胃癌（基礎研究）

１． 消化器発癌の基礎

成長因子の１つであるTGF-alphaを高発現するトランスジェニックマウスはメネトリエ病のモデルとして知られている。このマウスおよびメネトリエ病の胃では、正常胃では幽門腺にしか発現していないホメオボックス遺伝子Pdx1が胃底腺でも発現し、ガストリンも発現してくることから、真の意味での化生がおこっていると考えられた。

骨髄細胞は臓器障害時に修復目的にとりこまれていることが知られていたが、上皮にとりこまれるかどうかは不明であった。ヘリコバクターピロリ感染のモデルであるヘリコバクターフェリス慢性感染マウスの胃にはTFF2が高発現する化生(SPEM)がおきるが、このSPEMには大量の骨髄細胞が取り込まれ、そこで分化、増殖していることがわかった。これが発癌のもとになる細胞となっている可能性もある。

参考文献

1. Nomura S, Settle SH, Leys C, Means AL, Peek R, Leach SD, Wright CV, Coffy RJ, Goldenring JR. gastric fundus epithelium associated with Menetrier’s disease and TGFa overexpression. Gastroeterology 2005 (in press)
2. Houghton JM, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, Fox JG, Goldenring JR Wang TC. Gastric cancer originating from bone marrow derived cells. Science 306: 1568-1571, 2004
3. Suzuki A，Kusakai G， Kishimoto A, Lu J，Ogura T Lavin MF, Esumi E. Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein. J Biol Chem 278：48-53, 2002
4. Kakazu N, Ashihara E, Hada S, Ueda T, Sasaki H, Terada M, Abe T. Development of spectral colour banding in cytogenetic analysis. Lancet 357 (9255) :529-530,2001

２． ヘリコバクターピロリ感染と胃発癌

ヘリコバクター・ピロリ菌 (Helicobacter pylori = H. pylori ) 感染は胃癌の発生に対して発癌プロモーターとして作用し、その持続感染により胃癌の発生リスクが有意に上昇する。さらに、H. pylori 感染および高濃度食塩の摂取による胃癌発生リスクを比較すると、発癌リスクとして高濃度食塩よりもH. pylori 感染の作用が強力であり、さらに両因子の存在により胃癌の発生リスクが強く促進される。しかし、H. pylori 感染後に一定期間が経過してからH. pylori の除菌を行うと、非除菌群に比べて発癌率が1/3程度にまで低下し、すなわちH. pylori 感染による発癌促進効果は除菌により有意に予防されることが明らかとなった。

参考文献

1. Nozaki K, Tanaka H, Ikehara Y, Cao X, Nakanishi H, Azuma T, Yamazaki S, Yamaoka Y, Shimizu N, Mafune K, Kaminishi M, Tatematsu M. Helicobacter pylori-dependent NF-kappa B Activation in newly established Mongolian gerbil gastric cell lines. Cancer Sci 2005 (in press)
2. Cao X, Tuskamoto T, Nozaki K, Mizoshita T, Ogasawara N, Tanaka H, Takenaka M, Kaminishi M, Tatematsu M. β-Cathenin gene alteration in glandular stomach adenocarcinomas in N-methyl-N-nitrosoures-treated and Helicobacter pylori-infected Mongolian gerbils.Cancer Sci 95:487-490, 2004
3. Matsuhashi N, Nakajima A, Nomura S, Kaminishi M. Inflammatory fibrinoid polyps of the stomach and Helicobacter pylori.J Gastroenterol Hepatol 19: 346-347, 2004
4. M. Tatematsu, K. Nozaki, T. Tsukamoto. Helicobacter pylori infection and gastric carcinogenesis in animal models. Gastric Cancer 6:1-7,2003
5. Nozaki K, Shimizu N, Ikehara Y, Inoue M, Tsukamoto T, Inada K, Tanaka H, Kumagai T, Kaminishi M, Tatematsu M. Effect of early eradication on Helicobacter pylori-related gastric carcinogenesis in Mongolian gerbils. Cancer Sci 94:235-239, 2003
6. Cao X, Tsukamoto T, Nozaki K, Tanaka H, Shimizu N, Kaminishi M, Kumagai T, Tatematsu M. Earlier Helicobacter pylori infection increases the risk for N-Methyl-N-nitrosourea-induced stomach carcinogenesis in Mongolian gerbils. Jpn J Cancer Res 93:1293-1293, 2002
7. Nozaki K，Shimizu N，Inada K，Tsukamoto T，Inoue M, Kumagai T，Sugiyama A，Mizoshita T，Kaminishi M，Tatematsu M. Synergistic Promoting Effects of Helicobacter pylori Infection and High-salt Diet on Gastric Carcinogenesis in Mongolian Gerbils. Jpn J Cancer Res 93：1083-1089, 2002
8. Nozaki K，Shimizu N，Tsukamoto T，Inada K，Cao X，Ikehara Y，Kaminishi M, Sugiyama A, Tatematsu M. Reversibility of Heperotopic Proliferative Glands in Glandular Stomach of Helicobacter pylori-infected Mongolian Gerbils on Eradication. Jpn J Cancer Res 93：374-381, 2002
9. Ikehara Y, Nishikawa S, Yasutomi H, Kitamura T, Matsuo K, Shimizu N, Inada K, .Kodera Y, Yamamura Y, Narimatsu N, Hamajima N, Tatematsu M. Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibody. Cancer Epidemiology, Biomarkers & Prevention 10: 971-977. 2001
10. Shimuzu N, Ikehara Y, Inada K, Nakanishi H, Tsukamoto T, Nozaki K, Kaminishi M, Kuramoto S, Sugiyama A, Katsuyama T, Tatematsu M. Eradication diminishes enhancing effects of Helicobacter pylori infection on glandular stomach carcinogenesis in Mongolian Gerbils. Cancer Res 60:1512-1514,2000
11. N Shimizu, Y kehara,K.Nozaki, M Kaminishi, H Tsuda, A Sugiyama, T Katsuyama, M Tatematsu. Effects of lactoferrin administration in Helicobacter pylori infection animal model,Lactoferrin: Structure, Function and Applications, Shimazaki K.(ed.), ELSEVIER SCIENCE B.V, Amsterdam , 209-215, 2000
12. Shimizu N, Inada K, Nakanishi H, Tsukamoto T, Ikehara Y, Kaminishi M, Kuramoto S, Sugiyama, A, Katsuyama T, Tatematsu M. Helicobacter pylori infection enhances glandular stomach carcinogenesis in Mongolian gerbils treated with chemical carcinogens. Carcinogenesis 20: 669- 676, 1999
13. N. Shimizu，K. Inada，T. Tsukamoto，H. Nakanishi，Y. Ikehara，A. Yoshikawa，M. Kaminishi，S. Kuramoto，M. Tatematsu, New animal model of glandular stomach carcinogenesis in mongolian gerbils infected with Helicobacter pylori and treated with a chemical carcinogen, J Gastroenterol 34: 61-66, 1999
14. Shimizu N, Kaminishi M, Tatematsu M, Tsuji E, Yoshikawa A, Yamaguchi H, Aoki F, Oohara T. Helicobacter pylori promote development of pepsinogen-alterd pyloric glands, a preneoplastic lesion of glandular stomach of BALB/c mice pretreated with N-methyl-N-nitrosourea. Cancer Letter 123:63-39,1998
15. K Kobayashi, N Shimizu, T Tsukamoto, K Inade, H Nakanishi, K Goto, M Mutai, M.Tatematsu. Dose-dependent promoting effects of catechol on glandular stomach carcinogenesis in BALB/c mice initiated with N-methyl-N-nitrosourea. Jpn J Cancer Res 88:1143-48,1998
16. M Tatematsu, M Yamamoto, N.Shimizu, A Yoshikawa, H Fukami, M Kaminishi, T Oohara, A.Sugiyama, T Ikeno. Induction of glandular stomach cancers in Helicobacter pylori sensitive Mongolian gerbils treated with N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine in the drinking water. Jpn. J. Cancer Res. 89 :97-104,1998
17. Sugiyama, F. Maruta, T. Ikeno, K. Ishida, S. Kawasaki, T. Katsuysma, N. Shimizu, M. Tatematsu. Helicobacter pylori Infection Enhances MNU (N-methyl-N-nitrosourea)-induced Stomach Carcinogenesis in the Mongolian Gerbil. Cancer Res. 58:2067-2069,1998
18. M Tatematsu, M Yamamoto,N. Shimizu, A.Yoshikawa, H Fukami, M Kaminishi , T Oohara, A Sugiyama, T Ikeno. Induction of glandular stomach cancers in Helicobacter pylori-sensitive Mongolian gerbils treated with N-Methyl-N-nitrosourea and N-Methyl-N-nitro-N-nitrosoguanidine in drinking water. Jpn J Cancer Res.89:97-104,1998

