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| 1.
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Fujimura, Takashi ; Ohta, Tetsuo ; Oyama, Katsunobu ; Miyashita, Tomoharu ; Miwa, Koichi ; 藤村, 隆 ; 太田, 哲生 ; 尾山, 勝信 ; 宮下, 知治 ; 三輪, 晃一
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金沢大学医薬保健研究域医学系<br />Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were developed as one of the anti-inflammatory
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drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs (NSAIDs). However, coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis (FAP), which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration (FDA) immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum, and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors. © 2006 The WJG Press. All rights reserved.
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| 2.
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出口, 康
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| 3.
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Shibata, Kazuhiko ; Kitagawa, Shunsuke ; Fujimura, Masaki ; Matsuda, Tamotsu
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金沢大学医薬保健研究域医学系<br />We report a rare case of a woman with inflammatory carcinoma, an unusual type of cutaneous metastasi
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s, arising from signet-ring cell carcinoma of the stomach, who developed chylothorax as the skin lesion progressed over the chest. No thoracoabdominal lymphadenopathy which can cause obstruction of the thoracic duct was shown by computed tomography. Although a very rare condition, inflammatory carcinoma could be a cause of non-traumatic chylothorax.
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| 4.
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Mitsui, Fumihiko ; Dobashi, Yoh ; Imoto, Issei ; Inazawa, Johji ; Kono, Koji ; Fujii, Hideki ; Ooi, Akishi
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金沢大学大学院医学系研究科がん細胞学<br />This study was conducted to assess the frequencies of protein overexpression and gene amplificat
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ion of Myc and to identify the mechanisms of Myc gene amplification, especially with regards to its possible coamplification with ERBB2 or EGFR in gastric adenocarcinomas. By immunohistochemical analysis of a total of 300 formalin-fixed and paraffin-embedded gastric adenocarcinomas, the nuclear overexpression of MYC was found in 47 tumors (16%). A fluorescence in situ hybridization (FISH) analysis revealed that nine (19%) of the 47 tumors with protein overexpression had cancer cells with high levels of Myc amplification, whereas only seven (6%) of the 122 tumors without protein overexpression showed high-level Myc gene amplification. Such Myc amplification was significantly correlated with positive nuclear protein overexpression. The coamplification of ERBB2 or EGFR with Myc that was found in six and four cases, respectively, is believed to be non-incidental because those frequencies were significantly higher than the individual frequencies observed for the total examined cases (ERBB2: 7%; EGFR: 4%). The high levels of gene amplification of these three genes, as visualized by FISH, could be broadly classified into two typical types, namely, 'multiple scattered signals' and 'large clustered signals'. Using two-color FISH, the coexistence of coamplified Myc and ERBB2, or Myc and EGFR, within single nuclei in various combinations of amplification types and copy numbers, could be ascertained in all nine cases, including one in which the synchronous 'multiple scattered type' coamplification of Myc and ERBB2 was observed. In three tumors, coamplification of ERBB2 and EGFR was found; however, ERBB2- and EGFR-amplified cell populations were separate and mutually exclusive. We propose that the non-incidental coamplification of Myc and either ERBB2 or EGFR occurred through translocation and subsequent rearrangement. © 2007 USCAP, Inc All rights reserved.
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| 5.
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Mitsui, Fumihiko ; Dobashi, Yoh ; Imoto, Issei ; Inazawa, Johji ; Kono, Koji ; Fujii, Hideki ; Ooi, Akishi
概要:
金沢大学医薬保健研究域医学系<br />医薬保健研究域・薬学系<br />This study was conducted to assess the frequencies of protein overexpression and ge
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ne amplification of Myc and to identify the mechanisms of Myc gene amplification, especially with regards to its possible coamplification with ERBB2 or EGFR in gastric adenocarcinomas. By immunohistochemical analysis of a total of 300 formalin-fixed and paraffin-embedded gastric adenocarcinomas, the nuclear overexpression of MYC was found in 47 tumors (16%). A fluorescence in situ hybridization (FISH) analysis revealed that nine (19%) of the 47 tumors with protein overexpression had cancer cells with high levels of Myc amplification, whereas only seven (6%) of the 122 tumors without protein overexpression showed high-level Myc gene amplification. Such Myc amplification was significantly correlated with positive nuclear protein overexpression. The coamplification of ERBB2 or EGFR with Myc that was found in six and four cases, respectively, is believed to be non-incidental because those frequencies were significantly higher than the individual frequencies observed for the total examined cases (ERBB2: 7%; EGFR: 4%). The high levels of gene amplification of these three genes, as visualized by FISH, could be broadly classified into two typical types, namely, 'multiple scattered signals' and 'large clustered signals'. Using two-color FISH, the coexistence of coamplified Myc and ERBB2, or Myc and EGFR, within single nuclei in various combinations of amplification types and copy numbers, could be ascertained in all nine cases, including one in which the synchronous 'multiple scattered type' coamplification of Myc and ERBB2 was observed. In three tumors, coamplification of ERBB2 and EGFR was found; however, ERBB2- and EGFR-amplified cell populations were separate and mutually exclusive. We propose that the non-incidental coamplification of Myc and either ERBB2 or EGFR occurred through translocation and subsequent rearrangement. © 2007 USCAP, Inc All rights reserved.
