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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
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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.
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Okamoto, Koichi ; Tajima, Hidehiro ; Nakanuma, Shinichi ; Sakai, Seisho ; Makino, Isamu ; Kinoshita, Jun ; Hayashi, Hironori ; Nakamura, Keishi ; Oyama, Katsunobu ; Nakagawara, Hisatoshi ; Fujita, Hideto ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Fushida, Sachio ; Fujimura, Takashi ; Harada, Shinichi ; Wakayama, Tomohiko ; Iseki, Shoichi ; Ohta, Tetsuo ; 岡本, 浩一 ; 田島, 秀浩 ; 中村, 信一 ; 牧野, 勇 ; 木下, 淳 ; 林, 泰寛 ; 中村, 慶史 ; 尾山, 勝信 ; 中川原, 寿俊 ; 藤田, 秀人 ; 高村, 博之 ; 二宮, 致 ; 北川, 裕久 ; 伏田, 幸夫 ; 藤村, 隆 ; 原田, 真市 ; 若山, 友彦 ; 井関, 尚一 ; 太田, 哲生
概要:
金沢大学医薬保健研究域医学系<br />We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facili
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tate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1αwas released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and metastasis of tumor cells expressing AT-1 and CXCR4.<br />Embargo Period 6 months
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中尾, 眞二 ; Nakao, Shinji
概要:
金沢大学医薬保健研究域医学系<br />余剰造血幹前駆細胞（HSPC）のマーカーであるCXCR4陽性のHSCPを活性化できれば、再生不良性貧血（再不貧）患者の造血機能を改善させられる可能性がある。免疫不全マウスの骨髄内にヒトCD34(+)細
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胞を移植したところ、3.3-20.4%のヒトCD45陽性細胞の再生を確認した。６pLOH陽性の再不貧患者単球由来iPS細胞からHSPCを誘導し、同じマウスに移植したところ、患者体内で優勢であった6pLOH(+)HSPCのCXCR4(+)細胞割合(平均10.2%)は野生型（50.7％）に比べて有意に低値であった。野生型CXCR4(+)HSPCをin vivoで活性化させる方法を現在検討中である。<br />A chemokine receptor CXCR4 is preferentially expressed by redundant hematopoietic stem/progenitor cells (HSPCs) that do not contribute to hematopoiesis. Stimulation of residual CXCR4(+) HSPCs may restore hematopoietic function of patients with acquired aplastic anemia (AA). First, we optimized method of engrafting an immune-deficient mouse (BRGS mouse) with cord-blood CD34(+) cells using intra-bone marrow injection, and confirmed the presence of human CD45(+) cells that accounted for 3.3-20.4% of the various tissue-derived cells. Next, we induced HSPCs from iPS cells that were generated from monocytes of AA patients possessing 6pLOH(+) leukocytes, which were predominant in the patients’ blood, as a result of uniparental disomy, and injected the HSPCs to the same mice. Regenerating human 6pLOH(+)CD34(+) cells in the mice expressed CXCR4 to a significantly lesser degree (mean 10.2%) than did 6pLOH(-)CD34(+) cells. We are currently exploring a method to activate CXCR4(+) HSPCs in vivo.<br />研究課題/領域番号:15K15360, 研究期間(年度):2015-04-01 - 2017-03-31
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安本, 和生 ; Yasumoto, Kazuo
概要:
ヒト胃癌の腹膜播種形成におけるケモカインの関与ならびにその役割を明らかにするために、<方法ならびに結果>1、ヒト胃癌継代細胞株数種を用いてケモカインレセプターの発現をRT-PCR法免疫細胞染色法を用いて検討した。腹膜播種指向性細胞株において
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選択的にCXCR4レセプターを高発現していることが判明した。CXCR4高発現胃癌細胞株を用いてその唯一のリガンドであるCXCL12(SDF-1a)に対する生物活性(遊走能・増殖能)の有無を検討した。リガンドの添加刺激に対し遊走能ばかりでなく増殖能をも有することが判明した。それら活性に対し、CXCR4のモノクローナル抗体投与は、生物活性を有意に抑制した.さらに、細胞内のSurvival signalsとして知られるAktならびにERKのリン酸化をも誘導することがウエスタンブロット法にて判明した。3、ヒト臨床検体を用いた検討では、腹膜播種症例と肝転移症例の進行再発胃癌症例の胃原発巣におけるCXCR4の発現を比較検討した結果、癌性腹膜炎を発症した症例群の原発巣では、肝転移を発症した症例群に比して有意差をもってCXCR4の発現が亢進していた。また、転移の臓器選択性を検討する目的で胃癌転移の好発臓器である肝臓・腹膜・リンパ節・胃粘膜におけるCXCL12(SDF-1a)の発現をRT-PCR法と免疫組織染色法を用いて検討した結果、大変興味深いことに、腹膜組織において恒常的なCXCL12(SDF-1a)の高発現が確認され、さらに癌性腹水中には高濃度のCXCL12(SDF-1a)が存在することが判明した。4、今後の臨床治療への応用を図ることを目的に、まずCXCR4を高発現するヒト胃癌細胞株をヌードマウス腹腔内に移植し、腹膜播種モデルを作製した。この系にCXCR4阻害剤(AMD3100)を腹腔内投与し、癌性腹水生成の有意な抑制と、腹膜転移結節の明らかな縮小を確認した。<結語>臨床的に胃癌腹膜播種再発を起こしやすい低分化腺癌や印環細胞癌は、選択的にCXCR4レセプターを高発現し、腹膜に高発現する唯一のリガンドCXCL12(SDF-1a)を介して腹腔内に遊走、腹膜上で増殖し、癌性腹水成立とともに腹水内においても増殖し、腹膜播種を形成・進展させていくことが強く示唆された。CXCR4レセプター阻害剤の腹腔内投与による腹膜播種抑制は、予防薬の開発という新たな分子標的治療として新しい治療コンセプトとなりうる可能性がある。<br />Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Since chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may also be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon intraperitoneal inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells showed vigorous migratory responses to its ligand CXCL12 (also called stromal-derived factor-1a, SDF-1a). CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase (ERK) of NUGC4 cells. We also demonstrated that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. In addition, we examined human clinical samples. Malignant ascites fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (average, 4.67 ng/mL). Moreover, immunohistochemical analysis demonstrated that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16 with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4-positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis. Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma.<br />研究課題/領域番号:16591303, 研究期間(年度):2004-2005<br />出典：「ヒト胃癌腹膜播種形成におけるケモカインとそのレセプター発現の臨床的意義」研究成果報告書 課題番号16591303 (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
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