-, CCR5-, or CCL3-deficient mice, intratumoral and intranodal DC infiltration and the subsequent cytotoxicity generation were attenuated in these mice. When parental cells were injected again after complete eradication of primary tumors by GCV treatment, the wild-type mice completely rejected the rechallenged cells, but the deficient mice exhibited impairment in rejection. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes. © Society for Leukocyte Biology.全文公開200910
続きを見る
|
||||
| 39.
論文 |
論文
|
Li, Ying-Yi ; Wu, Yu ; Tsuneyama, Koichi ; Baba, Tomohisa ; Mukaida, Naofumi
概要:
金沢大学がん研究所がん病態制御<br />We previously demonstrated that the proto-oncogene Pim-3 with serine/ threonine kinase activity was
…
aberrantly expressed in cancer cells but not in the normal cells of the pancreas. In order to elucidate the molecular mechanism underlying aberrant Pim-3 expression in pancreatic cancer cells, we constructed luciferase expression vectors linked to 5′-flanking deletion mutants of the human Pim-3 gene and transfected human pancreatic cancer cells with the resultant vectors. The region up to -264 bp was essential for constitutive Pim-3 gene expression, and the mutation in the Ets-1 binding site (between -216 and -211 bp) reduced luciferase activities. Moreover, Ets-1 mRNA and protein were constitutively expressed together with Pim-3 in human pancreatic cancer cell lines. Chromatin immunoprecipitation assay demonstrated constitutive binding of Ets-1 to the 5′-flanking region of human Pim-3 gene between -249 and -183 bp. Pim-3 promoter activity and its protein expression were induced by transfection with wild type-Ets-1 and were reduced by transfection with dominant negative-Ets-1 or Ets-1 small-interfering RNA (siRNA). Furthermore, dominant negative-Ets-1 and Ets-1 siRNA reduced the amount of Bad phosphorylated at its Ser 112 and induced apoptosis, when they were transfected into human pancreatic cancer cells. Finally, Pim-3 cDNA transfection reversed Ets-1 siRNA-induced increase in apoptosis and decrease in Bad phosphorylation at its Ser 112. These observations would indicate that the transcription factor Ets-1 can induce aberrant Pim-3 expression and subsequently prevent apoptosis in human pancreatic cancer cells. © 2009 Japanese Cancer Association.
続きを見る
|
||||
| 40.
論文 |
論文
|
Popivanova, B.K. ; Mukaida, Naofumi
概要:
Division of Molecular Bioregulation
|
||||
| 41.
論文 |
論文
|
Wu, Yu ; Baba, T. ; Mukaida, Naofumi
概要:
Division of Molecular Bioregulation
|
||||
| 42.
論文 |
論文
|
Li, Ying-Yi ; Popivanova, B.K. ; Mukaida, Naofumi
概要:
Division of Molecular Bioregulation
|
||||
| 43.
論文 |
論文
|
Tomita, Y. ; Yang, X. ; Kitakata, H. ; Popivanova, B.K. ; Nemoto-Sasaki, Y. ; Mukaida, Naofumi
|
||||
| 44.
論文 |
論文
|
Lu, P. ; Yang, X. ; Fujii, C. ; Mukaida, Naofumi
|
||||
| 45.
論文 |
論文
|
Yang, X. ; Fujii, C. ; Mukaida, Naofumi
|
||||
| 46.
論文 |
論文
|
Fujii, C. ; Li, Y. ; Popivanova, B. ; Nakamoto, Yasunari ; Mukaida, Naofumi
|
||||
| 47.
論文 |
論文
|
Tsuchiyama, T. ; Nakamoto, Yasunari ; Sakai, Y. ; Mukaida, Naofumi ; Sawabu, Norio ; Kaneko, Shuichi
|
||||
| 48.
論文 |
論文
|
Kitamura, K. ; Akiyama, M. ; Ishida, Y. ; Kondo, T. ; Mukaida, Naofumi
|
||||
| 49.
論文 |
論文
|
Fujii, C. ; Nakamoto, Yasunari ; Lu, P. ; Mukaida, Naofumi
|
||||
| 50.
論文 |
論文
|
Kitakata, H. ; Nemoto-Sasaki, Y. ; Yang, X. ; Takahashi, Yutaka ; Mai, M. ; Mukaida, Naofumi
|
||||
| 51.
論文 |
論文
|
Wang, H. ; Sasaki, Y. ; Nemoto-Sasaki, Y. ; Nakamura, Y ; Nakamoto, Yasunari ; Kaneko, Shuichi ; Inoue, M. ; Kobayashi, Kenichi ; Mukaida, Naofumi
|
||||
| 52.