３． 胃十二指腸逆流と残胃発癌

参考文献

1. Shimoyama S, Joujima Y, Oohara T, Kaminishi M. Dual roles of peptic ulcer in the carcinogenesis or extension of early gastric cancer. Annals of Surgical Oncology 6:495-499,1999
2. Kaminishi M, Shimizu N, Nomura S, Ohkura F, Shimoyama S, Yamaguchi H, Hashimoto M, Ogawa T, Sakai S, Oohara T. Different carcinogenesis in the gastric remnant following gastrectomy for gastric cancer. Cancer 77:1646-1653, 1996
3. Kaminishi M, Shimizu N, Shimoyama S, Yamaguchi H, Ogawa T, Sakai S, Kuramoto S, Oohara T. Etiology of gastric remnant cancer with special reference to the effects of denervation of the　gastric mucosa. Cancer 75:1490-1496,1995
4. Kaminishi M, Oohara T, Chiu ML, Aoki F, Yamaguchi H, Shimoyama S. Severe gastric mucosal changes following vagotomy with duodenogastric reflux. Journal of Clinical Gastroenterology 14 :S15-S24,1992
5. Kaminishi M, Sadatsuki H, Johjima Y, Oohara T, Kondo Y. A new model for production of　chronic gastric ulcer by duodenogastric reflux in rats. Gastroenterology 92:1913-1918,1987
6. Kaminishi M, Shimazu R, Kuramoto S, Oohara T, Kondo Y. A clinicopathological study of post-bulbar duodenal ulcer - Analysis of 6 cases and comparison to usual chronic duodenal　ulcer-Japanese Journal of Surgery 17:140-145,1987

４． 糖代謝と胃癌

参考文献

1. K. Hashimoto，K. Kato，K. Imamura，A. Kishimoto，H. Yoshikawa，Y. Taketani，H. Esumi. 5-amino-4-imidazolecarboxamide riboside confers strong tolerance to glucose. Biochem Biophys Res Commun 290：263-267, 2002
2. Lu J, KunimotoS, Yamazaki Y, Kaminishi M, Esumi H. Kigamicin D, a novel anticancer agent based on a new anti-austerity strategy targeting cancer cells’ tolerance to nutrient starvation. Cancer Sci 95:547-552, 2004

５． PPARγノックアウトマウスと胃癌

参考文献

６． Trefoil Peptideと胃発癌

ヘリコバクターピロリ感染のモデルであるヘリコバクターフェリス慢性感染マウスの胃にはTFF2が高発現する化生(SPEM)がおきる。TFF2を高発現する腺管内の部位は深部約２／３である。このTFF2発現部位で表層上皮細胞よりも高発現している遺伝子はGastritis Cystica Profundaでも高発現しており、発癌への関与が考えられた。