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Oyama, Katsunobu ; Fushida, Sachio ; Kaji, Masahide ; Takeda, Toshiya ; Kinami, Shinichi ; Hirono, Yasuo ; Yoshimoto, Katsuhiro ; Yabushita, Kazuhisa ; Hirosawa, Hisashi ; Takai, Yuki ; Nakano, Tatsuo ; Kimura, Hironobu ; Yasui, Toshiaki ; Tsuneda, Atsushi ; Tsukada, Tomoya ; Kinoshita, Jun ; Fujimura, Takashi ; Ohta, Tetsuo
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Background: We aimed to evaluate the efficacy of a new combination antiemetic therapy comprising aprepitant, granisetron
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, and dexamethasone in gastric cancer patients undergoing chemotherapy with cisplatin and S-1. Methods: Gastric cancer patients scheduled to receive their first course of chemotherapy with cisplatin (60 mg/m2) and S-1 (80 mg/m2) were treated with a new combination antiemetic therapy aprepitant, granisetron, and dexamethasone on day 1; aprepitant and dexamethasone on days 2 and 3; and dexamethasone on day 4. The patients reported vomiting, nausea, use of rescue therapy, and change in the amount of diet intake, and completed the Functional Living Index-Emesis (FLIE) questionnaire. The primary endpoint was complete response (CR; no emesis and use of no rescue antiemetics) during the overall study phase (0-120 h after cisplatin administration). The secondary endpoints included complete protection (CP; CR plus no significant nausea); change in the amount of diet intake; and the impact of chemotherapy-induced nausea and vomiting (CINV) on daily life during the overall, acute (0-24 h), and delayed (24-120 h) phases. Results: Fifty-three patients were included. CR was achieved in 88.7, 98.1, and 88.7 % of patients in the overall, acute, and delayed phases, respectively. The corresponding rates of CP were 67.9, 96.2, and 67.9 %. Approximately half of the patients had some degree of anorexia. FLIE results indicated that 79.5 % of patients reported "minimal or no impact of CINV on daily life". Conclusions: Addition of aprepitant to standard antiemetic therapy was effective in gastric cancer patients undergoing treatment with cisplatin and S-1. © 2013 Springer Japan.
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| 7.
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Oyama, Katsunobu ; Fushida, Sachio ; Kinoshita, Jun ; Makino, Isamu ; Nakamura, Keishi ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Tajima, Hidehiro ; Fujita, Hideto ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Tani, Takashi ; Fujimura, Takashi ; Ohta, Tetsuo
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Background: The prognosis of gastric cancer with para-aortic lymph node (PAN) metastasis is poor. We applied triple comb
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ination chemotherapy with docetaxel, cisplatin, and S-1 (DCS therapy) as pre-operative chemotherapy and investigated the outcome of the combination of this therapy and gastrectomy with para-aortic lymph node dissection (PAND). Methods: We retrospectively identified 44 patients with pathologically positive PAN who underwent curative surgery at Kanazawa University Hospital between 1990 and 2008. Among the 44 patients, 16 received pre-operative DCS therapy and subsequent surgical resection after two courses of the therapy. Results: Pre-operative DCS therapy showed high clinical response ratio (68.8%) and disease control ratio (100%). The pathological response ratio of resected specimen was 87.5%. At 2 years after surgery, the overall survival ratio was 93.8% and relapse-free survival was 75.0%. Pre-operative DCS therapy was only independent prognostic factor in multivariate analysis. Grade 3/4 toxicity was observed only in 25.0% of patients who underwent DCS therapy. Surgical complication was observed in 31.3% of patients, and this ratio was equal to that of patients who did not receive DCS therapy. Conclusion: Multimodal therapy comprising combined pre-operative DCS therapy and gastrectomy with PAND was extremely effective and feasible for advanced gastric cancer with PAN metastasis. J. Surg. Oncol © 2011 Wiley Periodicals, Inc.
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| 8.
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Oyama, Katsunobu ; Fushida, Sachio ; Kinoshita, Jun ; Okamoto, Koichi ; Makino, Isamu ; Nakamura, Keishi ; Hayashi, Hironori ; Inokuchi, Masafumi ; Nakagawara, Hisatoshi ; Tajima, Hidehiro ; Fujita, Hideto ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Fujimura, Takashi ; Ohta, Tetsuo
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Cytokeratin 18 (CK18) fragments are released into circulation during epithelial cell death. M30 (reflects caspase-cleave
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d CK18 fragment) and M65 (reflects total CK18 fragment) enzyme-linked immunosorbent assay (ELISA) detect circulating CK18 fragments released during caspase-dependent or total cell death, respectively; thus, CK18 has the potential of being a biomarker for epithelial cancers. In the present study, we investigated the serum levels of M30 and M65 in patients with gastric cancer, determined correlation of these levels with clinical features, and evaluated the usefulness of these enzymes as diagnostic and prognostic markers. We enrolled 54 gastric cancer patients and 12 healthy volunteers in this study. We measured the serum levels of M30 and M65 by quantitative ELISA. The levels of M30 and M65 in gastric cancer patients were significantly higher than those in healthy volunteers (P = 0.001, P < 0.001). The enzyme levels were elevated with the progress of gastric cancer. The sensitivity and specificity of M30 as a diagnostic marker were 67.5 and 90.9 %, respectively, and those of M65 were 70.1 and 90.9 %, respectively. The serum levels of M30 and M65 in patient with early gastric cancer were elevated in 38.1 and 66.7 %, respectively. Further, increased serum level of M65 is an independent indicator of poor prognosis (P = 0.036). The serum levels of M30 and M65 may be useful biomarkers for gastric cancer as diagnostic markers that can reflect the extent of cancer. Moreover, M65 levels can be used as a prognostic indicator. © 2012 Springer-Verlag.
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| 9.