論文 |
論文
|
Kitakata, H. ; Nemoto-Sasaki, Y. ; Takahashi, Yutaka ; Mai, M. ; Mukaida, Naofumi
|
||||
| 53.
論文 |
論文
|
Mukaida, Naofumi ; Nosaka, Takuto ; Nakamoto, Yasunari ; Baba, Tomohisa ; 向田, 直史 ; 馬場, 智久 ; 中本, 安成
概要:
金沢大学がん進展制御研究所<br />Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple step
…
s. Several lines of evidence have established an indispensable involvement of macrophages present at the primary tumor sites in various steps of metastasis, from primary tumor growth to its intravasation into circulation. The lungs encompass a large, dense vascular area and, therefore, are vulnerable to metastasis, particularly, hematogenous ones arising from various types of neoplasms. Lung tissues constitutively contain several types of tissue-resident macrophages and circulating monocytes to counteract potentially harmful exogenous materials, which directly reach through the airway. Recent advances have provided an insight into the ontogenetic, phenotypic, and functional heterogeneity of these lung macrophage and monocyte populations, under resting and inflammatory conditions. In this review, we discuss the ontogeny, trafficking dynamics, and functions of these pulmonary macrophages and monocytes and their potential roles in lung metastasis and measures to combat lung metastasis by targeting these populations. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.<br />Acknowledgments: This work is supported partially by Research Program on the Innovative Development and Application for New Drugs for Hepatitis B (17fk0310116h0001) from the Japan Agency for Medical Research and Development (AMED) (N.M., Y.N.) and Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University (N.M., Y.N.).
続きを見る
|
||||
| 54.
論文 |
論文
|
Popivanova, Boryana K. ; Kitamura, Kazuya ; Wu, Yu ; Kondo, Toshikazu ; Kagaya, Takashi ; Kaneko, Shuichi ; Oshima, Masanobu ; Fujii, Chifurni ; Mukaida, Naofumi ; 北村, 和哉 ; 近藤, 稔和 ; 加賀谷, 尚史 ; 金子, 周一 ; 大島, 正伸 ; 向田, 直史
概要:
金沢大学がん進展制御研究所<br />The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To unde
…
rstand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-α expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-α, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-α as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-α may be useful in treating colon cancer in individuals with UC.
続きを見る
|
||||
| 55.
論文 |
論文
|
Tanabe, Yamato ; Sasaki, Soichiro ; Mukaida, Naofumi ; Baba, Tomohisa ; 佐々木, 宗一郎 ; 向田, 直史 ; 馬場, 智久
概要:
金沢大学がん進展制御研究所<br />We previously demonstrated that cancer-associated fibroblasts (CAFs) accumulate at tumor sites throug
…
h the interaction between a chemokine, CCL3, and its receptor, CCR5, in the late phase of colitis-associated colon carcinogenesis. Here we examined the effect of a CCR5 antagonist, maraviroc, on tumor growth arising from the orthotopic injection of mouse or human colon cancer cell lines into the cecal wall by focusing on CAFs. Orthotopic injection of either cell line caused tumor formation together with leukocyte infiltration and fibroblast accumulation. Concomitant oral administration of maraviroc reduced tumor formation with few effects on leukocyte infiltration. In contrast, maraviroc reduced the intratumor number of α-smooth muscle actin-positive fibroblasts, which express epidermal growth factor, a crucial growth factor for colon cancer cell growth. These observations suggest that maraviroc or other CCR5 antagonists might act as novel anti-CRC drugs to dampen CAFs, an essential cell component for tumor progression.<br />This work was supported by a Grant-in-Aid for Young Scientists (B) 15K18406 from the Japan Society for the Promotion of Science (JSPS).
