Accumulation of microglial cells expressing ELR motif-positive CXC chemokines and their receptor CXCR2 in monkey hippocampus after ischemia-reparfusion

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1801号, 学位授与年月日 : 平成18年9月28日, 学位授与大学 : 金沢大学, 主査教授 : 須田 貴司, 副査教授 : 濱田 潤一郎, 東田 陽

Enhanced expression of a proto-oncogene, Pim-3, with serine/threonine kinase activity, in various type of tumors

Division of Molecular Bioregulatio

Crucial Involvement of the CCR2/CCL2 Interactions in Azoxymethane/Dextran Sodium Sulfate-induced Colon Carcinogenesis in Mice

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

Tumor necrosis factor (TNF) and chemokines in colitis-associated cancer

The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence 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

Restoring mucosal barrier function and modifying macrophage phenotype with an extracellular matrix hydrogel: potential therapy for ulcerative colitis

Background & Aims: Despite advances in therapeutic options, more than half of all patients with ulcerative colitis (UC) do not achieve long-term remission, many require colectomy, and the disease still has a marked negative impact on quality of life. Extracellular matrix (ECM) bioscaffolds facilitate the functional repair of many soft tissues by mechanisms that include mitigation of pro-inflammatory macrophage phenotype and mobilization of endogenous stem/progenitor cells. The aim of the present study was to determine if an ECM hydrogel therapy could influence outcomes in an inducible rodent model of UC. Methods: The dextran sodium sulfate (DSS)-colitis model was used in male Sprague Dawley rats. Animals were treated via enema with an ECM hydrogel and the severity of colitis was determined by clinical and histologic criteria. Lamina propria cells were isolated and the production of inflammatory mediators was quantified. Mucosal permeability was assessed in-vivo by administering TRITC-dextran and in-vitro using transepithelial electrical resistance (TEER). Results: ECM hydrogel therapy accelerated healing and improved outcome. The hydrogel was adhesive to colonic tissue, which allowed for targeted delivery of the therapy, and resulted in a reduction in clinical and histologic signs of disease. ECM hydrogel facilitated functional improvement of colonic epithelial barrier function and the resolution of the pro-inflammatory state of tissue macrophages. Conclusions: The present study shows that a nonsurgical and nonpharmacologic ECM-based therapy can abate DSS-colitis not by immunosuppression but by promoting phenotypic change in local macrophage phenotype and rapid replacement of the colonic mucosal barrie

Activation of epidermal growth factor receptor signaling by the prostaglandin E2 receptor EP4 pathway during gastric tumorigenesis

金沢大学がん進展制御研究所Cyclooxygenase-2 (COX-2) plays an important role in tumorigenesis through prostaglandin E2 (PGE2) biosynthesis. It has been shown by in vitro studies that PGE2 signaling transactivates epidermal growth factor receptor (EGFR) through an intracellular mechanism. However, the mechanisms underlying PGE2-induced EGFR activation in in vivo tumors are still not fully understood. We previously constructed transgenic mice that develop gastric tumors caused by oncogenic activation and PGE2 pathway induction. Importantly, expression of EGFR ligands, epiregulin, amphiregulin, heparin-binding EGF-like growth factor, and betacellulin, as well as a disintegrin and metalloproteinases (ADAMs), ADAM8, ADAM9, ADAM10, and ADAM17 were significantly increased in the mouse gastric tumors in a PGE2 pathway-dependent manner. These ADAMs can activate EGFR by ectodomain shedding of EGFR ligands. Notably, the extensive induction of EGFR ligands and ADAMs was suppressed by inhibition of the PGE2 receptor EP4. Moreover, EP4 signaling induced expression of amphiregulin and epiregulin in activated macrophages, whereas EP4 pathway was required for basal expression of epiregulin in gastric epithelial cells. In contrast, ADAMs were not induced directly by PGE2 in these cells, suggesting indirect mechanism possibly through PGE2-associated inflammatory responses. These results suggest that PGE2 signaling through EP4 activates EGFR in gastric tumors through global induction of EGFR ligands and ADAMs in several cell types either by direct or indirect mechanism. Importantly, gastric tumorigenesis of the transgenic mice was significantly suppressed by combination treatment with EGFR and COX-2 inhibitors. Therefore, it is possible that inhibition of both COX-2/PGE2 and EGFR pathways represents an effective strategy for preventing gastric cancer. © 2011 Japanese Cancer Association

Aberrant expression of serine/threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines

金沢大学がん研究所がん病態制御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