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山崎, 祐樹 ; 伏田, 幸夫 ; 尾山, 勝信 ; 木下, 淳 ; 牧野, 勇 ; 中村, 慶史 ; 藤田, 秀人 ; 二宮, 致 ; 藤村, 隆 ; 太田, 哲生
概要:
We report a case of advanced gastric cancer with para-aortic lymph node metastasis that underwent radical gastrectomy af
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ter neoadjuvant chemotherapy, and in this case, thoracoscopy was useful in excluding mediastinal lymph node metastasis. The patient was a 70-year-old man in whom a large type 2 advanced gastric cancer accompanied with para-aortic and mediastinal lymph node metastasis was diagnosed. We attempted combination therapy of Docetaxel, CDDP and TS-1. After 2 courses of treatment, the primary lesion and regional and para-aortic lymph nodes were significantly reduced in size, suggesting that this therapy had induced a partial response (PR). However, the size of mediastinal lymph node did not change. FDG-PET showed accumulation of FDG located in the mediastinal lymph node, in which metastasis was suspected. To judge the possibility of radical excision, we performed tho-racoscopic biopsy of the mediastinal lymph node. No metastasis was shown in the mediastinal lymph node biopsy, so we performed curative total gastrectomy with D3 lymph node dissection and cholecys-tectomy with curative intent. The pathological findings showed that there were very few cancer cells either in the primary lesion and only one lymph node (No.3). There has been no recurrence for two years after the operation. © 2012 The Japanese Society of Gastroenterological Surgery. 術前DCS（docetaxel，cisplatin，TS-1併用）療法が著効した大動脈周囲リンパ節転移を伴う進行胃癌を経験した．また，胸腔鏡下生検が縦隔リンパ節転移の除外診断に有用であったので報告する．症例は70歳の男性で，噴門直下から角上部に及ぶ大型の2型腫瘍を認めた．大動脈周囲・縦隔を含め多数のリンパ節腫大を認めた．DCS療法を2コース行い，原発巣・リンパ節転移巣ともに著明に縮小した．しかし，縦隔リンパ節に変化はなくPET-CTでも淡い集積を認め転移も否定できないため，胸腔鏡下に縦隔リンパ節生検を行ったところ，転移を認めなかった．根治切除可能と判断し大動脈周囲リンパ節郭清を伴う胃全摘術を行った．組織学的に腫瘍の大部分は壊死に陥り，原発巣の一部と壁在リンパ節1個にごく僅かに腫瘍細胞が残存していた．現在，術後2年が経過しているが，無再発生存中である．
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| 10.
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Tajiri, Ryosuke ; Ooi, Akishi ; Fujimura, Takashi ; Dobashi, Yoh ; Oyama, Takeru ; Nakamura, Ritsuko ; Ikeda, Hiroko
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A humanized monoclonal antibody against ERBB2 is used in neoadjuvant therapy for patients with gastric cancer. A critica
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l factor in determining patient eligibility and predicting outcomes of this therapy is the intratumoral heterogeneity of ERBB2 amplification in gastric adenocarcinomas. The aims of this study are to assess the underlying mechanisms of intratumoral heterogeneity of ERBB2 amplification; to characterize the diversity of coamplified oncogenes such as EGFR, FGFR2, MET, MYC, CCND1, and MDM2; and to examine the usefulness of multiple ligation-dependent probe amplification (MLPA) in the semicomprehensive detection of these gene amplifications. A combined analysis of immunohistochemistry and fluorescence in situ hybridization revealed ERBB2-amplified cancer cells in 51 of 475 formalin-fixed, paraffin-embedded gastric adenocarcinomas. The fraction of amplification-positive cells in each tumor ranged from less than 10% to almost 100%. Intratumoral heterogeneity of ERBB2 amplification, defined as less than 50% of cancer cells positive for ERBB2 amplification, was found in 41% (21/51) of ERBB2-amplified tumors. The combined analysis of MLPA and fluorescence in situ hybridization revealed that ERBB2 was coamplified with EGFR in 7 tumors, FGFR2 in 1 tumor, and FGFR2 and MET in 1 tumor; however, the respective genes were amplified in mutually exclusive cells. Coamplified ERBB2 and MYC coexisted within single nuclei in 4 tumors, and one of these cases had suspected coamplification in the same amplicon of ERBB2 with MYC. In conclusion, the amplification status of ERBB2 and other genes can be obtained semicomprehensively by MLPA and could be useful to plan individualized molecularly targeted therapy against gastric cancers. © 2014 Elsevier Inc.
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| 11.
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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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| 12.
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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
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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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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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| 14.
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Ooi, Akishi ; Oyama, Takeru ; Nakamura, Ritsuko ; Tajiri, Ryousuke ; Ikeda, Hiroko ; Fushida, Sachio ; Dobashi, Yoh
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New and effective treatments for advanced gastric cancer are urgently needed. Cyclins E and D1 form a complex with cycli
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n-dependent kinase 2, 4, or 6 to regulate G1-S transition. The G1-S regulatory genes encoding cyclin E (CCNE1), cyclin D1 (CCND1), and CDK6 (CDK6) are frequently amplified in gastric cancer and may therefore influence molecularly targeted therapies against ERBB2 or EGFR when coamplified. A total of 179 formalin-fixed and paraffin-embedded gastric cancer specimens were examined for these gene amplifications by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Amplification of at least 1 G1-S regulatory gene was found in 35 tumors (CCNE1 amplification, 15% of samples; CCND1, 6%; CDK6, 1%). In 13 of the 35 tumors, dual-color fluorescence in situ hybridization identified coamplification of the G1-S regulatory genes with ERBB2, EGFR, and/or KRAS in single cancer nuclei. The observation that cells with G1-S regulatory gene amplification contained clonal subpopulations with coamplification of ERBB2, EGFR, or KRAS in 5 early and 3 advanced cancers suggests that amplification of the G1-S regulatory genes represents an early event, which precedes ERBB2, EGFR, or KRAS amplification. Amplified CCNE1, CCND1, and CDK6 in advanced gastric cancer may be potentially useful as direct targets for molecular therapy or for combination therapy with ERBB2 or EGFR inhibitors. Multiplex ligation-dependent probe amplification could be a useful tool for identification of patients who would benefit from such therapies. © 2016 Elsevier Inc.<br />Embargo Period 12 months
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| 15.