続きを見る
|
||||
| 56.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
金沢大学がん進展制御研究所<br />肝臓の前がんからがん病変ならびに膵臓がんにおいて発現が亢進している,セリン/スレオニン・キナーぜ・Pim-3が,Badの112番目のセリン残基のリン酸化によってBadの不活化を起こすとともに,Bcl-X
…
Lの発現を誘導し,アポトーシスを抑制することでがん化に関与している可能性を我々は昨年度までに報告した。本年度,以下の結果を得た。(1)肝臓、膵臓以外の内胚葉由来臓器である大腸、胃のヒトの前がんならびにがん病変でのPim-3の発現を免疫染色法にて検討した結果,大腸では腺がんの存在しない正常粘膜ではPim-3が検出されないのに対して,腺がん病変周囲の正常粘膜の約20%,アデノーマの約90%,腺がん病変の約55%で,Pim-3タンパクが検出された。同様の結果が,胃のアデノーマならびに腺がん組織の検討によっても得られた。(2)Pim-3がBadの112番目のセリン残基を選択的にリン酸化することに基づく,Pim-3の試験管内での活性測定法を確立した。Pim-3の立体構造予測から推測された候補阻害剤14種を検討し,4種がPim-3活性を阻害し,そのうち2種が膵がん細胞株の試験管内での増殖を抑制することを認めた。(3)ヒト膵がん細胞株でのPim-3遺伝子の恒常的発現機構を検討し,膵がん細胞株で発現が亢進している転写因子Ets-1が,Pim-3遺伝子プロモーター上のEts-1結合領域に結合し,転写を誘導していることを明らかにした。<br />研究課題/領域番号:18659067, 研究期間(年度):2006 – 2007<br />出典：「膵癌選択的に発現しているキナーゼPim-3を分子標的とした新たな治療法の開発」研究成果報告書 課題番号18659067（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-18659067/)を加工して作成
続きを見る
|
||||
| 57.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
BCR-ABL陽性慢性骨髄性白血病（CML)マウスに対して、X線照射・骨髄移植を行うと、核型異常を示すドナー細胞由来顆粒球の出現と重篤な貧血からなる骨髄異形成症候群を呈する、ドナー細胞由来白血病（DCL）を発症した。レシピエントCML細胞由
…
来の細胞外小胞中の大量の二本鎖DNAが、ドナー細胞に水平伝播し、ドナー細胞内でSTING経路を介してインターフェロン経路が活性化され、ドナー由来の造血幹/前駆細胞のvitroでの複製能が低下することが明らかになった。さらに、CML発症マウスに対して、X線照射後に、STING欠損マウス由来の骨髄細胞を移植しても、DCL様の病態の出現が認められなかった。<br />Mice with BCR-ABL-positive chronic myelogenous leukemia (CML) developed donor cell-derived leukemia (DCL), myelodysplastic syndrome with donor cell-derived granulocytes with aberrant nuclear morphology and severe anemia, when normal donor cells were transplanted after irradiation. Recipient leukemia cell-derived extravesicles abundantly contain double-stranded DNA (dsDNA), which was horizontally transmitted into donor cells. In vitro studies demonstrated that dsDNA activated STING and subsequently interferon pathways in donor cells, thereby inhibiting replication capacity of donor hematopoietic stem/progenitor cells. Moreover, CML mice did not develop DCL when they received STING-deficient mouse-derived bone marrow cells after irradiation.<br />研究課題/領域番号:17K19681, 研究期間(年度):2017-06-30 - 2019-03-31
続きを見る
|
||||
| 58.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
腫瘍壊死因子・ケモカインの、がんの発症から進展過程における役割を、マウス・モデルにて解析した。その結果、慢性腸炎に伴う大腸がんの発症と進展過程において大腸局所で産生される腫瘍壊死因子が、肺転移モデルにおいては肺局所で産生されるケモカインであ
…
るCCL3が、それぞれ重要な役割を果たしていることが明らかとした。これらの結果は、腫瘍壊死因子・ケモカインががんの発症・進展過程において重要な役割を果たしていることを示唆している。<br />研究課題/領域番号:19390112, 研究期間(年度):2007-2008<br />出典：「炎症を基盤とするがん化過程における腫瘍壊死因子・ケモカインの役割の解析」研究成果報告書 課題番号19390112（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-19390112/19390112seika/)を加工して作成
続きを見る
|
||||
| 59.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
1)原癌遺伝子Pim-3に関する研究マウス肝癌発癌モデルにおける前癌と癌病変を、ディファレンシャル・ディスプレイ法を用いて解析した結果、正常肝組織では発現が認められない、セリン/スレオニン・キナーゼ活性を保有する原癌遺伝子Pim-3の発現が
…
