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岡本浩一編著 ; 奥田知将, 平大樹著
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Nakanuma, Shinichi ; Tajima, Hidehiro ; Okamoto, Koichi ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Onishi, Ichiro ; Takamura, Hiroyuki ; Kitagawa, Hirohisa ; Fushida, Sachio ; Tani, Takashi ; Fujimura, Takashi ; Kayahara, Masato ; Ohta, Tetsuo ; Wakayama, Tomohiko ; Iseki, Shoichi ; Harada, Shinichi ; 中村, 信一 ; 田島, 秀浩 ; 岡本, 浩一 ; 林, 泰寛 ; 中川原, 寿俊 ; 高村, 博之 ; 北川, 裕久 ; 伏田, 幸夫 ; 谷, 卓 ; 藤村, 隆 ; 萱原, 正都 ; 太田, 哲生 ; 若山, 友彦 ; 井関, 尚一 ; 原田, 真市
概要:
金沢大学医薬保健研究域医学系<br />In primary malignant liver tumors, trypsinogen-immunoreactivity was present in 70% of intrahepatic c
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holangiocarcinoma (ICC) specimens, but absent in hepato-cellular carcinoma (HCC) specimens. We suggest the secretion of trypsinogen to be a key difference in biological behavior between ICC and HCC cells. The purpose of this study was to investigate the secretion of tumor-derived trypsin and the expression of its specific receptor, protease-activated receptor-2 (PAR-2), in ICC using cell lines and surgical specimens. The expression of trypsinogen-1 mRNA was observed in three of four ICC cell lines, but none of three HCC cell lines. Western blot analysis detected trypsinogen-1 in serum-free conditioned medium from one of the ICC cell lines positive for the mRNA. Gelatin zymography revealed a gelatinolytic activity for trypsin, the activated form of trypsinogen, in the same conditioned medium. PAR-2 mRNA and protein were observed in ICC cell lines. The proliferative activity of ICC cells was increased by concentrations of trypsin as low as 10 nM, and peaked at 100 nM. The effect of trypsin was suppressed by a serine protease inhibitor, gabexate mesilate. PAR-2 expression was detected in 64% of ICC surgical specimens immunohistochemically. In addition, stroma fibroblasts expressed PAR-2 in 52% of ICC specimens. These results suggest that trypsinogen-1 contributes to the growth of ICC cells and also tumor-associated fibroblasts.<br />Embargo Period 6 months
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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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Tajima, Hidehiro ; Takamura, Hiroyuki ; Kitagawa, Hirohisa ; Nakayama, Akira ; Shoji, Masatoshi ; Watanabe, Toshifumi ; Tsukada, Tomoya ; Nakanuma, Shinichi ; Okamoto, Koichi ; Sakai, Seisho ; Kinoshita, Jun ; Makino, Isamu ; Nakamura, Keishi ; Hayashi, Hironori ; Oyama, Katsunobu ; Inokuchi, Masafumi ; Nakagawara, Hisatoshi ; Miyashita, Tomoharu ; Ninomiya, Itasu ; Fushida, Sachio ; Fujimura, Takashi ; Wakayama, Tomohiko ; Iseki, Shoichi ; Ikeda, Hiroko ; Ohta, Tetsuo ; 田島, 秀浩 ; 高村, 博之 ; 北川, 裕久 ; 中村, 信一 ; 岡本, 浩一 ; 木下, 淳 ; 牧野, 勇 ; 中村, 慶史 ; 林, 泰寛 ; 尾山, 勝信 ; 井口, 雅史 ; 中川原, 寿俊 ; 宮下, 知治 ; 二宮, 致 ; 若山, 友彦 ; 藤村, 隆 ; 井関, 尚一 ; 池田, 博子 ; 太田, 哲生
概要:
金沢大学医薬保健研究域医学系<br />A 33-year-old female was diagnosed with a solid pseudopapillary tumor (SPT) of the pancreas and mult