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Fushida, Sachio ; Oyama, Katsunobu ; Kinoshita, Jun ; Yagi, Yasumichi ; Okamoto, Kouichi ; Tajima, Hidehiro ; Ninomiya, Itasu ; Fujimura, Takashi ; Ohta, Tetsuo
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Background: In gastric cancer, poor prognosis is associated with peritoneal dissemination, which often accompanies malig
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nant ascites. We searched for a target molecule in peritoneal metastasis and investigated its clinical utility as a biomarker. Methods: Biopsy specimens from both primary lesions and peritoneal metastasis, and if possible, malignant ascites, were obtained from 40 patients with gastric cancer. Vascular endothelial growth factor (VEGF) expression was analyzed by immunohistochemical staining and enzyme-linked immunosorbent assay. Results: VEGF expression was seen in 70% of peritoneal samples. Of the 40 patients, 35 had malignant ascites. These 35 patients were divided into two groups: 15 with ascites found beyond the pelvic cavity (large group) and 20 whose ascites were within the pelvic cavity (small group). The two groups did not significantly differ by serum VEGF levels, but ascites VEGF levels in the large group were significantly higher than in the small group (P < 0.0001). Serum VEGF and ascites VEGF levels were highly correlated in the large group (r = 0.686). A high ascites VEGF level was found to be a risk factor for survival (P = 0.045). We include a report of a patient with chemoresistant refractory gastric cancer and symptomatic ascites who obtained 8 months of palliation from systemic bevacizumab. Conclusion: Anti-VEGF therapies are promising, and the ascites VEGF level is an important marker in managing patients with gastric cancer and peritoneal metastasis. © 2013 Fushida et al.
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Saito, Hiroto ; Fushida, Sachio ; Miyashita, Tomoharu ; Oyama, Katsunobu ; Yamaguchi, Takahisa ; Tsukada, Tomoya ; Kinoshita, Jun ; Tajima, Hidehiro ; Ninomiya, Itasu ; Ohta, Tetsuo
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Background: The theory of extravasated platelet aggregation in cancer lesions was recently introduced. We investigated t
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he association of platelet aggregation in gastric cancer stroma with clinicopathological features, chemotherapeutic response, pathological response, and survival. Methods: The study comprised 78 patients with advanced gastric cancer who had undergone gastrectomy with or without combination of docetaxel, cisplatin and S-1 (DCS) as preoperative chemotherapy between 2005 and 2014. The patients were divided into two groups: patients who had received preoperative DCS therapy forming the p-DCS group and patients who had not received preoperative DCS therapy forming the control group. The 39 patients in the control group had received gastrectomy and postoperative chemotherapy of S-1 alone. Platelet aggregation in biopsy specimens before preoperative DCS therapy in the p-DCS group and at the time of diagnosis in the control group were evaluated using CD42b immunohistochemical staining. Results: Twenty-four patients in the p-DCS group and 19 in the control group were found to have platelet aggregation in their cancer stroma. Patients with histologically confirmed platelet aggregation had significantly higher rates of chemoresistance (58.3%) than those without platelet aggregation (20.0%) (P = 0.019). According to multivariate analysis, CD42b expression (odds ratio: 5.102, 95% confidence interval: 1.039-25.00, P = 0.045) was correlated with chemoresistance. CD42b expression and histological non-responder status were both significantly correlated with poor overall survival (OS) (P = 0.012, P = 0.016); however, RECIST was not correlated with OS. In the control group, CD42b expression was also significantly correlated with poor overall survival (OS) (P = 0.033). In the p-DCS group, according to multivariate analysis, male sex (hazard ratio: 0.281, 95% confidence interval: 0.093-0.846, P = 0.024) was correlated with good prognosis and CD42b expression (hazard ratio: 4.406, 95% confidence interval: 1.325-14.65, P = 0.016) with poor prognosis. Conclusions: This study suggests that platelets in gastric cancer stroma may create a favorable microenvironment for chemoresistance. CD42b immunohistochemical staining of biopsy specimens is a promising candidate for being a prognostic marker in patients with gastric cancer. © 2017 The Author(s).
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| 17.
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Nakajima, Kenichi ; Kawano, Masaya ; Kinami, Shinichi ; Fujimura, Takashi ; Miwa, Koichi ; Tonami, Norihisa
概要:
金沢大学医学部附属病院核医学診療科<br />木南, 伸一<br />Objective: The physiology of gastrointestinal transfer function after proximal gastre
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ctomy with bypass-tract reconstruction is not well understood. We applied a simultaneous dual-radionuclide method with a hepatobiliary imaging and gastric emptying study to evaluate physiologic alterations occurring after surgery. Methods: Nineteen patients with early gastric cancer, including 9 preoperative control patients and 10 who had proximal gastrectomy and double-tract reconstruction surgery were examined by dual-radionuclide hepatobiliary and gastric emptying studies (99mTc PMT and 111In DTPA). Retention fraction in the stomach at 3 minutes (R3) and 60 minutes (R60) and gastric emptying half-time (GET) were calculated. Bile reflux and mixture of bile and food were also evaluated. Results: The retention fractions of R3 and R60 were significantly lower in the double-tract reconstruction group than those in the preoperative group. GET differed significantly between the double-tract and preoperative groups (20.7 min ± 7.1 min and 36.2 min ± 11.0 min, p = 0.0018). The mixture of bile and food was not good in the double-tract reconstruction group (p = 0.014 vs. preoperative). Patients with a large residual stomach showed slower initial emptying (p = 0.0068) and a better mixture of bile and food (p = 0.058) compared to those with a small residual stomach. The bile reflux was not significantly increased after surgery. Conclusion: The dual-radionuclide gastrointestinal and hepatobiliary imaging was feasible and could demonstrate characteristic transit patterns of the foods and bile in the double-tract reconstruction procedure. A larger residual stomach, if possible, is desirable to provide better transfer and mixing of bile and foods.