選択的に亢進していることを見出した。ヒト肝癌組織でも同様にPim-3の発現の亢進を認めた。さらにヒト肝癌細胞株でPim-3の恒常的な発現が認められた上に、Pim-3発現をsiRNA法にて抑制すると、肝癌細胞株のアポトーシスが誘導された。Pim-3は、肝臓のみならず、膵臓・大腸などの内胚葉由来臓器でも正常状態では発現が認められないのに対して、これらの臓器の前癌から癌病変部位において発現が亢進していた。ヒト膵癌細胞株ならびにヒト大腸癌細胞株においても、Pim-3の恒常的な発現とともに、好アポトーシス分子であるBadが112番目のセリン残基がリン酸化された不活型として存在している上に、Pim-3と共局在していた。Pim-3の発現をsiRNA法にて抑制すると、Badの112番目のセリン残基のリン酸化が減弱するとともに、抗アポトーシス分子であるBc1-XLの発現も低下し、細胞のアポトーシスが誘導された。以上の結果から、Pim-3は肝臓・膵臓・大腸などの内胚葉由来臓器においてアポトーシスを抑制することによって癌化に関与していること、さらに癌化に伴って発現が亢進するがんマーカーとしての挙動を示すことも示唆された。2)ケモカインの癌の進展・転移過程での役割の解析ジエチルニトロサミン投与による肝癌発症モデルでは、発癌の初期過程で、CCL3-CCR1系が抑制的に働くのに対して、後期では血管新生を誘導することで促進的に働くことを見出した。さらに、肝転移モデルでは、CCL2-CCR2系がIto細胞の活性化→血管新生を促進することで、肝転移を促進することを見出した。<br />1)Aberrant expression of a proto-oncogene with serine/threonine kinase activity; Pim-3, in malignant lesions of endoderm-derived organs. We compared gene expression patterns in pre-malignant and malignant lesions in murine hepatocarinogenesis model, by using fluorescent differential display method. As a result, we observed that a proto-oncogene with serine/threonine kinase activity, Pim-3 was aberrantaly expressed in pre-malignant and malignant lesions, but not normal hepatic tissues. Similar observations were obtained also on human hepatocellular carcinoma (HCC) and normal liver tissues. Pim-3 was constitutively expressed in human HCC cell lines and the inhibition of Pim-3 expression by short interfering RNA induced the apoptosis of human HCC cell lines. Pim-3 was not detected in other endoderm-derived organs such as pancreas and colon, but its expression was enhanced in the pre-malignant lesions and malignant lesions of these organs. In both human pancreatic cancer and colorectal can cer cell lines, Pim-3 was constitutively expressed and a pro-apoptotic molecule, Bad was co-localized with Pim and was phosphorylated at 112-Ser, which represents its inactive form. The inhibition of Pim-3 expression by short interfering RNA reduced the phosphorylation of Bad at 112-Ser and the expression of an anti-apoptotic molecule, Bcl-XL and eventually enhanced the apoptosis. These observations suggest that aberrant expression of Pim-3 can contribute to carcinogenesis in endoderm-derived organs, including liver, pancreas, and colon, by inhibiting apoptosis and that Pim-3 can be a novel tumor marker to detect pre-malignant and malignant lesions of these organs.2)Roles of chemokines and hepatocarcinogenesis and liver metastasis We observed that a chemokine, CCL3 and its receptor, CCR1, can inhibit the carcinogenesis in the early phase of murine hepatocarcinogenesis induced by diethylnitrosamine administration but that the CCL3-CCR1 axis can promote carcinogenesis of the same hepatocarcinogenesis, by inducing angiogenesis. We further demonstrated that another chemokine, CCL2 and its receptor, CCR2, can promote liver metastasis by activating hepatic stellate cells (Ito cells) and eventually accelerating neovascularization.<br />研究課題/領域番号:16390163, 研究期間(年度):2004-2006<br />出典：「微小転移巣での発現遺伝子群の包括的解析に基づく、新規がんマーカーの検索」研究成果報告書 課題番号16390163 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
続きを見る
|
||||
| 60.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
本研究は、肝臓での炎症の遷延化過程に関与している内因性因子を同定するために、種々のマウスの肝障害モデルの分子病理学的解析を行い、以下の研究成果を得た。1)インターフェロン(IFN)-γが炎症性サイトカイン産生と炎症性細胞の浸潤を制御すること
…