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iple liver metastases at the Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital (Kanazawa, Japan). Distal pancreatectomy and postoperative systemic chemotherapy with gemcitabine (GEM) and S-1, an oral fluoropyrimidine derivative, was administered, however, liver metastases became enlarged and local recurrence occurred. Therefore, the patient was referred to the Department of Gastroenterologic Surgery at the Graduate School of Medicine (Kanazawa, Japan) for hepatic arterial infusion (HAI) chemotherapy. Oral S-1 (80 mg/m2) was administered as well as HAI chemotherapy with GEM (1,000 mg/standard liver volume). Following 18 cycles, tumor sizes were reduced and 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) examination revealed obvious reduction of tumor FDG uptake. Transarterial tumor embolization (TAE) was performed for the previously unresectable right subphrenic liver tumor, and the other tumors were surgically resected. The resected tumors were diagnosed as liver metastases and a local recurrence of SPT in the postoperative pathological examination, which revealed that the resected tumors were composed of sheets of bland cells, which were positive for CD10, CD56, vimentin, neuron-specific enolase and α-antitrypsin. The postoperative course was uneventful, and the patient is currently under observation at an outpatient clinic; postoperative adjuvant chemotherapy with oral S-1 has continued, and additional TAE is planned. In the future, if the middle segment of the liver becomes enlarged, surgery for the residual right lobe tumor may be possible. This case demonstrates one method of SPT treatment: Preoperative HAI chemotherapy with GEM, plus oral S-1 and TAE. If complete resection can be achieved, the majority of patients with SPT have a favorable prognosis. In patients with unresectable metastases from SPT, it is crucial to conduct systematic multimodal treatment to maximize treatment success. © 2015, Spandidos Publications. All Rights Reserved.<br />Embargo Period 6 months
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Yoshimoto, Katsuhiro ; Tajima, Hidehiro ; Ohta, Tetsuo ; Okamoto, Koichi ; Sakai, Seisho ; Kinoshita, Jun ; Furukawa, Hiroyuki ; Makino, Isamu ; Hayashi, Hironori ; Nakamura, Keishi ; Oyama, Katsunobu ; Inokuchi, Masafumi ; Nakagawara, Hisatoshi ; Itoh, Hiroshi ; Fujita, Hideto ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Fushida, Sachio ; Fujimura, Takashi ; Wakayama, Tomohiko ; Iseki, Shoichi ; Shimizu, Koichi ; 田島, 秀浩 ; 太田, 哲生 ; 岡本, 浩一 ; 木下, 淳 ; 古川, 裕之 ; 牧野, 勇 ; 林, 泰寛 ; 中村, 慶史 ; 尾山, 勝信 ; 井口, 雅史 ; 中川原, 寿俊 ; 藤田, 秀人 ; 高村, 博之 ; 二宮, 致 ; 藤村, 隆 ; 若山, 友彦 ; 井関, 尚一 ; 清水, 康一
概要:
金沢大学医薬保健研究域医学系<br />Several recent studies have reported that selectins are produced during ischemia-reperfusion injury,
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and that selectin ligands play an important role in cell binding to the endothelium and in liver metastasis. Portal clamping during pancreaticoduodenectomy with vessel resection for pancreatic head cancer causes hepatic ischemia-reperfusion injury, which might promote liver metastasis. We investigated the liver colonization of pancreatic cancer cells under hepatic ischemia-reperfusion and examined the involvement of E-selectin and its ligands. A human pancreatic cancer cell line (Capan-1) was injected into the spleen of mice after hepatic ischemia-reperfusion (I/R group). In addition, to investigate the effect of an anti-E-selectin antibody on liver colonization in the IR group, mice received an intraperitoneal injection of the anti-E-selectin antibody following hepatic ischemia-reperfusion and tumor inoculation (IR+Ab group). Four weeks later, mice were sacrificed and the number of tumor nodules on the liver was compared to mice without hepatic ischemia-reperfusion (control group). The incidence of liver metastasis in the I/R group was significantly higher (16 of 20, 80%) than that in the control group (6 of 20, 30%) (P<0.01). Moreover, mice in the I/R group had significantly more tumor