胃と腸45巻5号

2010年04月発行

特集 早期大腸癌2010

主題 3．大腸癌の発生・発育進展

2）形態的特徴と比較した早期大腸癌の発生・発育進展―遺伝子異常─文献考察

著者： 藤盛孝博¹ 廣瀬元彦¹² 尾形英生¹³ 田中宏幸¹ 山岸秀嗣¹ 藤盛友佳理¹ 鈴木克昌¹ 関川昭¹ 市川一仁¹ 冨田茂樹¹ 福井広一¹ 井村穣二¹ 寺野彰⁴ 五十嵐良典² 長廻紘⁵ 前田盛⁶

所属機関： ¹獨協医科大学病理学（人体分子） ²東邦大学（大森）消化器内科 ³獨協医科大学第1外科 ⁴獨協医科大学 ⁵東京女子医大消化器病センター ⁶兵庫県病院事業管理（病院局）

ページ範囲：P.631 - P.647

文献概要

要旨　早期大腸癌の発生・進展に関する最近の分子病理学的文献を紹介した．その中で以下を示した．（1）早期大腸癌をSM浸潤距離と簇出を組み合わせることでリンパ節転移高危険群の抽出が可能なこと，（2）E-cadherinなどの接着関連因子の減弱が転移と相関する，またある種のサイトカインの極性の変化もまた転移と関係する，（3）T. Tn細胞から生まれた転移性細胞株との比較で両者にわずかな遺伝子異常しかないことと種々の細胞膜に存在するサイトカインらが転写活性を上げることなどがわかった，（4）平坦型癌はras遺伝子の関与が少なく，同じ傾向がLST-NGにもみられ，平坦という組織学的な共通性がK-ras遺伝子変異の頻度に反映していると考えられた，（5）大腸癌においてp53の異常はその調整遺伝子の解析からみてほとんどの癌でp53遺伝子システムが異常であることがわかった，（6）動物実験モデルでp53ホモノックアウトにおいて平坦型癌が作製できた，（7）IBD cancerにおいてER遺伝子のメチル化やDNMT-1を解析することで癌化高危険群の検出に有効であることがわかった，（8）鋸歯状病変の細分類においてSSA/Pの認識が施設によって異なることがわかった，などである．分子病理学的な知識が一般化することで日常医療に役立つ可能性を示した．

参考文献

1）菅井有，幅野渉．大腸癌における分子異常．胃と腸 43 : 1965-1974, 2008

2）八尾隆史．大腸癌の発生・発育進展に関する病理学的解析．胃と腸 43 : 1957-1964, 2008

3）味岡洋一，岩永明人，渡辺順，他．炎症性腸疾患における癌化・発育進展─潰瘍性大腸炎における大腸癌の組織発生．胃と腸 43 : 1935-1946, 2008

4）尾田恭，加来英典，後藤英世，他．疫学，検診からみた大腸癌の発生・発育進展とその特徴．胃と腸 43 : 1884-1890, 2008

5）斉藤裕輔，富永素矢，小澤賢一郎，他．臨床病理学的観点からみた大腸癌の発生・発育過程とその特徴─大腸癌の発生における腺腫の癌化（adenoma-carcinoma sequence）とde novo発癌．胃と腸 43 : 1891-1896, 2008

6）藤盛孝博，山岸秀嗣，尾形英生，他．胃癌診断に必要な病理の知識．消内視鏡 22 : 18-36, 2010

7）Ueno H, Murphy J, Jass JR, et al. Tumour‘budding' as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology 40 : 127-132, 2002

8）Imai T. Growth patterns in human carcinoma. Their classification and relation to prognosis. Obstet Gynecol 16 : 296-308, 1960

9）河内洋，江石義信，小池盛雄，他．SM癌治療における簇出の意義．（監）武藤徹一郎，（編）杉原健一，藤盛孝博，五十嵐正広，他．大腸疾患NOW2009．pp127-132，日本メディカルセンター，東京，2009

10）Kitajima K, Fujimori T, Fujii S, et al. Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma : a Japanese collaborative study. J Gastroenterol 39 : 534-543, 2004