を通して、Propionibacterium acnes (P. acnes)にて感作後のリポ多糖類投与による急性肝障害ならびにアセトアミノフェン投与による急性肝障害の発症過程に、垂要な役割を果たしていることを証明した。2)四塩化炭素反復投与による肝線維症の発症過程で、IL-6は線維化過程の促進に働く一方で、肝細胞の血清蛋白産生能の保持の両面に働くことを示唆する結果を得た。3)Dimethylnitrosamine反復投与時、TNFレセプターp55を介したシグナルによって、クッパー細胞・伊東細胞の集積が起き、その結果線維化が生じる可能性が示唆された。4)脾臓内への腫瘍細胞接種によっておきる肝転移過程において、肝臓内でのTNF-αの発現増強が起き、その結果起きる肝類洞血管内皮上でのVCAM-1発現の増強が、肝転移巣形成過程に密接に関与していることが示唆された。5)ヒト肝癌組織では、肝癌組織内で産生されるIL-1がautocrineあるいはparacrine的にCCケモカインの一つであるCCL3の産生を誘導し、これが肝癌細胞などで恒常的に発現しているCCL3の特異的レセプターであるCCR1に作用する可能性が示唆された。これらの炎症モデルの発症と遷延化に関与している内因性因子を検索するために、炎症モデルでの野生型マウスと種々の遺伝子欠損マウスとの間での遺伝子発現パターンの差異を検討している。<br />In order to identify an endogenous bioactive substance(s) which are involved in the chronic phases of inflammation in liver, we analyzed several liver dysfunction models in mice from molecular pathological viewpoints.#1. We proved that interferon (IFN)-γ regulated the production of pro-inflammatory cytokines and the infiltration of inflammatory cells including neutrophils and macrophages, thereby contributing to the development of lipopolysaccharide (LPS)-induced acute liver injury in Propioniobaciterium acnes-primed mice and acetaminophen-induced acute fatal liver dysfunction.#2. We obtained the evidence to suggest that interleukin (IL)-6 have bifacial roles in carbon tetrachloride-induced chronic liver fibrosis; induction of fibrogenic process and maintenance of the hepatocyte capacity to produce serum proteins such as albumin, by up-regulating the expression of a potent fibrogenic factor, transforming growth factor-β_1 and hepatocyte growth factor, respectively.#3. We have provided evidence that tumor necrosis factor receptor p55-mediated signals regulated the accumulation of Kupffer and Ito cells, thereby inducing liver fibrosis.#4. We observed that intrasplenic injection of tumors induced TNF-α expression and subsequent vascular adhesion molecule-1 expression in sinusoidal endothelial cells in liver, thereby inducing liver metastasis.#5. We observed that CCL3, induced by endogenously produced IL-1, might interact with its specific receptor, CCR1, constitutively expressed on hepatoma cells, in human hepatoma tissues.We are in the process to analyze the gene expression patterns between wild-type and various types of cytokine-related gene-deficient mice in the above mentioned inflammation models, in order to identify the molecule(s) which is crucially involved in the development of chronic liver inflammation.<br />研究課題/領域番号:11470516, 研究期間(年度):1999-202<br />出典：「肝障害の遷延化に関与する因子の検索に基づく、慢性肝障害の新規の早期診断法の開発」研究成果報告書 課題番号11470516 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
続きを見る
|
||||
| 61.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
本研究を通して以下の研究成果を得た。1)マウス・メスの排卵後にIL-8の機能的ホモログであるマクロファージ炎症性蛋白(MIP)-2が、膣上皮で一過性に産生され、膣上皮への好中球浸潤を引き起すことを明らかにした。2)IgA腎症の急性型では尿中
…
1L-8濃度が高く、尿中MCP-1濃度が検出感度以下であった。腎不全への移行が多い慢性型では、尿中MCP-1濃度が上昇しているのに対して、尿中IL-8濃'度の上昇は軽度であった。半月板形成性糸球体腎炎では、腎臓内で産生されるMIP-1αが半月板形成に、MCP-1が間質病変に関与していることを示唆する結果を得た。糖尿病腎症においては、間質のマクロファージがMCP-1陽性であり、尿中MCP-1濃度も上昇していた。3)IL-8遺伝子導入した癌細胞株を接種すると、血管新生と腫瘍形成が亢進した。癌病巣の低酸素状態の壊死近傍部位でIL-8蛋白・mRNAの発現が認められた。種々の癌細胞株を低酸素状態に暴露したところ、NF-κBとAP-1の2種類の転写因子が協調的に活性化され、IL-8遣伝子の転写が亢進していた。さらに、胃癌細胞株ではIL-8レセプターを発現していて、IL-8に反応して転移関連遺伝子の発現が誘導されていた。4)肝癌細胞株では、PEA3とAP-1とが協調的に恒常的に活性化されることによって、IL-8遺伝子転写が恒常的に起こっていた。C型肝炎ウイルス感染患者では、血清1L-8濃度のみが、慢性肝炎ならびに肝硬変患者に比べて、肝癌患者において上昇していた。さらにC型肝炎ウイルスのnonstructural protein(NS)5A蛋白遺伝子導入によって、IL-8遺伝子の転写と蛋白産生が誘導された。5)臍帯血中においてCD34陽性CCR1陰性細胞に赤芽球系の前駆細胞のほとんどが含まれることを明らかにした。