nodules compared to those in the control group (median, 9.9 vs. 2.7 nodules) (P<0.01). In the I/R+Ab group, only 2 of 5 (40%) mice developed liver metastases. RT-PCR and southern blotting of the liver extracts showed that the expression of IL-1 and E-selectin mRNA after hepatic ischemia-reperfusion was significantly higher than the basal levels. Hepatic ischemia-reperfusion increases liver metastases and E-selectin expression in pancreatic cancer. These results suggest that E-selectin produced due to hepatic ischemia-reperfusion is involved in liver metastasis.<br />Embargo Period 6 months
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齋藤, 裕人 ; 尾山, 勝信 ; 伏田, 幸夫 ; 柄田, 智也 ; 岡本, 浩一 ; 中沼, 伸一 ; 木下, 淳 ; 牧野, 勇 ; 中村, 慶史 ; 林, 泰寛 ; 井口, 雅史 ; 中川原, 寿俊 ; 宮下, 知治 ; 藤田, 秀人 ; 田島, 秀浩 ; 高村, 博之 ; 二宮, 致 ; 北川, 裕久 ; 藤村, 隆 ; 太田, 哲生
概要:
We report a case of gastric adenosquamous carcinoma producing granulocyte-colony stimulating factor (G-CSF). A 60-year-o
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ld man was admitted to our hospital complaining of upper abdominal pain. Endoscopic examination revealed a large type 5 advanced gastric cancer with bleeding from the low body of stomach to the antrum, accompanied with para-aortic and mesenteric lymph node metastasis. He had marked leukocytosis, and serum levels of G-CSF were elevated. Histological diag-nosis of the biopsy specimen was adenosquamous carcinoma producing G-CSF. We attempted combination chemotherapy with docetaxel, cisplatin and S-1 (DCS). After 1 course of treatment, the primary lesion was reduced in size. However, the size of the metastatic lymph node was larger. Chemotherapy was not effective enough, and the patient died 3 months after ending chemotherapy. 症例は60歳、男性。上腹部痛を主訴に受診。上部消化管内視鏡で胃体下部から前庭部の小弯後壁に易出血性の5型胃癌を認め、画像所見で傍大動脈・腸間膜リンパ節転移を認めた。生検にて腺癌成分と扁平上皮癌成分の混在を認めた。来院時より白血球数が著明に増多し、血清G-CSF高値、生検組織の免疫組織染色で腫瘍組織のG-CSF発現を認めた。以上よりG-CSF産生胃腺扁平上皮癌と診断し、化学療法（DCS (docetaxel/ cisplatin/ S-1併用)療法）を1コース行ったところ原発巣の縮小を認めたが、転移リンパ節の増大を認めた。急激な病状悪化により3ヶ月の経過で死亡した。
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寺川, 裕史 ; 尾山, 勝信 ; 渡邉, 利史 ; 柄田, 智也 ; 岡本, 浩一 ; 木下, 淳 ; 古河, 浩之 ; 牧野, 勇 ; 中村, 慶史 ; 林, 泰寛 ; 井口, 雅史 ; 中川原, 寿俊 ; 宮下, 知治 ; 田島, 秀浩 ; 高村, 博之 ; 二宮, 致 ; 北川, 裕久 ; 伏田, 幸夫 ; 藤村, 隆 ; 太田, 哲生
概要:
An 83-year-old woman was diagnosed as having advanced gastric cancer with multiple lymph node and hepatic metastases. Hi
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stopathological examination revealed that the tissue was human epidermal growth factor receptor 2 (HER2) positive. The patient underwent gastrojejunostomy to improve stomach obstruction. Thereafter, S-1 and trastuzumab combination chemotherapy was administered as first-line treatment; irinotecan (CPT-11), cisplatin, and trastuzumab combination chemotherapy, as second-line treatment; and docetaxel plus trastuzumab combination chemotherapy, as third-line treatment. Although both primary and metastatic lesions decreased in size temporarily, their size increased again, and the patient died 1 year and 7 months later. The level of serum HER2-extracellular domain (ECD) was a valuable indicator of response to chemotherapy. Thus, serum HER2-ECD could be a useful biomarker for HER2-positive gastric cancer.症例は83歳, 女性. 多発リンパ節転移, 多発肝転移を伴う進行胃癌を指摘された. 生検検体のHER2判定は陽性であった. 通過障害改善目的の胃空腸バイパス術後に化学療法を開始した. first-lineにS-1+trastuzumab, second-lineとしてirinotecan(CPT-11)+cisplatin+trastuzumab, third-lineとしてdocetaxel+trastuzumabを行った. いずれも一時的には治療効果が得られたが不応となり, 1年7か月後に永眠された. 経過中, 血清HER2-ECD値の増減と治療効果に相関を認めた. 血清HER2-ECD値はHER2陽性胃癌の治療効果を反映するバイオマーカーとなる可能性が示唆された.