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| 18.
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論文
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米村, 豊 ; 遠藤, 良夫 ; 栃折, 静 ; 坂東, 悦郎 ; 川村, 泰一 ; 嶋田, 努 ; 宮本, 謙一 ; 田中, 基弘 ; 佐々木, 琢磨
概要:
In vitro chemosensitivity test using a collagen-gel method was done on 165 primary gastric cancers. All of 5-FU, CBDCA,
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CDDP and docetaxel showed a high sensitivity. The effects of per oral (po) administration of TS-1, a combination of po TS-1 and intraperitoneal (ip) administration of CDDP, ip 5-FU and ip docetaxel, were evaluated in athymic mice bearing peritoneal dissemination of a gastric cancer cell line (MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice). Nude mice were inoculated by ip with 10(7) MKN-45-P cells. No survival benefit was obtained after po administration of TS-1 (12 mg/kg) alone or ip CDDP alone. However, a combination of po TS-1 (8 mg/kg x 10 days, from day 3) and ip CDDP (3.5 mg/kg, day 6 and 13) showed a significant survival improvement than that of po TS-1 or ip CDDP treatment alone. ip administration of 30 mg/kg (3 times/week x 3 weeks) or 15 mg/kg (6 times/week x 3 weeks) of 5-FU significantly improved the survival of mice bearing MKN-45-P. 5-FU concentration of ascites after ip administration of 30 mg/kg of 5-FU was 600-fold higher than po administration of 12 mg/kg of TS-1 at peak level. ip injections of docetaxel of 8 mg/kg, and 2 mg/kg improved the survival of 4 and 1 mice, respectively, and they were tumor-free on day 90. Survival of mice treated with ip injection of CBDCA (100 mg/kg, on day 3, or 50 mg/ kg on day 3 and 10) was significantly better than the control group. These results suggest the potential of po TS-1 + ip CDDP, ip 5-FU, ip docetaxel and ip CBDCA administration for the treatment of peritoneal dissemination of gastric cancer.コラーゲンゲル法により原発胃癌の薬剤感受性を調べたところ, CBDCA, CDDP, 5-FU, docetaxel(DOC)が高い感受性を示した. 胃癌高度腹膜転移株MKN-45-PをTS-1(12mg/kg)で治療した群では, 治療開始日に関係なく対照群の生存率と差がなかった. 5-FU 15mg/kg ip, 18回, 30mg/kg ip, 9回投与群ではTS-1 12mg/kg po(計20回)や対照群に比べ有意に生存率がよかった. 5-FU 30mg/kg ip投与群の注入液の5-FU濃度は600μg/mlと高値を示した. TS-1 12mg/kg投与60分での腹水中5-FU, CDHP濃度は927±558ng/ml, 1,483±719ng/mlであった. CDDP3.5mg ip投与(6, 13日)群, TS-1単独群, 対照群ではMST36, 28, 32日で差を認めなかった. しかし, CDDP+TS-1(8mg/kg)群ではMST50日で有意に他の3群より生存率が良好であった. DOC8mg/kg, 2mg/kg ip投与群ではMST90, 63日で, それぞれ4匹, 1匹は腹膜播種が消失していた. DOC8mg/kg ip投与後は8時間後も腹水中DOC濃度(4.58±0.28μg/ml)は高い濃度を維持していたが, iv投与では腹水中濃度はip投与後に比べ1/100の値であった. また, 腹膜播種組織内のDoc濃度はip投与8時間ではiv投与後に比べ有意に高い値(4.65±1.33μg/gr)を示した. CBDCA50mg/kg(day3, 7ip)100mg/kg(day3, ip)投与群では有意に対照群より生存率が良好であった. MSTは対照群26.3日, 100mg/kg群37.7日, 50mg/kg群40.3日であった. しかし, 体重減少を認めた例はなかった. 以上より胃癌高度腹膜転移株MKN-45-Pによる腹膜播種モデルにおいて, 5-Fu ip, Ts-1 po+CDDP ip, Doc ip, CBDCA ip療法は有効であり, 臨床への応用が期待される.
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| 19.