参考文献

1. Nomura s, Baxter T, Yamaguchi H, Leys C, Varapetian AB, Fox JG, Lee JR, Wang TC, Goldenring JR Spasmolytic polypeptide expressing metaplasia to pre-neoplasia in H.felis-infected mice. Gastroneterology 127: 582-594, 2004
2. Yamaguchi H, Goldenring JR, Kaminishi M, Lee JR. Identification of Spasmolytic Polypeptide Expressing Metaplasia(SPEM) in Remnant Gastric Cancer and Surveillance Postgastrectomy Biopsies. Dig Dis Science 47：573-578, 2002
3. Yamaguchi H, Goldenring JR, Kaminishi M, Lee JR. Association of spasmolytic polyppeptide-expressing metaplasia with carcinogen adminstration and oxyntic atrophy in rats. Lab Invest 82: 1045-1052, 2002

７． 腸上皮化生の単クローン性

癌は１つの細胞から分裂増殖したものだといわれている。胃単一腺管も１つの細胞から分裂増殖した単位だといわれていた。しかし、正常胃腺管にも複数の細胞から分裂増殖したものがあることがわかった。前癌病変といわれている腸上皮化生では１つの細胞から分裂増殖した腺管の割合が増加しているかと思えば逆であり、複数の細胞から分裂増殖したものが半数以上あることがわかった。これより、骨髄細胞の取込みが予測された。

参考文献

1. Nomura S, Kaminishi M, Takagi N, Esumi H. Analysis of promotor region of X-linked pgk-1 gene polymorphisms : Evidence for polyclonality of adult mouse gastric glands, Dig Dis Sci 49: 218-223, 2004
2. Nomura S, Tatemichi M, Kaminishi M, Esumi G. A novel method for detecting single glandular intestinal metaplasia in the mucosal surface of the fixed stomach using methylene blue. Jpn J Cancer Res 92:659-665,2001
3. S Nomura，M Tatemichi，T Ogura，H Sano，N Nagata，H Esumi. Mutagenic Activation of Environmental Carcinogens by Microsomes of Gastric Mucosa with Intestinal Metaplasia, Cancer Res,59,3893-3898,1999
4. M Tatemichi, S Nomura, T Ogura, H Sone，H Nagata，H Esumi. Mutagenic activation of environmental carcinogenesis by microsomes of gastric mucosa with intestinal metaplasia. Cancer Res 59: 3893-3898,1999
5. Nomura S, Kaminishi M, Sugiyama K, Oohara T, Esumi H. Clonal analysis of isolated intestinal metaplastic glands using X linked polymorphism. GUT 42:663-668,1998
6. Nomura S, Kaminishi M, Sugiyama K, Oohara T, Esumi H. Clonal analysis of isolated single fundic and pyloric gland of stomach using X -linked polymorphism. Biochemical and Biophysical Research Communications 226:385-390,1996

８． 癌の浸潤・転移

参考文献

1. Shimoyama S, Kaminishi M. angiogenin in sera as an independent prognostic factor in gastric cancer. J cancer Res Clin Oncol 129:239-244, 2003
2. S. Shimoyama，N. Shimizu，E. Tsuji，K. Yamasaki，M. Kawahara，M. Kaminishi. Distribution of angiogenin and its gene message in colorectal cancer patients and their clinical relevance. Anticancer Res 22：1045-1052, 2002
3. Shimoyama S, Kaminishi M. Increased angiogenin expression in gastric cancer correlated with cancer progression. J Cancer Res Clin Oncol 126:468-474,2001
4. Shimoyama S, Kaminishi M. Angiogenin: Its clinical implications in malignancy. Austral-Asian J Cancer 1: 32-36, 2001
5. Tanaka S, Ueno H, Mafune K, Mori M, Wands JR, Sugimachi K. A novel isoform of human fibroblast growth factor 8 is induced by androgens and associated with progression of esophageal carcinoma. Dig Dis Sci 46: 1016-1021, 2000
6. Shimoyama S, Gansauge F, Gansauge S, Oohara T, Kaminishi M, Beger HG. Increased angiogenin expression in obstructive chronic pancreatitis surrounding pancreatic cancer but not in pure chronic pancreatitis. Pancreas 18:225-230,1999
7. S Shimoyama，F Gansauge，S Gansauge，M Kaminishi，HG Beger. Basal expression and cytokine induction of intercellular adhesion molecule-1 in human pancreatic cancer cell line. J Exp Clin Cancer Res 18:107-110, 1999
8. S Shimoyama，K Yamazaki，M Kawahara，M Kaminishi. Increased serum angiogenin concentration in colorectal cancer is correlated with cancer progression. Clin Cancer Res 5: 1125-1130, 1999

９． 消化器癌の分子メカニズム

胃発癌の母地として萎縮性胃炎があることは知られている。萎縮性胃炎の粘膜においては壁細胞が減少し、表層上皮細胞が増加する。また、TFF2が高発現する化生(SPEM)が生じる。通常のマウスとガストリンを持たないマウスに壁細胞を急性に殺す薬を投与し、急性の胃粘膜萎縮をおこさせ、粘膜細胞の構成の違いを観察したところ、表層上皮細胞の増加は高ガストリン血症により起こることがわかった。SPEMはガストリンを持たないマウスではむしろ早く生じることがわかった。

参考文献

1. Nomura S, Yamaguchi H, Ogawa M, Wang TC, Lee JR, Goldenring JR. Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild type and gastrin deficient mice. Am J Physiol 2005 (in press)
2. T. Tsukamoto, M Yamamoto, N. Ogasawara, T. Ushijima, T. Nomoto, H. Fujita, T. Matsushima, K. Nozaki, X. Cao. beta-Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas. Cancer Sci 94: 1046-1051, 2003
3. Kawahara M, Kammori M，Kanauchi H，Noguchi C，Kuramoto S，Endo H，Kaminishi M，Takubo K. Prognostic indicators of gastrointestinal carcinoid tumors, with special refrence to the immunohistochemical detection of p21, p53, E-cadherin, cyclin D1, Rb, bcl-2, and Ki-67. J Surg Oncol 28: 140-146, 2002
4. Imamura K, Ogura T, Kishimoto A, Kaminishi M, Esumi H. Cell Cycle Regulation via p53 Phosphorylation by a 5'-AMP Activated Protein Kinase Activator, 5-Aminoimidazole-4-Carboxamide-1-β-Ribofuranoside, in a human Hepatocellular Carcinoma Cell Line. Biochem Biophy Res Commun 287: 562-567, 2001

