胃と腸38巻1号

2003年01月発行

今月の主題 胃癌―診断と治療の最先端 主題

胃癌の生物学的悪性度に関する最新の知見

著者： 太田光彦¹ 三森功士¹ 岸原文明¹ 井上裕¹ 森正樹¹

所属機関： ¹九州大学生体防御医学研究所細胞機能制御学部門分子腫瘍学分野

ページ範囲：P.95 - P.106

　分子生物学的研究の進歩や解析法の開発により遺伝子病としての胃癌の姿がはっきりしてきた．臨床と直結した視点から生物学的悪性度に関して現在までの研究成果をみると，今日までに多くの興味深い遺伝子が報告されている．例えば，癌抑制遺伝子や癌遺伝子はもとより，細胞周期関連遺伝子p27やSkp2，プロテアーゼのMMPsやその阻害剤TIMPs，接着因子E-cadherin，βcatenin，血管新生因子のVEGF，dThdPaseやangiopoietin-2，ケモカインであるCCR7，など多くの遺伝子の変異が胃癌の悪性度と相関することがわかってきた．本稿では，新しい知見を基に特に胃癌の悪性度に関する報告をまとめた．個々の分子を検討して，臨床的に胃癌の悪性度を規定することは困難である．そこで，われわれはcDNAマイクロアレイを用いた解析で個々の症例の予後を判定する方法を開発したので紹介する．本法は今後ますます進む癌の個別診断，個別治療の先駆けとして期待されている．

参考文献

1）Motojima K, Furui J, Kohara N, et al. Expression of Kirsten-ras p 21 in gastric cancer correlates with tumor progression and is prognostic. Diagn Mol Pathol 3 : 184-191, 1994

2）Hattori Y, Odagiri H, Nakatani H, et al. K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes. Proc Natl Acad Sci USA 87 : 5983-5987, 1990

3）Tokunaga A, Onda M, Okuda T, et al. Clinical significance of epidermal growth factor (EGF), EGF receptor, and c-erbB-2 in human gastric cancer. Cancer 75 : 1418-1425, 1995

4）Nakajima M, Sawada H, Yamada Y, et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer 85 : 1894-1902, 1999

5）Lim BH, Soong R, Grieu F, et al. p53 accumulation and mutation are prognostic indicators of poor survival in human gastric carcinoma. Int J Cancer 69 : 200-204, 1996

6）Starzynska T, Markiewski M, Domagala W, et al. The clinical significance of p53 accumulation in gastric carcinoma. Cancer 77 : 2005-2012, 1996

7）Tamura G, Maesawa C, Suzuki Y, et al. Mutations of the APC gene occur during early stages of gastric adenoma development. Cancer Res 54 : 1149-1151, 1994

8）Wu CW, Chen GD, Jiang KC, et al. A genome-wide study of microsatellite instability in advanced gastric carcinoma. Cancer 92 : 92-101, 2001

9）Nakashima H, Hiroshi I, Mori M, et al. Microsatellite instability in Japanese gastric cancer. Cancer 75 : 1503, 1995

10）Chiaravalli AM, Cornaggia M, Furlan D, et al. The role of histological investigation in prognostic evaluation of advanced gastric cancer. Analysis of histological structure and molecular changes compared with invasive pattern and stage. Virchows Arch 439 : 158-169, 2001

11）Theuer CP, Campbell BS, Peel DJ, et al. Microsatellite instability in Japanese vs European American patients with gastric cancer. Arch Surg 137 : 960-966, 2002

12）Ohtani M, Isozaki H, Fujii K, et al. Impact of the expression of cyclin-dependent kinase inhibitor p 27 Kip 1 and apoptosis in tumor cells on the overall survival of patients with non-early stage gastric carcinoma. Cancer 85 : 1711-1718, 1999

13）Mori M, Mimori K, Shiraishi T, et al. p27 expression and gastric carcinoma. Nat Med 3 : 593, 1997

14）Masuda TA, Inoue H, Sonoda H, et al. Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma : modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. Cancer Res 62 : 3819-3825, 2002

15）Mori M, Mimori K, Yoshikawa Y, et al. Analysis of the gene-expression profile regarding the progression of human gastric carcinoma. Surgery 131 : S39-47, 2002

16）Honda M, Mori M, Ueo H, et al. Matrix metalloproteinase-7 expression in gastric carcinoma. Gut 39 : 444-448, 1996

17）Yamashita K, Azumano I, Mai M, et al. Expression and tissue localization of matrix metalloproteinase 7 (matrilysin) in human gastric carcinomas. Implicationsfor vessel invasion and metastasis. Int J Cancer 79 : 187-194, 1998

18）Inoue T, Yashiro M, Nishimura S, et al. Matrix metalloproteinase-1 expression is a prognostic factor for patients with advanced gastric cancer. Int J Mol Med 4 : 73-77, 1999

19）Allgayer H, Babic R, Grutzner KU, et al. Tumorassociated proteases and inhibitors in gastric cancer : analysis of prognostic impact and individual risk protease patterns. Clin Exp Metastasis 16 : 62-73, 1998