<br />1) A functional interleukin-8 (IL-8) homologue, macrophage inflammatory protein (MIP)-2, was produced by mouse vaginal epithelium, periodically after ovulation and caused neutrophil infiltration into vaginal epithelium.2) In acute type of IgA nephropathy, urinary IL-8 levels were increased with undetectable urinary monocyte chemoattractant protein (MCP)-1. In contrast, MCP-1 but not IL-8 levels were increased in urines from chronic type of IgA nephropathy patients. Moreover, crescentic glomerulonephritis, MIP-lα and MCP-1 produced in the kidney, were responsible for crescent formation and interstitial lesions, respectively. Furthermore, in diabetic nephropathy, macrophages in interstitium were positive for MCP-1 and urinary MCP-1 levels were increased.3) IL-8 protein and mRNA were detected near necrotic areas inside tumor tissues, where oxygen content is presumed to be low. The exposure of several types of cell lines to hypoxia activated two transcription factors, NF-_kB and AP-1, and eventually induced IL-8 gene transcription. Human gastric cancer cell lines transfected with IL-8 gene exhibited faster tumor formation with enhanced angiogenesis when injected into nude mice, compared with parental cells. Moreover, most of gastric cancer cell lines expressed IL-8 receptors and IL-8 induced the expression of metastasis-related genes in some gastric cancer cell lines.4) In hepatoma cell lines, two distinct transcription factors, PEA3 and AP-1, were constitutively activated, which resulted in constitutive IL-8 gene transcription. Among patients infected with human hepatitis C virus, serum IL-8 levels were increased in patients suffering from hepatoma, when compared with chronic hepatits and liver cirrhosis patients. Moreover, the transduction of nonstructural protein (NS) 5A of human hepatitis C virus induced IL-8 gene transcription as well as IL-8 protein secretion.5) In cord blood, CCR1 expression among CD34-positive cells, was restricted to erythroid progenitor cells.<br />研究課題/領域番号:10557249, 研究期間(年度):1998-2001<br />出典：「ケモカインならびにレセプターの分析法の開発とその病態検査学的意義の検討」研究成果報告書 課題番号10557249(KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
続きを見る
|
||||
| 62.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
本研究を通して、以下の研究成果を挙げた。1)マウス・メスの排卵直後に膣局所で産生されるインターロイキン8(IL-8)ホモログが、性周期依存的に起きる好中球の膣粘膜への浸潤を制御していることを明らかにした。 2)モノクロタリン投与による実験的
…
肺高血圧モデルで、肺局所で産生される単球走化因子(MCP-1)が、肺へのマクロファージ浸潤とそれに引き続く肺の組織障害を制御している事を明らかにした。 3)IgA腎症で、急性型では尿中IL-8が上昇するのに対して、腎不全に移行しやすい慢性型では尿中MCP-1濃度の上昇がIL-8に比べて顕著であるなど、病型によって腎局所でケモカインが選択的に産生される可能性を認めた。 3)半月板形成性腎炎では、腎臓内で産生されるmacrophage inflammatory protein-1α(MIP-1α)が半月板形成に関与するのに対して、MCP-1が間質病変の成立に関与していることを示唆する結果を得た。 4)IL-8遺伝子を導入した癌細胞株を接種すると、接種部位での血管新生とともに腫瘍形成が亢進する事から、IL-8の血管新生作用を確認した。腫瘍の壊死部の近傍でIL-8蛋白・mRNAの発現が認められた。壊死部の近傍は低酸素状態であると考えられるので、種々のがん細胞株を低酸素状態に暴露したところ、IL-8遺伝子の転写ならびに産生が誘導された。さらに胃癌組織中の癌細胞そのものが、IL-8レセプターを発現していることも明らかになった。 5)活性化補体第5成分(C5a)刺激によって、単球細胞株でNF-κBならびにAP-1が活性化されることによって、IL-8遺伝子転写ならびに蛋白産生が誘導されることが明らかになった。 6)急性肝障害モデルで、インターフェロンγの組織障害への関与を明らかにした。