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Oguma, Keisuke ; Oshima, Hiroko ; Aoki, Masahiro ; Uchio, Ryusei ; Naka, Kazuhito ; Nakamura, Satoshi ; Hirao, Atsushi ; Saya, Hideyuki ; Taketo, Makoto Mark ; Oshima, Masanobu
概要:
金沢大学がん研究所がん幹細胞研究センター<br />The activation of Wnt/β-catenin signalling has an important function in gastrointestinal tumor
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igenesis. It has been suggested that the promotion of Wnt/β-catenin activity beyond the threshold is important for carcinogenesis. We herein investigated the role of macrophages in the promotion of Wnt/β-catenin activity in gastric tumorigenesis. We found β-catenin nuclear accumulation in macrophage-infiltrated dysplastic mucosa of the K19-Wnt1 mouse stomach. Moreover, macrophage depletion in Apc Δ716 mice resulted in the suppression of intestinal tumorigenesis. These results suggested the role of macrophages in the activation of Wnt/β-catenin signalling, which thus leads to tumour development. Importantly, the conditioned medium of activated macrophages promoted Wnt/β-catenin signalling in gastric cancer cells, which was suppressed by the inhibition of tumour necrosis factor (TNF)-α. Furthermore, treatment with TNF-α induced glycogen synthase kinase 3β (GSK3β) phosphorylation, which resulted in the stabilization of β-catenin. We also found that Helicobacter infection in the K19-Wnt1 mouse stomach caused mucosal macrophage infiltration and nuclear β-catenin accumulation. These results suggest that macrophage-derived TNF-α promotes Wnt/β-catenin signalling through inhibition of GSK3β, which may contribute to tumour development in the gastric mucosa. © 2008 European Molecular Biology Organization | All Rights Reserved.
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| 20.
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Ju, Xiaoli ; Ishikawa, Tomo-o ; Naka, Kazuhito ; Ito, Kosei ; Ito, Yoshiaki ; Oshima, Masanobu
概要:
RUNX3 is a tumor suppressor for a variety of cancers. RUNX3 suppresses the canonical Wnt signaling pathway by binding to
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the TCF4/β-catenin complex, resulting in the inhibition of binding of the complex to the Wnt target gene promoter. Here, we confirmed that RUNX3 suppressed Wnt signaling activity in several gastric cancer cell lines; however, we found that RUNX3 increased the Wnt signaling activity in KatoIII and SNU668 gastric cancer cells. Notably, RUNX3 expression increased the ratio of the Wnt signaling-high population in the KatoIII cells. although the maximum Wnt activation level of individual cells was similar to that in the control. As found previously, RUNX3 also binds to TCF4 and β-catenin in KatoIII cells, suggesting that these molecules form a ternary complex. Moreover, the ChIP analyses revealed that TCF4, β-catenin and RUNX3 bind the promoter region of the Wnt target genes, Axin2 and c-Myc, and the occupancy of TCF4 and β-catenin in these promoter regions is increased by the RUNX3 expression. These results suggest that RUNX3 stabilizes the TCF4/β-catenin complex on the Wnt target gene promoter in KatoIII cells, leading to activation of Wnt signaling. Although RUNX3 increased the Wnt signaling activity, its expression resulted in suppression of tumorigenesis of KatoIII cells, indicating that RUNX3 plays a tumor-suppressing role in KatoIII cells through a Wnt-independent mechanism. These results indicate that RUNX3 can either suppress or activate the Wnt signaling pathway through its binding to the TCF4/β-catenin complex by cell context-dependent mechanisms. © 2014 The Authors.
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| 21.
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Echizen, Kanae ; Hirose, Osamu ; Maeda, Yusuke ; Oshima, Masanobu
概要:
Cyclooxygenase-2 (COX-2) and its downstream product prostaglandin E2 (PGE2) play a key role in generation of the inflamm
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atory microenvironment in tumor tissues. Gastric cancer is closely associated with Helicobacter pylori infection, which stimulates innate immune responses through Toll-like receptors (TLRs), inducing COX-2/PGE2 pathway through nuclear factor-κB activation. A pathway analysis of human gastric cancer shows that both the COX-2 pathway and Wnt/β-catenin signaling are significantly activated in tubular-type gastric cancer, and basal levels of these pathways are also increased in other types of gastric cancer. Expression of interleukin-11, chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and CXCL5, which play tumor-promoting roles through a variety of mechanisms, is induced in a COX-2/PGE2 pathway-dependent manner in both human and mouse gastric tumors. Moreover, the COX-2/PGE2 pathway plays an important role in the maintenance of stemness with expression of stem cell markers, including CD44, Prom1, and Sox9, which are induced in both gastritis and gastric tumors through a COX-2/PGE2-dependent mechanism. In contrast, disruption of Myd88 results in suppression of the inflammatory microenvironment in gastric tumors even when the COX-2/PGE2 pathway is activated, indicating that the interplay of the COX-2/PGE2 and TLR/MyD88 pathways is needed for inflammatory response in tumor tissues. Furthermore, TLR2/MyD88 signaling plays a role in maintenance of stemness in normal stem cells as well as gastric tumor cells. Accordingly, these results suggest that targeting the COX-2/PGE2 pathway together with TLR/MyD88 signaling, which would suppress the inflammatory microenvironment and maintenance of stemness, could be an effective preventive or therapeutic strategy for gastric cancer. © 2016 Japanese Cancer Association.
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| 22.