11）大熊誠尚，矢永勝彦，森正樹．大腸癌の分子生物学─大腸癌における癌幹細胞．大腸癌 Frontier 1 : 67-71, 2008

12）Ichikawa K, Fujimori T, Chibana Y, et al. In the field of gastrointestinal pathology. In Muto T, Mochizuki H, Masaki T（eds）. Tumor Budding in Colorectal Cancer. Nova Science Publishers Inc, New York, pp3-13, 2006

13）Hori H, Fujimori T, Fujii S, et al. Evaluation of tumor cell dissociation as a predictive marker of lymph node metastasis in submucosal invasive colorectal carcinoma. Dis Colon Rectum 48 : 938-945, 2005

14）Chibana Y, Fujii S, Ichikawa K, et al. Tumor cell dissociation score highly correlates with lymph node metastasis in superficial esophageal carcinoma. J Gastroenterol Hepatol 20 : 1371-1378, 2005

15）Kaihara T, Kawamata H, Imura J, et al. Redifferentiation and ZO-1 reexpression in liver-metastasized colorectal cancer : possible association with epidermal growth factor receptor-induced tyrosine phosphorylation of ZO-1. Cancer Sci 94 : 166-172, 2003

16）Kaihara T, Kusaka T, Nishi M, et al. Defferentiation and decreased expression of adhesion molecules, E-cadherin and Zo-1, in colorectal cancer are closely related to liver metastasis. J Exp Clin Cancer Res 22 : 117-123, 2003

17）Fidler IJ. Critical factors in the biology of human cancer metastasis : twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 50 : 6130-6138, 1990

18）Furihata T, Sakai T, Kawamata H, et al. A new in vivo model for studying invasion and metastasis of esophageal squamous cell carcinoma. Int J Oncol 19 : 903-907, 2001

19）Kawamata H, Furihata T, Omotehara F, et al. Identification of genes differentially expressed in a newly isolated human metastasizing esophageal cancer cell line, T. Tn-At1, by cDNA microarray. Cancer Sci 94 : 699-706, 2003

20）Yoshitake N, Fukui H, Yamagishi H, et al. Expression of SDF-1 alpha and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer. Br J Cancer 98 : 1682-1689, 2008

21）Weinberg RA. The Biology of Cancer. Garland Science, New York, 2006

22）Maeyama M, Koga H, Selvendiran K, et al. Switching in discoid domain receptor expressions in SLUG-induced epithelial-mesenchymal transition. Cancer 113 : 2823-2831, 2008

23）Graham TA, Weaver C, Mao F, et al. Crystal structure of a beta-catenin/T cf complex. Cell 103 : 885-896, 2000

24）Leber MF, Efferth T. Molecular principles of cancer invasion and metastasis（review）. Int J Oncol 34 : 881-895, 2009

25）Haggitt RC, Glotzbach RE, Soffer EE, et al. Prognostic factors in colorectal carcinomas arising in adenomas : implications for lesions removed by endoscopic polypectomy. Gastroenterology 89 : 328-336, 1985

26）松田尚久，藤井隆広，池原久朝，他．Ip・Isp型大腸癌の深達度診断─治療法決定のために．胃と腸 37 : 1559-1570, 2002

27）長廻紘，里中和広，平山大介，他．表面型早期大腸癌における腫瘍高の臨床病理学的検討．日消誌 88 : 763, 1991

28）田村智．de novo癌の発育過程─表面微細構造から．Intestine 13 : 403-410, 2009

29）Hirohashi S. Inactivasion of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol 153 : 333-339, 1998

30）日下利広，甲斐原司，佐野寧，他．大腸sm癌に対する内視鏡的切除の可能性─分子病理学的立場から．胃と腸 34 : 785-794, 1999

31）Auguste P, Lemiere S, Larrieu-Lahargue F, et al. Molecular mechanisms of tumor vascularization. Crit Rev Oncol Hematol 54 : 53-61, 2005