１０． 胃癌発生とDNAメチル化

DNA塩基配列そのものではなく、DNAの修飾要素として細胞分裂の際に娘細胞に情報伝達されるものを総称してエピジェネティクスと呼び、その代表がシトシンメチル化である。プロモーター領域のDNAメチル化は、胃癌発生において遺伝子不活化の主なメカニズムとなっている。
我々はこれまでに、遺伝子プロモーター領域のメチル化異常をゲノム網羅的・効率的に抽出できるよう、ゲノム解析法の改良を報告し、胃癌で異常メチル化によりサイレンシングされる遺伝子を新規に同定してきた。同定した遺伝子が高頻度にメチル化した胃癌は未分化型と強く相関し、メチル化異常の蓄積が胃癌組織型に関与する可能性を初めて報告した。同定した遺伝子のうち、Lysyl Oxidaseがメチル化及びLOHにより不活化される胃癌の新しい癌抑制遺伝子であることを発見した。ゲノム全体のメチル化シトシン量は多くの胃癌で逆に低下しており、正常でメチル化されているプロモーターや繰り返し配列の低メチル化と相関して起きること、プロモーターの異常メチル化とは独立して認められることも示した。また、一般人口の10%もの人に認められるエピジェネティクス異常であるIgf2インプリンティング消失が、腸管腫瘍リスクを上昇させることを動物モデルにより証明した。

参考文献

1. Sakatani T, Kaneda A, Iacobuzio-Donahue CA, Carter MG, Witzel SB, Okano H, Ko MSH, Ohlsson R, Longo DL, Feinberg AP. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science, Published online 24 February 2005; 10.1126/science.1108080.
2. Furuta J, Kaneda A, Umebayashi Y, Otsuka F, Sugimura T, Ushijima T. Silencing of the thrombomodulin gene in human malignant melanoma. Melanoma Res, 15:15-20, 2005.
3. Abe M, Ohira M, Kaneda A, Yagi Y, Yamamoto S, Kitano Y, Takato T, Nakagawara A, Ushijima T. CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas. Cancer Res, 65: 828-834, 2005.
4. Ushijima T, Watanabe N, Shimizu K, Miyamoto K, Sugimura T, Kaneda, A. Decreased fidelity in replicating CpG methylation patterns in cancer cells. Cancer Res, 65: 11-17, 2005.
5. Okochi-Takada E, Ichimura S, Kaneda A, Sugimura T, Ushijima, T. Establishment of a detection system for demethylating agents using an endogenous promoter CpG island. Mutat. Res, 568: 187-194, 2004.
6. Kaneda A, Wakazono K, Tsukamono T, Watanabe N, Yagi Y, Tatematsu M, Kaminishi M, Sugimura T, Ushijima, T. Lysyl Oxidase is a tumor-suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. Cancer Res, 64: 6410-6415, 2004.
7. Kaneda A, Kaminishi M, Sugimura T, Ushijima T. Decreased expression of the seven ARP2/3 complex genes in human gastric cancers. Cancer Lett, 212: 203-210, 2004.
8. Kaneda A, Tsukamoto T, Takamura-Enya T, Watanabe N, Kaminishi M, Sugimura T, Tatematsu M, Ushijima T. Frequent hypomethylation in multiple promoter CpG islands is associated with global hypomethylation, but not with frequent promoter hypermethylation. Cancer Sci, 95: 58-64, 2004.
9. Ushijima T, Watanabe N, Okochi E, Kaneda A, Sugimura T, Miyamoto K. Fidelity of the methylation pattern and its variation in the genome. Genome Res, 13: 868-874, 2003.
10. Kaneda A, Takai D, Kaminishi M, Okochi E, Ushijima T. Methylation-sensitive-representational difference analysis and its application to cancer research. Ann N Y Acad Sci, 983: 131-141, 2003.
11. Kaneda A, Kaminishi M, Yanagihara K, Sugimura T, Ushijima, T. Identification of silencing of nine genes in human gastric cancers. Cancer Res, 62: 6645-6650, 2002.
12. Abe M, Okochi E, Kuramoto T, Kaneda A, Takato T, Sugimura T, Ushijima T. Cloning of the 5' Upstream Region of the Rat p16 Gene and Its Role in Silencing. Jpn J Cancer Res, 93: 1100-1106, 2002.
13. Kaneda A, Kaminishi M, Nakanishi Y, Sugimura T, Ushijima T. Reduced expression of the insulin-induced protein 1 and p41 Arp2/3 complex genes in human gastric cancers. Int J Cancer, 100: 57-62, 2002.
14. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell, 109: 113-124, 2002.

１１． 胃癌発生とホメオボックス遺伝子

参考文献

1. Mizoshita T, Inada K, Tsukamoto T, Nozaki K, Joh T, Itoh M, Yamamura Y, Ushijima T, Nakamura S, Tatematsu M. Expression of the intestine-specific transcription factors, Cdx 1 and Cdx 2, correlats shift to an intestinal phenotype in gastric cancer cells. J Cancer Res Clin Oncol 130:29-36,2004

１２． 胃癌のマイクロアレイ解析

プロテオミクスを用いた胃癌と胃粘膜との比較は発癌のメカニズムを知る上で重要である。しかし、胃生険組織は小さく、プロテオミクスを行うに十分な量の組織が得られないこともある。シスチンというアミノ酸にラベルをすることにより、従来の方法よりも少ない量のタンパクでもプロテオミクス解析が可能であることがわかり、胃癌の解析に役立つものと思われる。