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Jiang, Pei-Hong ; Motoo, Yoshiharu ; Garcia, Stephane ; Iovanna, Juan Lucio ; Pebusque, Marie-Josephe ; Sawabu, Norio
概要:
金沢大学がん研究所<br />Aim: Overexpression of tumor protein p53-induced nuclear protein 1 (TP53INP1) induces G1 cell cycle arres
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t and increases p53-mediated apoptosis. To clarify the clinical importance of TP53INP1, we analyzed TP53INP1 and p53 expression in gastric cancer. Methods: TP53INP1 and p53 expression were examined using immunohistochemistry in 142 cases of gastric cancer. The apoptosis of gastric cancer cells was analyzed using the TUNEL method. The relationship between the expression of TP53INP1 and clinicopathological factors was statistically analyzed. Results: TP53INP1 was expressed in 98% (139/142 cases) of non-cancerous gastric tissues and was down-expressed in 64% (91/142 cases) of gastric cancer lesions from the same patients. TP53INP1 expression was significantly decreased (43.9%) in poorly differentiated adenocarcinoma compared with well or moderately differentiated adenocarcinoma (81.6%). Cancers invading the submucosa or deeper showed lower positively (59.1%) compared with mucosal cancers (85.2%). Decrease or loss of TP53INP1 expression was significantly correlated with lymphatic invasion (54.3% vs 82.0% without lymphatic invasion) and node-positive patients (31.3% vs 68.3% in node-negative patients). P53 was expressed in 68 (47.9%) patients of gastric cancer, whereas it was absent in normal gastric tissues. A significant association was also observed between TP53INP1 status and the level of apoptosis in tumor cells: the apoptotic index in TP53INP1-positive tissues was significantly higher than that in TP53INP1-negative portions. Finally, when survival data were analyzed, loss of TP53INP1 expression had a significant effect in predicting a poor prognosis (P=0.0006). Conclusion: TP53INP1-positive rate decreases with the progression of gastric cancer. TP53INP1 protein negativity is significantly associated with aggressive pathological phenotypes of gastric cancer. TP53INP1 is related to the apoptosis of gastric cancer cells. The decreased expression of the TP53INP1 protein may reflect the malignant grade of gastric cancer and is regarded as an adverse prognostic factor. © 2006 The WJG Press. All rights reserved.
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| 23.
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大井, 章史 ; Oi, Akishi
概要:
本研究は癌抑制遺伝子p53と、DCCがそれぞれ存在する染色体17,18の数的異常を胃癌組織切片上で検索し、それぞれの染色体の2倍体から多倍体あるいはモノソミへの変化を検討し、同時にPCR-LOH法を用いてp53及びDCCのallelic l
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ossを検出し数的異常との関係を解明することを目的とした。 まず、凍結切片とホルマリン固定パラフィン包埋切片を用いたin situ hybridizationの比較を行ったところ後者の方ですぐれた結果を得られた為、以下の研究は凍結切片のかわりにホルマリン固定パラフィン包埋切片を用いて行った。ビオチン標識プローブを蛍光色素とペロキシダーゼ反応で検出する方法を比較検討したところ、前者の方が染色体数の計測が容易であった。またジゴキシゲニン標識に比べ、ビオチン標識の方が良好な結果が得られた。 染色体の数的異常とallelic imbalanceの比較では17、番染色体にallelic imbalanceのみられた33例、18番染色体にallelic imbalanceのみられた20例についてFISHを行いそれぞれ28例、18例で良好な結果が得られた。17番染色体のpolysomyは14例にみられた9例がpolyclonalであった。18番染色体のmonosomyは2例、polyclonalは7例でmonsomyは2例にみられ、これらの症例では同染色体上の遺伝子は必然的にallelic lossを呈すると考えられる。またpolysomyの症例のうちtrisomyでは必然的に50%のallelic imbalanceを呈すると考えられ、PCR-LOHでみられる。allelic imbalanceは必ずしも遺伝子の選択的な物理的欠質を意味しない。A llelic imbalanceの解析には遺伝子に特異的なプローブを用いたFISH法によりcopy数を直接する事が必要と考えられる。<br />This study was designed to facilitate understanding of the process of gastric cancer progression by clarifying numerical changes of chromosomes 17 and 18 on gastric cancer sections. For DNA hybridization, we chose two chromosome-specific alpha-centromeric probes : one for chromosome 17 on whose short arm, tumor suppressor gene p53 located and the other for chromosome 18 on whose long arm tumor suppressor gene DCC located. In addition, to know the relationship between the numerical changes of these chromosomes and allelic loss of p53 and DCC,PCR-LOH was done using microsatelite polymorphism located at or linked to these genes.In order to dissolve technical problems, we first compared the results of hybridization done by using frozen sections, and by formalin-fixed paraffin-embedded sections. We confirmed that the hybridization was not less efficient when formalin-fixed paraffin-embedded tissues were used than when frozen sections were used. Second, we compared two detection methods, i.e ., fluorescence detection and peroxidase detection. By the former method, the specimen had disadvantage of fading of fluorescences, however because virtually no background staining, the enumeration was easier than when peroxidase detection was applied. Thus finally we chose fluorescence in situ hybridization (FISH) on formalin-fixed paraffin-embedded section as the regular detection tmethod.The 33 tumors which had allelic imbalance of p53 by PCR-LOH,and 20 tumors which had allelic imbalance of DCC were examined by FISH for numerical aberrations of chromosomes 17 and 18, respectively. FISH for chromosome 17 was successful in 28 tumors and for chromosome 18 in 18 tumors. Polysomy 17 was found in 14 and polysomy 18 in 7. No monosomy 17 was found, however monosomy 18 was found in 2 tumors. By PCR-LOH,the distinction of allelic imbalance due to numerical aberrations from those due to the selective physical deletion of genetic loci was impossible, although it is easy to detect numerical chromosomal aberrations by FISH.In this study it is shown that FISH is a useful tool to clarify chromosomal changes on formalin-fixed paraffin-embedded specimen.<br />研究課題/領域番号:07670196, 研究期間(年度)1995–1996<br />出典：「胃癌凍結切片を用いた17番及び18番染色体の数的異常の解析」研究成果報告書 課題番号07670196 (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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| 24.