32）Abe A, Fukui H, Fujii S, et al. Involvement of cyclooxygenase-2 and vascular endothelial growth factor in vascularization and lymph node metastasis of colorectal cancers with submucosal invasion. J Gastroen Hepathol 22 : 1071-1077, 2007

33）藤盛孝博，長廻紘，里中和広，他．ras遺伝子異常からみた表面型早期大腸癌の特異性．胃と腸 27 : 111-117, 1992

34）Fujimori T, Satonaka K, Yamamura-Idei Y, et al. Non-involvement of ras mutations in flat colorectal adenomas and carcinomas. Int J Cancer 57 : 51-55, 1994

35）Kusaka T, Fukui H, Sano Y, et al. Analysis of K-ras codon 12 mutations and p53 overexpression in colorectal nodule-aggregating tumors. J Gastroen Hepathol 15 : 1151-1157, 2000

36）Minamoto T, Sawaguchi K, Mai M, et al. Infrequent K-ras activation in superficial-type（flat）colorectal adenomas and adenocarcinomas. Cancer Res 54 : 2841-2844, 1994

37）Yamagata S, Muto T, Uchida Y, et al. Lower incidence of K-ras codon 12 mutation in flat colorectal adenomas than in polypoid adenomas. Jpn J Cancer Res 85 : 147-151, 1994

38）Hasegawa H, Ueda M, Watanabe M, et al. K-ras gene mutations in early colorectal cancer...flat elevated vs polyp-forming cancer...Oncogene 10 : 1413-1416, 1995

39）日下利広，甲斐原司，藤井茂彦，他．IIcとLST非顆粒型の相違点と類似点─病理の立場から．早期大腸癌 4 : 349-356, 2000

40）Peyssonnaux C, Eychène A. The Raf/MEK/ERK pathway : new concepts of activation. Biol Cell 93 : 53-62, 2001

41）Kolch W. Meaningful relationships : the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351 : 289-305, 2000

42）Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 417 : 949-954, 2002

43）Yuen ST, Davies H, Chan TL, et al. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62 : 6451-6455, 2002

44）Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62 : 6997-7000, 2002

45）Singer G, Oldt R 3rd, Cohen Y, et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95 : 484-486, 2003

46）Chan TL, Zhao W, Leung SY, et al. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 63 : 4878-4881, 2003

47）Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107 : 1183-1188, 1994

48）Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2（COX-2）. Cell 29 : 803-809, 1996

49）Sano H, Kawahito Y, Wilder RL, et al. Expression of cycloocygenase-1 and -2 in human colorectal cancer. Cancer Res 55 : 3785-3789, 1995

50）Fujita M, Fukui H, Kusaka T, et al. Relationship between cyclooxygenase-2 expression and K-ras gene mutation in colorectal adenomas. J Gastroenterol Hepatol 15 : 1277-1281, 2000

51）Lane DP. Cancer. p53, guardian of the genome. Nature 358 : 15-16, 1992

52）Yao T, Utsunomiya T, Nagai E, et al. p53 expression patterns in colorectal adenomas and early carcinomas : a special reference to depressed adenoma and non-polypoid carcinoma. Pathol Int 46 : 962-967, 1996

53）Yukawa M, Fujimori T, Maeda S, et al. Comparative clinicopathological and immunohistochemical study of ras and p53 in flat and polypoid type colorectal tumors. Gut 35 : 1258-1261, 1994

54）Haupt Y, Maya R, Kazaz A, et al. Mdm2 promotes the rapid degradation of p53. Nature 387 : 296-299, 1997

55）Kaserer K, Schmaus J, Bethge U, et al. Staining patterns of p53 immunohistochemistry and their biological significance in colorectal cancer. J Pathol 190 : 450-456, 2000

56）Kressner U, Inganäs M, Byding S, et al. Prognostic value of p53 genetic changes in colorectal cancer. J Clin Oncol 17 : 593-599, 1999

57）Fujii S, Fujimori T, Chiba T. Usefulness of analysis of p53 alteration and observation of surface microstructure for diagnosis of ulcerative colitis-associated colorectal neoplasia. J Exp Clin Cancer Res 22 : 107-115, 2003