参考文献

1. Greengauz-Roberts O, Stoppler H, Nomura S, Yamaguchi H, Goldenring JR, Podolsky RH, Lee JR, Dynan WS. Saturation labeling with cysteine-reactive cyanine fluorescent dyes provides increased sensitivity for proten expression profiling of laser microdissected clinical specimens・ Proteomics 2005 (in press)

１３． 腹水細胞診のマイクロアレイによる治療・予後予測

胃癌再発予測診断系の開発と臨床応用

胃癌の微小な腹膜播種診断においてCEAは優れたマーカーであるが、偽陽性・偽陰性症例も存在する。そこでmicroarrayを用い包括的な遺伝子スクリーニングを行い、候補遺伝子12個を得た。このうち5遺伝子は定性的なnested PCRで応用可能であったが、迅速で客観的かつ正確な診断系の確立のため、Real-time PCRを導入し、特異度92%感度93%とCEA単独を上回る診断系を確立した。さらに腹膜再発以外の再発形式をも予測しており、独立した再発予後予測因子となりうることが示された。この診断系により、術中や術後の再発予防のための補助化学療法を行うべき症例の選別が可能となることが期待される。

また現在、一本のチューブで複数の遺伝子の発現を測定するMultiplex PT-PCR法と、キャノンとの共同開発によるカスタムアレイを組み合わせた高感度な診断系も構築中である。

参考文献

1. Mori K, Aoyagi K, Ueda T, Danjoh I, Tsubosa Y, Yanagihara K, Matsuno Y, sasako M, Sakamoto H, Mafune K, Kaminishi M, Yoshida T, Terada M, Sasaki H. Highly specific marker genes for detecting minimal gastric cancer cells in cytology negative peritoneal washings. BBRC 313:931-937, 2003

１４． 細胞分化と消化器癌

参考文献

1. K. Takubo，N. Honma，M. Sawabe，T. Arai，N. Izumiyama-Shimomura，M. Kammori，K. Sasajima，Y. Esaki. Oncocytic Adenocarcinoma of the Stomach: Parietal Cell Carcinoma. Am J Surg Pathol 26：458-465, 2002
2. Kawahara M, Kammori M, Kanauchi H, Noguchi C, Kuramoto S, Kaminishi M. Immunohistochemical prognostic indicators of gastrointestinal carcinoid tumors. Eur J Surg Oncol 28: 140-146,2001
3. Yoshikawa A, Inada K, Yamachika T, Shimizu N, Kaminishi M, Tatematsu M. Phenotypic shift in human differentiated gastric cancers from gastric to intestinal epithelial cell type during disease progression. Gastric Cancer 1:134-141, 1999
   Y. kehara，N Shimizu，M Kono，S Nishihara，H Nakanishi，T Kitamura，H Narimatsu，S Tsuji，M Tatematsu. A novel glycosyltransferase with a polyglutamine repeat; a new candidate for GDlα synthase (ST6GalNAc V). FEBS Lett 463: 92-96,1999
4. Yamachika, H Nakanishi, K Inada, T Tsukamoto, N Shimizu, K Kobayashi, S Fukushima, M Tatematsu. N-methyl-N-nitrosourea concentration-rather than total intake-dependent induction of undifferentiated adenocarcinomas in the glandular stomach of BALB/c mice. Jpn. J. Cancer Res. 89: 385-391,1998
5. K Inada, H Nakanishi, Y Fujimitsu, N Shimizu, M Ichinose, K Miki, S Nakamura, M.Tatematsu. Gastric and intestinal mixed and solely intestinal types of intestinal metaplasia in the human stomach. Pathology International 47:831-841,1998

１５． 癌に対する化学療法の腸管副作用防止の探索

参考文献

1. Tsuji E, Hiki N, Nomura S, Fukushima R, Kojima J, Ogawa T, Mafune K, Mimura Y, Kaminishi M. Simaltaneous onset of acute inflammatory response, sepsis-like symptoms and intestinal mucosal injury after cancer chemotherapy. Int J Cancer 107: 303-308, 2003

１６． テロメラーゼを用いた消化管癌の診断

参考文献

1. Ding H, Schertzer M, Wu X, Gertsenstein M, Selig S, Kammori M, Pourval R, Poon S, Vulto I, Chavez E, Tam PPL, Nagy A, Lansdorp PM. Regulation of murine telomere length by Rtel: An essential gene encoding a helicase-like protein. Cell 117: 872-886, 2004
2. Kammori M, Mafune K, Hashimoto M, Ogawa T, Kaminishi M, Takubo K. Clinical application of human telomerase reverse transcriptase gene expression in thyroid follicular tumors by fine-needle aspiration using in situ hybridization. Int J Oncol 22: 985-991, 2003
3. Kammori M, Nakamura K, Ogawa T, Mafune K, Tatutomi Y, Obara T, Onoda N, Fujiwara M, Izumiyama N, Mori M, Kaminishi M, Takubo K. Demonstration of human elomerase reverse transcriptase (hTERT) in human parathyroid tumors by in situ hybridization with a new oligonucleotide probe. Clinic Endocrinol 581:43-48, 2003
4. M. Kammori, K. Nakamura, H. Kamnauchi, T. Obara, M.Kawahara, Y. Mimura, M. Kaminishi, K. Takubo. Consistent decrease in telomere lemgth in parathyroid tumors but alteration in telomere activity limited to malignancies: Preliminary report. World J Surg 26: 1083-1087, 2002
5. M. Kammori, K. Nakamura, H. Kamnauchi, T. Obara, M.Kawahara, Y. Mimura, M. Kaminishi, K. Takubo. Consistent decrease in telomere lemgth in parathyroid tumors but alteration in telomere activity limited to malignancies: Preliminary report. World J Surg 26: 1083-1087, 2002
6. Kammori M, Kanauchi H, Nakamura T, Kawahara M,Weber T, Mafune K, Kaminishi M, Takubo K. Demonstration of human telomerase reverse transcriptase in human colorectal carcinomas by in situ hybridization. Int J Oncol 20:15-21,2002
7. H. Kanauchi，N. Wada，OH. Clark，QY. Duh. Apoptosis regulating genes，bcl-2 and bax，and human telomerase reverse transcriptase（hTERT）mRNA expression in adrenal tumors: Possible diagnostic and prognostic importance. Surgery 132：1021-1027, 2002
8. Kammori M, Takubo K, Nakamura K, Furugouri E, Endo H, Kanauchi H, Mimura Y, Kaminishi M. Telomerase activity and telomere length in benign and malignant human thyroid tissues. Cancer Letter 159:175-181,2000
9. K Takubo, K Nakamura, N Izumiyama, E Furugori, M Sawabe, T Arai, Y Esaki, K Mafune, M Kammori, M Fujiwara. Telomere shortening with aging in human liver. J Gerontol: BIOLOGICAL SCIENCES, 55 A(11) B533-B536, 2000
10. K Takubo, K Nakamura, N Izumiyama, M Sawabe, T Arai, Y Esaki, Y Tanaka, K Mafune, M Fujiwara, M Kammmori. Telomere shortening with aging in human esophageal mucosa. Age 22: 95-99, 2000
11. K Nakamura, E Furugori, Y Esaki, T Arai, M Sawabe, I Okayasu, M Fujiwara, M Kammori, K Mafune, M Kato. Correlation of telomere lengths in normal and cancers tissue in the large bowel. Cancer Lett 158: 179-184, 2000