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寺川, 裕史 ; 尾山, 勝信 ; 渡邉, 利史 ; 柄田, 智也 ; 岡本, 浩一 ; 木下, 淳 ; 古河, 浩之 ; 牧野, 勇 ; 中村, 慶史 ; 林, 泰寛 ; 井口, 雅史 ; 中川原, 寿俊 ; 宮下, 知治 ; 田島, 秀浩 ; 高村, 博之 ; 二宮, 致 ; 北川, 裕久 ; 伏田, 幸夫 ; 藤村, 隆 ; 太田, 哲生
概要:
症例は59歳, 男性. 進行胃癌に対し, 胃全摘術(D2郭清, 脾合切)を施行した. 病理診断は多発胃癌で病変は2か所あり, ML, AntLess, type 3, por, pT3, ly1, v0およびM, Post, 0-IIc,
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tub1, pT1b2, ly0, v0, pN2M0P0H0, pStage IIIAであった. 術後3年6か月目に, 顔面, 頸部, 体幹, 上肢に小結節が多数出現した. 皮膚結節の生検では胃癌の転移に矛盾しない所見であり, 胃癌多発皮膚転移と診断した. さらに多発骨転移・リンパ節転移を認め, 化学療法を行っている. 胃癌の皮膚転移部位は, 臍部, いわゆるSister Mary Joseph's noduleが最多であるが, それ以外の部位に多発する症例はまれである. 「はじめに」 内臓悪性腫瘍の皮膚転移は一般的にはまれとされ, その頻度は3～10%程度と報告されている1, 2). A 59-year-old man with gastric cancer underwent a total gastrectomy with splenectomy and D2 lymph node dissection. Pathological findings after the first operation were as follows: ML, AntLess, type 3, por, pT3, ly1, v0, and M, Post, 0-II c, tub1, pT1b2, ly0, v0, pN2M0P0H0, pStage IIIA. At 3 years and 6 months after the operation, multiple small nodules were noted on the skin of his face, neck, body, and arms. Biopsy of a skin lesion indicated that it was a metastatic skin cancer resulting from an adenocarcinoma. Thus, we diagnosed the lesions as skin metastases originating from an adenocarcinoma of the stomach. We also detected the presence of multiple metastases to the bone and lymph nodes, and we have treated the patient with chemotherapy. Metastases to the umbilicus from gastric cancer are termed as Sister Mary Joseph's nodules (SMJN). Although cases of SMJN are often reported, cases of multiple metastases from gastric cancer, without invasion to the umbilicus, are rare.
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山口, 貴久 ; 伏田, 幸夫 ; 柄田, 智也 ; 木下, 淳 ; 尾山, 勝信 ; 渡邉, 利史 ; 岡本, 浩一 ; 中村, 慶史 ; 二宮, 致 ; 藤村, 隆 ; 太田, 哲生
概要:
癌組織に浸潤するマクロファージには腫瘍促進作用を有するものが存在し, M2マクロファージと呼ばれている. 胃癌癌性腹膜炎患者の腹腔内マクロファージのphenotypeを評価した. 胃癌癌性腹膜炎患者から採取した腹水あるいは腹腔洗浄液から細胞
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を回収し, 比較対照群をStage I, II患者の腹腔洗浄液とした. CD45(汎白血球マーカー), CD68(汎マクロファージマーカー), CD163 (M2マクロファージマーカー)を染色し, フローサイトメトリーにて計測した. 癌性腹膜炎患者の腹腔内には多量の腹腔内マクロファージが存在し, その約71%と大部分がM2マクロファージであることがわかった. またM2マクロファージを多数有するStage IV症例の腹腔内マクロファージを継時的に検討したところ, パクリタキセルを含んだ腹腔内化学療法により, M2マクロファージの比率が減少することがわかった. 腹腔内マクロファージは腹膜播種増悪と関連しており, 治療ターゲットとなることが示唆された.
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岡本, 浩一 ; 田島, 秀浩 ; 太田, 哲生 ; 中沼, 伸一 ; 林, 泰寛 ; 中川原, 寿俊 ; 大西, 一朗 ; 高村, 博之 ; 北川, 裕久 ; 伏田, 幸夫 ; 谷, 卓 ; 藤村, 隆 ; 萱原, 正都
概要:
Angiotensin II (Ang II) plays an important role in stromal fibrosis and tumor progression in cancer tissues. Now we inve
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stigated the role of Ang II in the cross-interaction between intrahepatic cholangiocarcinoma (ICC) cells and hepatic stellate cells (HSCs). The concentrations of Ang II in ICC tissues were significantly higher than those of hepatocellular carcinoma and normal liver. The expression of Ang II type 1 receptor (AT-1) in ICC specimens, two ICC cell lines, and HSC cell line, LI-90 was demonstrated by immunostain and Western blot. The proliferative activity of ICC cells and HSCs added Ang II dose-dependently increased and telmisartan inhibited the proliferative effects in MTT assay. HSCs added Ang II showed a higher expression of α-smooth muscle actin (α-SMA) compared with control cells. Telmisartan also inhibited the activation of HSCs added Ang II. Ang II in ICC tissues may play a pivotal role in tumor growth and stromal fibrosis and Ang II receptor blocker will be a potential therapy in cancer tissue expressing AT-1.
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