58）Fujii S, Katsumata D, Fujimori T. Limits of diagnosis and molecular markers for early detection of ulcerative colitis-associated colorectal neoplasia. Digestion 77 : 2-12, 2008

59）Horiuchi H, Kawamata H, Omotehara F, et al. Negative immunohistochemical staining of p53 protein does not always reflect wild-type p53 gene in cancer cells．J Gastroenterol 39 : 801-803, 2004

60）喜納勇，新井冨生．大腸癌の成立過程─とくにprogressionによる癌の成立．病理と臨 6 : 1052-1056, 1988

61）Takeda J, Kitajima K, Fujii S, et al. Inhibitory effects of etodolac a selective COX-2 inhibitor, on the occurrence of tumors in colitis-induced tumorigenesis model in rats. Oncol Rep 11 : 981-985, 2004

62）Fujii S, Fujimori T, Kawamata H, et al. Development of colonic neoplasia in p53 deficinet mice with experimental colitis induced by dextran sulphate sodium. Gut 53 : 710-716, 2004

63）Furihata T, Kawamata H, Kubota K, et al. Evaluation of the malignant potential of aberrant crypt foci by immunohistochemical staining for beta-catenin in inflammation-induced rat colon carcinogenesis. Int J Mol Med 9 : 353-358, 2002

64）Watanabe T, tada M, Nagai H, et al. Helicobacter pylori infection induces gastric cancer in mongolian gerbils. Gastroenterology 115 : 642-648, 1998

65）Colitic cancer．藤盛孝博．消化管の病理学，2版．医学書院，pp182-201，2008

66）Tominaga K, Fujii S, Mukawa K, et al. Prediction of colorectal neoplasia by quantitative methylation analysis of estrogen receptor gene in nonneoplatic epithelium from patients with ulcerative colitis. Clin Cancer Res 11 : 8880-8885, 2005

67）Rideell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease : standardized classification with provisional clinical applications. Hum Pathol 14 : 931-968,1983

68）斎藤奈津子，藤井茂彦，関川昭，他．発生─潰瘍性大腸炎合併大腸腫瘍における遺伝子異常の役割．Intestine 13 : 241-250, 2009

69）Tarmin L, Yin J, Harpaz N, et al. Adenomatous polyposis coli gene mutations in ulcerative colitis-associated dysplasias and cancers versus sporadic colon neoplasms. Cancer Res 55 : 2035-2038, 1995

70）Lashner BA, Shapiro BD, Husain A, et al. Evaluation of the usefulness of testing for p53 mutations in colorectal cancer surveillance for ulcerative colitis.Am J Gastroenterol 94 : 456-462, 1999

71）Hsieh CJ, Klump B, Holzmann K, et al. Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res 58 : 3942-3945, 1998

72）Mikami T, Yoshida T, Numata Y, et al. Low frequency of promoter methylation of 06-methylguanine DNA methyltransferase and hMLH1 in ulcerative colitis-associated tumors : comparison with sporadic colonic tumors. Am J Clin Pathol 127 : 366-373, 2007

73）Moriyama T, Matsumoto T, Nakamura S, et al. Hypermethylation of p14（ARF）may be predictive of colitis cancer in patients with ulcerative colitis. Dis Colon Rectum 50 : 1384-1392, 2007

74）Issa Jp, Ahuja N, Toyota M, et al. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 61 : 3573-3577, 2001

75）Sato F, Harpaz N, Shibata D, et al. Hypermethylation of the p14（ARF）gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res 62 : 1148-1151, 2002

76）Wheeler JM, Kim HC, Efstathiou JA, et al. Hypermethylation of the promoter region of the E-cadherin gene（CDH1）in sporadic and ulcerative colitis associated colorectal cancer. Gut 48 : 367-371, 2001

77）Fleisher AS, Esteller M, Harpaz N, et al. Microsatellite instability in inflammatory bowel disease─associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res 60 : 4864-4868, 2000