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Nicholas, Barker
概要:
金沢大学医薬保健研究域医学系<br />新たな治療標的となるがん幹細胞集団を見出し、胃がん進行に対するそれらの寄与を見積もるためには、ヒト胃がんの発生を正確に模倣できる侵襲性・転移性胃がんマウスモデルの開発が喫緊の課題である。我々は、Lgr
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5陽性の胃がん細胞ががん幹細胞である可能性を検証し、胃がんの進展に対するそれらの役割を明らかにするため、炎症依存的に侵襲性胃がんを発症する新規胃がんマウスモデルを作製した。これらのマウスモデルは、将来の抗がん治療の有効性/選択性を正確に評価するためのスクリーニング方法としても非常に重要であり、得られた知見は独創的で胃がん研究分野に大きな影響を与えると予想される。<br />There is an urgent, unmet need for accurate mouse models of invasive, metastatic gastric cancer that can be used to derive important mechanistic insight into gastric cancer progression and to identify candidate cancer stem cell populations as novel therapeutic targets. We generated the first inflammation-driven mouse models of invasive gastric cancer for use in studying gastric cancer development in the stomach, with a particular focus on understanding the role of Lgr5+ stem cells and Lgr5+ cancer stem cells in this process.These mouse models will also be invaluable as screening modalities for accurately evaluating the efficacy/selectivity of future anti-cancer therapeutics. The mouse models and experimental procedures detailed here are original and will deliver results that are expected to have a major impact on the gastric cancer research field.<br />研究課題/領域番号:17H01399, 研究期間(年度):2017-04-01 – 2020-03-31<br />出典：「Developing mouse models of inflammation-driven invasive gastric cancer to reveal novel therapeutic targets」研究成果報告書 課題番号17H01399（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/report/KAKENHI-PROJECT-17H01399/17H01399seika/)を加工して作成
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| 25.
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大島, 正伸 ; Oshima, Masanobu
概要:
Wntシグナルの亢進は胃癌発生の重要な原因のひとつであると考えられている。また、胃癌組織では、プロスタグランジン合成酵素のCOX-2とプロスタグランジンE_2(PGE_2)変換酵素のmPGES-1の発現誘導も認められており、これらにより産生
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されるPGE2が胃癌発生に重要であると考えられている。しかし、WntシグナルとPGE_2経路の相互作用については不明な点が多かった。そこで、それぞれのシグナル経路を胃粘膜上皮で活性化させた2系統のトランスジェニックマウスを作製して交配実験を行ない、各シグナルの単独および相互作用による胃癌発生への影響について研究を行なった。胃粘膜上皮でWmtシグナルを活性化したK19-Wnt1マウスでは、未分化な上皮細胞のマーカーであるTFF2の陽性細胞数が増加し、細胞分化の抑制が認められた。また、このモデルでは胃粘膜に微小隆起病変が発生し、組織学的には異形性を伴う前癌病変であった。これらは、腫瘍形成には至らなかったので、Wntシグナル亢進は発癌の引き金になり得るが、それだけでは発癌に十分ではないと考えられた。一方、胃粘膜でPGE2産生を亢進したK19-C2mEマウスは、胃粘膜上皮でCOX-2とmPGES-1を同時に発現している。このマウスでは、粘液細胞化生をともなう過形成病変が認められた。すなわち、PGE2経路は細胞増殖の亢進と分化方向の制御に重要である可能性が考えられた。しかし、PGE2シグナル亢進だけでは異形性病変は発生しなかった。多くのヒト胃癌組織ではWntシグナルとPGE2経路の双方が亢進していると考えられるので、双方のマウスモデルを交配してダブルトランスジェニックマウス(K19-Wnt1/C2mE)を作製した。その結果、異形性を伴う胃癌発生が全ての個体で認められた。したがって、WntとPGE2の双方の活性化により胃癌が発生する事が明らかとなった。<br />Accumulating evidence indicates that the Wnt signaling as well as prostaglandin E_2 (PGE_2), a downstream product of cyclooxygenase 2 (COX-2), plays a key role in gastric tumorigenesis. However, the molecular mechanism remains poorly understood how the Wnt and PGE_2 pathways contribute to gastric tumorigenesis. To investigate their roles in gastric cancer, we have generated transgenic mice activating both pathways in the gastric epithelial cells, and examined their phenotypes. First, we constructed K19-C2mE mice that expressed COX-2 and mPGES-1 in the gastric mucosa using the keratin 19 (K19) promoter. mPGES-1 is a PGE_2 converting enzyme induced simultaneously with COX-2 in a variety of cancers. K19-C2mE mice showed mucous cell metaplasia and hyperplasia in the glandular stomach with heavy macrophage accumulation. Activation of mucosal macrophages and inflammatory response were responsible for metaplastic hyperplasia in K19-C2mE mice. We next constructed K19-Wntl transgenic mice expressing Wntl in the gastric mucosa under the control of K19 promoter. K19-Wntl mice had a significant suppression of epithelial differentiation, and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. However, K19-Wntl mice did not develop gastric tumors. We then crossed K19-Wnt1 mice with K19-C2mE to obtain K19-Wnt1/C2mE compound transgenic mice. Importantly, increase of PGE_2 through induction of COX-2 and mPGES-1 in the K19-Wnt1 mice converted the preneoplastic lesions into malignant gastric tumors. These results indicate that simultaneous activation of both Wnt and PGE_2 pathways causes malignant gastric tumors. Accordingly, K19-Wntl/C2mE mouse model is a useful, tool to study the genetic mechanism of gastric carcinogenesis through activation of the Wnt and PGE_2 pathways.<br />研究課題/領域番号:17390114, 研究期間(年度):2005-2006<br />出典：「胃癌発生におけるWntシグナル亢進とCOX-2発現誘導の相互作用」研究成果報告書 課題番号17390114 (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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