20）Mori M, Mimori K, Shiraishi T, et al. Analysis of MT1-MMP and MMP2 expression in human gastric cancers. Int J Cancer 74 : 316-321, 1997

21）Mimori K, Mori M, Shiraishi T, et al. Clinical significance of tissue inhibitor of metalloproteinase expression in gastric carcinoma. Br J Cancer 76 : 531-536, 1997

22）Nekarda H, Schmitt M, Ulm K, et al. Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res 54 : 2900-2907, 1994

23）Heiss MM, Babic R, Allgayer H, et al. Tumorassociated proteolysis and prognosis : new functional risk factors in gastric cancer defined by the urokinasetype plasminogen activator system. J Clin Oncol 13 : 2084-2093, 1995

24）Plebani M, Herszenyi L Cardin R, et al. Cysteine and serine proteases in gastric cancer. Cancer 76 : 367-375, 1995

25）Yamamichi K, Uehara Y, Kitamura N, et al. Increased expression of CD44v6 mRNA significantly correlates with distant metastasis and poor prognosis in gastric cancer. Int J Cancer 79 : 256-262, 1998

26）Lewis FR, Mellinger JD, Hayashi A, et al. Prophylactic total gastrectomy for familial gastric cancer. Surgery 130 : 612-619, 2001

27）Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature 392 : 402-405, 1998

28）Woo DK, Kim HS, Lee HS, et al. Altered expression and mutation of beta-catenin gene in gastric carcinomas and cell lines. Int J Cancer 95 : 108-113, 2001

29）Ishii Y, Ochiai A, Yamada T, et al. Integrin alpha6beta4 as a suppressor and a predictive marker for peritoneal dissemination in human gastric cancer. Gastroenterology 118 : 497-506, 2000

30）Tanigawa N, Amaya H, Matsumura M，et al. Correlation between expression of vascular endothelialgrowth factor and tumor vascularity, and patient outcome in human gastric carcinoma. J Clin Oncol 15 : 826-832, 1997

31）Maeda K, Kang SM, Onoda N, et al. Expression of p53 and vascular endothelial growth factor associated with tumor angiogenesis and prognosis in gastric cancer. Oncology 55 : 594-599, 1998

32）Konno H, Baba M, Tanaka T, et al. Overexpression of vascular endothelial growth factor is responsible for the hematogenous recurrence of early-stage gastric carcinoma. Eur Surg Res 32 : 177-181, 2000

33）Karayiannakis AJ, Syrigos KN, Polychronidis A, et al. Circulating VEGF levels in the serum of gastric cancer patients : correlation with pathological variables, patient survival, and tumor surgery. Ann Surg 236 : 37-42, 2002

34）Yoshikawa T, Tsuburaya A, Kobayashi O, et al. Plasma concentrations of VEGF and bFGF in patients with gastric carcinoma. Cancer Lett 153 : 7-12, 2000

35）Takebayashi Y, Miyadera K, Akiyama S, et al. Expression of thymidine phosphorylase in human gastric carcinoma. Jpn J Cancer Res 87 : 288-295, 1996

36）Tanigawa N, Amaya H, Matsumura M, et al. Tumor angiogenesis and expression of thymidine phosphorylase/platelet derived endothelial cell growth factor in human gastric carcinoma. Cancer Lett 108 : 281-290, 1996

37）Maeda K, Kang SM, Ogawa M, et al. Combined analysis of vascular endothelial growth factor and platelet-derived endothelial cell growth factor expression in gastric carcinoma. Int J Cancer 74 : 545-550, 1997

38）Kimura H, Konishi K, Nukui T, et al. Prognostic significance of expression of thymidine phosphorylase and vascular endothelial growth factor in human gastric carcinoma. J Surg Oncol 76 : 31-36, 2001

39）Konno S, Takebayashi Y, Aiba M, et al. Clinicopathological and prognostic significance of thymidine phosphorylase and proliferating cell nuclear antigen in gastric carcinoma. Cancer Lett 166 : 103-111, 2001

40）Osaki M, Sakatani T, Okamoto E, et al. Thymidine phosphorylase expression results in a decrease in apoptosis and increase in intratumoral microvessel density in human gastric carcinomas. Virchows Arch 437 : 31-36, 2000

41）Etoh T, Inoue H, Tanaka S, et al. Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma : possible in vivo regulation via induction of proteases. Cancer Res 61 : 2145-2153, 2001

42）Chen CN, Cheng YM, Lin MT, et al. Association of color Doppler vascularity index and microvessel density with survival in patients with gastric cancer. Ann Surg 235 : 512-518, 2002

43）Ansel KM, Ngo VN, Hyman PL, et al. A chemokinedriven positive feedback loop organizes lymphoid follicles. Nature 406 : 309-314, 2000

44）Mashino K, Sadanaga N, Yamaguchi H, et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res 62 : 2937-2941, 2002

45）Inoue H, Matsuyama A, Mimori K, et al. Prognostic score of gastric cancer determined by cDNA microarray. Clin Cancer Res 11 : 3475-3479, 2002