１７． 消化管疾患に対する診断・治療

参考文献

1. Shimoyama S, Yasuda H, Hashimoto M, Tatsutomi Y, Aoki F, Mafune K, Kaminishi M. Linear array endoscopic ultrasonography for preoperative staging performance in gastric cardia cancer. Gastrointestinal Endoscopy 60:50-55, 2004
2. Shimoyama S, Aoki F, Kawahara M, Yahagi N, Motoi T, Kuramoto S, Kaminishi M. early gastric cancer development in a familial adenomatous polyposis patient. Dig Dis Sci 49:260-265, 2004
3. Shimoyama S, Seto Y, Aoki F, Ogawa T, Toma T, Endo H, Itouji T, Kaminishi M. A case of gastric cancer with metastasis to the gingiva. J Gastroenterol Hepatol 19:831-835, 2004
   Seto Y, Shimoyama S, Kitayama J, Mafune K, Kaminishi M, Aikou T, Arai K, Ohta K, Nashimoto , Yamagishi H. Lymph node metastasis and preoperative diagnosis of the depth of invasion in early gastric cancer. Gastric Cancer 4:34-38,2001
4. Kammori M, Seto Y, Haniuda N, Kawahara M, Takubo K, Endo H, Kaminishi M. A Case of Bone Metastasis from Gastric Carcinoma after a Nine-year Disease-free Interval. Jpn J Clin Oncol 31: 407-409, 2001
5. Shimoyama S, Kuramoto S, Kawahara M, Yamasaki K, EndoH, Murakami T, Kaminishi M. A rare case of pseudomyxoma peritonei presenting an unusual inguinal hernia and splenic metastasis. J Gastroenterol Hepatol 16: 825-829, 2001
6. Mafune K, Tanaka Y, Suda Y, Izumo T. Outcome of patients with non-Hodgkinユs lymphoma of the stomach after gastrectomy: Clinicopathologic study and reclassification according to the revised European-American lymphom a classification. Gastric Cancer 4: 137-143, 2001
7. K Mafune, Y Tanaka, K Takubo. Autopsy findings in patients with esophageal carcinoma: Comparison between resection and nonresection groups. J Surgical Oncol 74: 196 - 200, 2000
8. K Mafune, Y Tanaka. Influence of multimodality therapy on the cellular immunity of patients with esophageal cancer. Ann Surg Oncol 7: 609-616, 2000
9. S Nomura, M Sasako, H Katai, T Sano, K Maruyama. Decreasing complication rates with stapled esophagojejunostomy following a learning curve. Gastric Cancer 3: 97-101,2000
10. T Mimura, S Kuramoto, K Yamasaki, M Kaminishi. Familial adenomatous polyposis. J Clin Gastroenterol 28: 372-376, 2000
11. Tanaka S, Ueno H, Mafune K, Mori M, Wands JR, Sugimachi K. A novel isoform of human fibroblast growth factor 8 is induced by androgens and associated with progression of esophageal carcinoma. Dig Dis Sci 46: 1016-1021, 2000
12. Shimoyama S, Gansauge F, Gansauge S, Oohara T, Kaminishi M, Beger HG. Increased angiogenin expression in obstructive chronic pancreatitis surrounding pancreatic cancer but not in pure chronic pancreatitis. Pancreas 18:225-230,1999
13. HG.Beger, F Treitschke, F Gansauge, N Harada，N Hiki，T Mattfeldt, Tumor of the ampulla of Vater: experience with local or radical resection in 171 consecutively treated patients. Arch Surg ,134,526-532, 1999
14. M　Kammori，M　Kaminishi，K　Kobayashi ，H　Endo，H　Hashimoto，K　Takubo, Immunohistochemical analysis of PAI-2 (plasminogen activator inhibitor type 2) and p53 protein of early gastric cancer. A preliminary report. Jpn J Clin Oncol 29:187-191,1999
15. A.Yoshikawa, S Kuramoto, T Mimura, K Kobayashi, S Shimoyama, H Yasuda, M Kaminishi , M Yamakawa, T Oohara, T Murakami. Peutz-Jeghers Syndrome manifesting complete intussusception of the appendix and associated with a focal cancer of the doudenum and a cystadenocarcinoma of the Pancreas .Dis Colom Rectum 41:517-521, 1998
16. S Shimoyama, T Konishi, M Kawahara, K Hojo, Y Takeda, T Nagayama. Complete response of esophageal cancer achieved by combination therapy with 5-fluorouracil, low dose cisplatin and radiation: Repot of a case. Surgery Today 28:1163-1167,1998
17. S Shimoyama, T Konishi, . Kawahara, S.Araki, K Hojo, S Hamakawa, T Nagayama. A rare case of primary malignant mesothelioma originating from the rectovaginal tissue Hepato-Gastroenterol 45:1593-1597,1998