78）O'Sullivan JN, Bronner MP, Brentnall TA, et al. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet 32 : 280-284, 2002

79）Nishikawa M, Oshitani N, Matsumoto T, et al. Accumulation of mitochondrial DNA mutation with colorectal carcinogenesis in ulcerative colitis. Br J Cancer 93 : 331-337,2005

80）樫田博史，池原伸直，工藤進英，他．大腸鋸歯状病変における発育進展・癌化．胃と腸 43 : 1897-1910, 2008

81）江頭由太郎，芥川寛，枝川豪，他．大腸癌の発育進展における大腸鋸歯状病変の意義─早期大腸癌に合併する大腸鋸歯状病変の臨床病理学的検討．胃と腸 43 : 1911-1923, 2008

82）Torlakovic E, Snover DC. Serrated adenomatous polyposis in humans. Gastroenterology 110 : 748-755, 1996

83）Torlakovic E, Skovlund E, Snover DC, et al. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 27 : 65-81, 2003

84）Ajioka Y, Watanabe H, Jass JR, et al. Infrequent K-ras codon 12 mutaion in serrated adenomas of human colorectum. Gut 42 : 680-684, 1998

85）Jass JR. Hyperplastic-like polyps as precursors of microsatellite-unstable colorectal cancer. Am J Clin Pathol 119 : 773-775, 2003

86）O'Brien MJ, Yang S, Cleebanoff JL, et al. Hyperplastic（serrated）polyps of the colorectum : relationship of CpG island methylator phenotype and K-ras mutation to lacaton and histologic subtype. Am J Surg Pathol 28 : 423-434, 2004

87）Yang S, Farraye FA, Mack C, et al. BRAF and KRAS Mutations in hyperplastic polyps and serrated adenomas of the colorectum : relationship to histology CpG island methylator status. Am J Surg Pathol 28 : 1452-1459,2004

88）樋口哲郎，杉原健一．大腸鋸歯状病変の発癌．武藤徹一郎（監），杉原健一，藤盛孝博，五十嵐正広，他（編）．大腸疾患NOW2008．日本メディカルセンター，東京，pp102-108，2008

89）Torlakovic E, Gomez JD, Driman DK, et al. Sessile serrated adenoma（SSA）vs. traditional serrated adenoma（TSA）. Am J Surg Pathol 32 : 21-29, 2008

90）Wu JM, Montgomery EA, Lacobuzio-Donahue CA. Frequent beta-catenin nuclear labeling in sessile serrated polyps of the colorectum with neoplastic potential. Am J Clin Pathol 129 : 416-423, 2008

91）尾形英生，椿昌裕，加藤広行，他．病理の立場からHPとSSA/Pを分けるポイント．武藤徹一郎（監），藤盛孝博（編）．大腸疾患NOW2010（特別号）．日本メディカルセンター，pp162-170，2010

92）Yachida S, Mudali S, Martin SA, et al. Beta-catenin nuclear labeling is a common feature of sessile serrated adenomas and correlates with early neoplastic progression after BRAF activation. Am J Surg Pathol 33 : 1823-1832, 2009

93）Sheridan TB, Fenton H, Lewin MR, et al. Sessile serrated adenomas with low-and high-grade dysplasia and early carcinomas : an immunohistochemical study of serrated lesions“caught in the act”. Am J Clin Pathol 126 : 564-571, 2006

94）Owens R, Chiosea SI, Kuan SF. Selective expression of gastric mucin MUC6 in colonic sessile serrated adenoma but not in hyperplastic polyp aids in morphological diagnosis of serrated polyps. Mod Pathol 21 : 660-669, 2008

95）Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutasions and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359 : 1757-1765, 2008

96）Endo Y, Marusawa H, Kou T, et al. Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers. Gastroenterology 135:889-898, 2008

97）Tao Y, Hart J, Lichtenstein L, et al. Inducible heat shock protein 70 prevents multifocal flat dysplastic lesions and invasive tumors in an inflammatory model of colon cancer. Carcinogenesis 30:175-182, 2009