<br />This study was performed to clarify the pathophysiological roles of chemokines and their receptors in various types of diseases. Through these studies, we obtained the results as follows.1) Macrophage inflammatory protein (MIP)-2, a functional homologue of human interleukin-8 (IL-8), was produced periodically at mouse vaginal epithelium immediately after the ovulation. Moreover, locally produced MIP-2 was involved in postovulatory neutrophil migration into vagina.2) Subcutaneous injection of monocrotaline into rats caused chronic pulmonary hypertension accompanied with intrapulmonary macrophage infiltration. Monocyte chemoattractant protein (MCP)-1 was produced at the onset of macrophage infiltration. The administration of anti-MCP-1 antibodies reduced macrophage infiltration and alleviated pulmonary hypertension. These results suggest that MCP-1 was involved in the pathogenesis of monocrotaline-induced pulmonary hypertension, through inducing macrophage infiltration.3) In an acute typ e of IgA nephropathy, urinary IL-8 levels were increased with no increase in urinary MCP-1 levels. In contrast, in a chronic type of IgA nephropathy which is prone to develop chronic renal failure, urinary MCP-1 levels were markedly increased while urinary IL-8 levels were not. Moreover, we found that urinary MIP-lα and MCP-1 levels correlated with crescent formation and interstitial lesions in chronic crescentic glomerulonephritis, respectively. Thus, various chemokines were produced locally and differentially at the diseased kidney, thereby contributing to the establishment of various renal lesions.4) Angiogenesis and tumor formation was enhanced by IL-8 cDNA transfection into gastric cancer cell lines. Moreover, we observed IL-8 mRNA and protein expression near necrotic areas in the tumor sites. Because the area close to necrosis is presumed to be hypoxic, we rendered human ovarian cancer and melanoma cell lines hypoxia. Hypoxia activated two types of transcription factors, AP-1 and NF-κBB, thereby inducing IL-8 production. Furthermore, we obtained definitive evidence on the presence of IL-8 receptors on human gastric cancer cells. Collectively, these results suggest that IL-8 may be involved in tumor progression by inducing angiogenesis and changing the phenotypes of cancer cells.5) We observed that C5a activated AP-1 and NF-κB, thereby inducing IL-8 production in a human monocyte cell line.6) We obtained the evidence that interferon-γ was involved in granuloma formation in Propinibacterium acnes-primed mice and subsequent lipopolysaccharide-induced liver tissue damage, by regulating macrophage infiltration and the production of several cytokines including tumor necrosis factor (TNF)-α IL-12, and IL-18.<br />研究課題/領域番号:10044254, 研究期間(年度):1998-1999<br />出典：「ケモカインならびにそのレセプターの病態生理学的役割の解析を通した抗炎症剤の開発」研究成果報告書 課題番号10044254 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
続きを見る
|
||||
| 63.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
がんの発症から進展過程におけるケモカインの役割を、マウス発がんモデルを用いて解析した。その結果、アゾキシメタンと硫酸デキストラン溶液との投与によって生じる、慢性腸炎に伴う大腸がんの発症と進展過程において大腸局所で産生されるケモカインCCL2
…