１８． 癌に対するminimally invasive surgery

参考文献

1. Shimoyama S, Mafune K, Kaminishi M. Indications for a pylus preserving gastrectomy for gastric cancer with proper muscle invasion. Arch Surg 138:1235-1239, 2003
2. Seto Y, Kaminishi M, Yafune A. An Experimental Study of Jejunal Pouch Replacements following Total Gastrectomy Hepatogastroenterol 49：853-856,2002
3. Shimoyama S, Yasuda H, Mafune K, Kaminishi M. Indications of a minimized surgery of lymphadenectomy for submucosal gastric cancer. Ann Surg Oncol 9: 625-631, 2002
4. Seto Y, Yamaguchi H, Shimoyama S, Shimizu N, Aoki F, Kaminishi M. Results of local resection with regional lymphadenectomy for early gastric cancer. Am J Surgery 182: 498-501, 2001
5. Shimoyama S, Seto Y, Yasuda H, Kaminishi M. Wider indications for the local resection of gastric cancer by adjacent lymphadenectomy. J Surg Oncol, 75: 157-164, 2000
6. Zang D, Shimoyama S, Kaminishi M. Feasibility of pylorus-preserving gastrectomy with a wider scope of lymphadenectomy. Archives of Surgery 133:993-997, 1998

１９． 腹腔鏡補助下手術

参考文献

HKanauchi, Y Mimura, N Hiki, M Kaminishi. Catecholamine and cytokine response to laparoscopic adrenalectomy in patients with pheochromocytoma. Biom Pharm 54 (Suppl) 1: 191-193, 2000

２０． リンパ節郭清の最適範囲

参考文献

1. Shimoyama S, Joujima Y, Yasuda H, Oohara T, Kaminishi M. Prospectively performed modified D1 lymphadenectomy for clinically diagnosed mucosal, node negative gastric cancer: Our findings over the past decade. Int Surg 85: 202-208, 2000
2. Kaminishi M, Shimoyama S, Yamaguchi H, Yamada H, Ogawa T, Kawahara M, Joujima Y, Oohara T. Results of subtotal gastrectomy with complete dissection of the N2 lymph nodes preserving the spleen and pancreas in gastric cancer operation. Hepato-gastroenterology 41:384 -387,1994

２１． センチネルリンパ節とマイクロメタ

参考文献

1. Kubota K, Nakanishi H, Hiki N, Shimizu N, Tsuji E, Yamaguchi H, Mafune K, Tange T, Tatematsu M, Kaminishi M. Quantitative detection of micrometastases in the lymph nodes of gastric cancer patients with real-time RT^PCR: A comparative study with immunihistochemistry. Int J Cancer 105:136-143, 2003

２２． 癌の標準・拡大治療の探索

参考文献

1. Shimoyama S, Aoki F, Shimizu N, Tasuomi Y, Mafune K, Kaminishi M. activiy and safety of a low dose, fractional administration of irinotecan hydrochloride (CPT-11) in combination with cisplatin for relapsed gastric cancer patients. A preliminart report. Int J Clin Oncol 81:49-52, 2003
2. Kubota K, KatoH, Tachimori Y, Watanabe H, Yamaguchi H, Nakanishi Y, Iinuma G. Surgical Therapy for Recurrent Esophageal Cancers at Anastomoses after Esophagectomy. Hepato-Gastroenterology 48:1364-1367,2001
3. Shimoyama S, Shimizu N, Kaminishi M. Type-oriented intraoperative and adjuvant chemotherapy and survival after curative resection of advanced gastric cancer. World Journal of Surgery 23:284- 292.1999
4. S. Shimoyama，Y. Mochizuki，O. Kusada，M. Kaminishi. Supra-additive antitumor activity of 5FU with tumor necrosis factor-related apoptosis-inducing ligand on gastric and colon cancers in vitro. Int J Oncol 21：643-648, 2002
5. Shimoyama S, Seto Y, Yasuda H, Kaminishi M. Wider indications for the local resection of gastric cancer by adjacent lymphadenectomy. J Surg Oncol, 75: 157-164, 2000
6. Kaminishi M, Yamaguchi H, Shimizu N, Nomura S, Yashikawa A, Hashimoto M, Sakai S, Oohara T. Stomach-partitioning gastrojejunostomy for unresectable gastric carcinoma. Archives of Surgery 132:184-187,1997

２３． 食道癌に対する術前放射線化学療法

参考文献

1. Shimoyama S, Aoki F, Murakami T, Toyoda K, Kaminishi M. The feasibility of daily concurrent chemoradiation therapy as a nonsurgical management for esophageal cancer: Our experience and theoretical backgrounds. J Surg Oncol 74: 134-137, 2000
2. Shimoyama S, Konishi T, kawahara M, Aoki F, Harada N, Shimizu N, Murakami T, Kaminishi M. Expression and alteration of p53 and p21 influence the sensitivity of chemoradiation therapy for esophageal cancer. Hepato-gastroenterology 45:1497-1504,1998

２４． ペパーミントオイルの消化管運動抑制効果の臨床応用

消化器内視鏡検査における消化管の過剰な蠕動は正確な診断の妨げとなり，微小癌などの微細な病変を見逃す原因となる．一般的にはScopolamine butylbromide (BuscopanR) や Glucagon などの抗蠕動 薬が使用されるが，BuscopanR は緑内障，前立腺肥大，不整脈などを有する患者には使用禁忌で、Glucagonは抗蠕動効果が非常に弱いなどの欠点がある．Peppermint oil (PO) はCalcium channel を介して腸管平滑筋の弛緩作用があることが知られている．そこでわれわれはPOを消化器内視鏡検査の抗蠕動薬として、上部・下部内視鏡、ERCPなどの診断や　ESDなどの治療に応用している．また、上部のバリウム造影検査や、超音波内視鏡への応用も現在検討中である．

参考文献

1. Hiki N, Kurosaka H, Tatsutomi Y, Shimoyama S, Tsuji E, Kojima J, Shimizu N, Ono H, Hirooka T, Noguchi C, Mafune K, Kaminishi M. Peppermint oil reduces gastric spasm during upper endoscopy: a randomized, double-blind, double-dummy controlled trial. Gastrointest Endosc 57:475-482, 2003

２５． 術後障害からみた胃切除後再建法の工夫

参考文献

1. Kubota K, Hiki N, Shimizu N, Noguchi C, Tange T, Mfune K, Kaminishi M. Utility of (c13) urea breath test for Helicobacter pylori infection in partial gastrectomy patients. Dig Dis Sci 4811:2135-2138, 2003
2. Kubota K, Shimoyama S，Shimizu N, Noguchi C, Mafune M，Kaminishi M. Tange T. Studies of 13C-urea breath test for diagnosis of Helicobacter pylori infection in patients after partial gastrectomy. Digestion 65：82-86, 2002

２６． 手術前後における胃・食道運動解析

参考文献

1. Kubota K, Shimizu N, Nozaki K, Takeshita Y, Ueda T, Imamura K, Hiki N, Yamaguchi H, Shimoyama S, Mafune K, Kaminishi M. Efficacy of triple therapy plus cetraxate for the Helicobacter pylori eradication in partial gastrectomy patients. Dig Dis Sci 2005 (in press)

２７． イレウスの発生機序

参考文献

1. Hiki N, Takeshita Y, Kubota K, Tsuji E, Yamaguchi H, Shimizu N, Imamura K, ShimoyamaS, Mafune K, Kaminishi M. A seasonal variation in the onset of postoperative adhesive small bowel obstruction is related to changes in the climate. Dig Liver Dis 36:125-129, 2004

２８． 外科侵襲とサイトカイン

参考文献

1. Hiki N, Mimura Y, Hatao F, Kojima J, Ogawa T, Tsuji E, Kaminishi M. Sublethal endotoxin administration evokes super-resistance to systemic hypoxia in rats. J Trauma injyry Infection Critical Care 54:584-589, 2003
2. Ogawa T, Nussler AK, Tuzuner E, Mimura Y, Kaminishi M,. Beger HG. Inhibition of nitric oxide synthase does not influence urinary nitrite plus nitrate excretion after renal ischemic injury. Langenbeck's . Arch Surg 386: 518-524, 2002
3. T. Ogawa，Y. Mimura，M. Kaminishi. Renal denervation abolishes the protective effects of ischaemic preconditioning on function and haemodynamics in ischaemia-reperfused rat kidneys. Acta Physiol Scand 174：291-297, 2002
4. Ogawa T, Nussler AK, Tuzumer E, Neuhaus P, Kaminishi M, Mimura Y, Beger HG. Contribution of nitric oxide to the protective effects of ischemic preconditioning in ischemia-reperfused rat kidneys. J Lab Clin Med 138: 50-58,2001
5. Asai K, Hiki N, Mimura Y, Ogawa T, Unou K, Kaminishi. M. Gender differences in cytokine secretion by human peripheral blood mononuclear cell:role of estrogen in modulating lps-induced cytokine secretion in an ex vivo septic model. Shock16: 340-343, 2001
6. Ogawa T, Mimura Y. Zink dificiency exacerbates functional disturbance in ischemia-reperfused rat kidneys. Biomed Res Trace Elements 12: 91-96, 2001
7. Hiki N, Mimura Y, Ogawa T, Kojima J, Hatao F, Kaminishi M. Pathophysiological relevance of the CD14 receptor in surgical patients: biological activity of endotoxin is regulated by the CD14 receptor. J Endotoxin Res 7: 1-6,2001
8. Hiki N, Berger D, Mimura Y, Frick J, Dentener MA, Buurman WA, Seidelmann M, Kaminishi M, Beger HG. Endotoxin binding proteins during major elective eurgery: rolr of sCD14 for phagocytic activation. World J Surg 24:499-506,2000
9. T Ogawa, Y Mimura, N Hiki, H Kanauchi, M Kaminishi. Ischaemic preconditioning ameliorates functional disturbance and impaired renal perfusion in rat ischaemia-reperused kidneys. Clin Experimental Pharmacol Physiol 27: 997-1001, 2000
10. N.Hiki ，D.Berge，M.A. Dentener，Y.Mimura，W.A.Buurman，C. Prigl，E.Tsuji，M.Kaminishi ，T.Oohara，H.G. Beger, Changes in endotoxin binding proteins during major elective surgery: Important role for sCD14 in regulating biological activity of systemic endotoxin, Clin Diag Lab Immunol　6: 844-850, 1999
11. T Ogawa，Y Mimura. Antioxidunt effect of zimc on acute renal failure induced by ischemia reperfusion injury in rats. Am J Nephrol 19: 609-614,1999
12. N.Hiki, Y.Mimura. Effect of renal denervation on phosphate excretion in endotoxemic rats.Endocrine J 44-1:379-744,1998
13. N Hiki, Y Mimura. Atrial natriuretic peptide has no potential to protect against endotoxin-induced acute renal failure in the absence of renal nerves. Endocrine J 45-1:75-81, 1998
14. N Hiki, D Berger, CPE Boelke, H Wiedeck, M Seidelmann, L Staib, T Oohara, M.Kaminishi, HG Beger. Endotoxin binding and elimination by monocytes: the secretion of soluble CD14 represents an inducible mechanism counteracting reduced expression of membrane CD14 during sepsis and in a patient with paroxysmal nocturnal hemoglobinuria. Infect.Immun 66-3: 1135-1141,1998
15. N.Hiki, Y Mimura. Atrial natriuretic peptide has no potential to protect against endotoxin-induced acute renal failure in the absence of renal nerves. Endocrine J. 45:75-81,1998