が、サイクロオキシゲナーゼ(COX)-2を発現しているマクロファージの浸潤を引き起こすことによって、大腸がん発症に密接に関与していることを明らかにした。さらに、別のケモカインであるCCL3が、同じ大腸がん発症モデルにおいて、がんの進展過程に認められる線維化に深く関与している可能性を示唆する結果を得た。一方で、肝臓がん細胞株を皮下接種したマウスに対するラジオ波照射時に、CCL3を静脈内に投与すると、照射された腫瘍部位への樹状細胞の動員が誘導され、腫瘍に対して特異的免疫応答が増強することを明らかにした。したがって、内因性に産生される場合とは異なり、薬理量のCCL3の投与は樹状細胞の移動過程を制御することによって、腫瘍免疫反応を誘導する可能性が示唆された。<br />We investigated the pathophysiological roles of chemokines in mouse tumor models. We proved that a chemokine, CCL2, was produced in colon tissues during the course of carcinogenesis process caused by the combined treatment of azoxymethane and dextran sodium sulfate. The produced CCL2 induced the migration of cyclooxygenase-2-expressing macrophages, thereby contributing to the development and progression of carcinomas. Moreover, another chemokine, CCL3, was produced in the same carcinogenesis step and contributed to the establishment of fibrosis in the later phase of the process. On the contrary, we observed that anti-tumor effects after radiofrequency ablation of mouse hepatoma were augmented by an intravenous injection of CCL3, which could trigger the migration of dendritic cells into the ablated sites, thereby inducing a tumor-specific immunity. Thus, in contrast to endogenously produced CCL3, a pharmacological dose of CCL3 may induce tumor-specific immunity by regulating the migratory process of dendritic cells.<br />研究課題/領域番号:21390117, 研究期間(年度):2009-2011
続きを見る
|
||||
| 64.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
金沢大学がん進展制御研究所<br />従来の研究成果から、単球走化因子(MCP-1)遺伝子導入したがん細胞株の腫瘍形成能・転移能が低下することが明らかになっている。本年度は、MCP-1による遺伝子治療法の基礎的検討のために、(1)腫瘍免疫成
…
立過程でのMCP-1の役割(2)自殺遺伝子併用によるMCP-1遺伝子治療法によるがん退縮効果の機序を検討した。その結果、(1)IL-4遺伝子導入colon 26細胞の腫瘍拒絶過程において、IL-4遺伝子導入株を接種したマウスの所属リンパ節では、MCP-1の発現が誘導される結果、抗原提示能を有するMCP-1レセプターを保有する樹状細胞が所属リンパ節へと動員され、腫瘍が効果的に拒絶されることを示唆する結果を得られた。(2)CAGプロモーター下流にチミディン・キナーゼ(tk)遺伝子とMCP-1遺伝子とを、IRES配列をはさんだ形で並列して連結させたアデノウイルスベクターを作成した。tkを単独で発現させるアデノウイルスベクターに比べて、今回作成したベクターによるtkの発現量は同程度であった。しかし、MCP-1産生量は、MCP-1遺伝子単独発現ベクターに比較して、今回作成したベクターは約1/10程度であった。しかし、ヒト肝がん細胞株を接種したヌードマウスの腫瘍内に、このベクターを接種して、ガンシクロビールを全身投与すると、腫瘍壊死因子の産生を伴い、マクロファージ依存性に、腫瘍が完全に退縮することが認められた。したがって、MCP-1を用いた遺伝子治療法の場合には、発現されるMCP-1量が低くても、標的細胞の動員・活性化を引き起こすことができる可能性があると考えられた。さらに、細胞膜に発現するMCP-1キメラ蛋白を発現するアデノウイルスベクターを開発し、このベクターの投与によって、細胞膜に生物活性を保有するMCP-1が発現していることを確認した。<br />研究課題/領域番号:14030030, 研究期間(年度):2002<br />出典：「がん細胞選択的発現ベクターによる、ケモカイン遺伝子治療法の基礎的検討」研究成果報告書 課題番号14030030（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-14030030/)を加工して作成
続きを見る
|
||||
| 65.
論文 |
論文
|
向田, 直史 ; Mukaida, Naofumi
概要:
金沢大学がん進展制御研究所<br />HBs抗原で免疫した野生型のマウス骨髄細胞を、骨髄細胞を枯渇させたHBsトランスジェニックマウスに移植することによって、急性肝炎→慢性肝炎→前癌状態→肝癌と発症するモデルを用いて、前癌状態において選択的
…
に発現が変化する遺伝子群を、蛍光ディファレンシャル・ディスプレイ(FDD)法にて包括的に検索し、同定した。その結果、(1)5種類の未知遺伝子ならびに、19種類の既知遺伝子の発現が増強していたのに対して、19種類の既知遺伝子の発現が低下していた。(2)5種類の未知遺伝子を定量的RT-PCR法にて検討したところ、このモデルのみならず、diethylnitrosamine投与による肝癌発症モデルでの前癌状態においても、これらの遺伝子発現が肝臓内で発現が増強していることを確認した。(3)このモデルの前癌状態で発現が増強していた既知遺伝子のうち、機能の詳細が不明であるセリン・スレオニン・キナーゼ、pim-3の発現様式について検討した結果、HBs-Tgマウスでの肝癌発症モデルとdiethylnitrosamine投与による肝癌発症モデルとの両者において、前癌状態においてpim-3の発現が増強していることを、半定量的RT-PCR法にて確認した。(4)ヒトpim-3の塩基配列の報告がなかったため、ヒトpim-3の完全長cDNAをクローニングして、その塩基配列を決定した。ヒトpim-3cDNAは全長約2.4kbで、981bp(326アミノ酸)からなるopen reading frameを保有していて、これまでに報告されているマウス・ラットpim-3とアミノ酸レベルで94%一致していることが明らかになった。さらに、ヒト肝癌細胞株でpim-3が恒常的に発現していることも確認した。<br />研究課題/領域番号:14021035, 研究期間(年度):2002<br />出典：「B型肝炎ウイルス発癌モデルでの肝臓での特異的発現遺伝子の包括的検索」研究成果報告書 課題番号14021035（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-14021035/)を加工して作成
続きを見る
|
