臨床検査55巻5号

2011年05月発行

今月の主題 癌幹細胞と検査医学 各論

大腸癌

著者： 加藤弘¹ 山下継史¹ 渡邊昌彦¹

所属機関： ¹北里大学医学部外科

ページ範囲：P.489 - P.494

大腸癌は，遺伝子変異や修飾の蓄積で生じ進行する．これまで，この変化はすべての大腸上皮細胞に起きうると考えられてきたが，最近の研究で，臓器特異的幹細胞の存在が指摘され，大腸腺窩底部に位置する大腸幹細胞に遺伝子変異が蓄積し癌化する大腸癌幹細胞モデルが支持されている．この理論では，数％にも満たないわずかな癌細胞のみが腫瘍再形成能を有する．このレビューではまず，大腸腺窩の構造と大腸正常上皮幹細胞との関連を説明し，次に大腸癌幹細胞についての知見をまとめ，臨床応用の可能性についても議論する．

参考文献

1) Parkin DM, Bray F, Ferlay J, et al:Global cancer statistics, 2002. CA Cancer J Clin　55：74-108，2005

2) Cheng H, Bjerknes M, Amar J:Methods for the determination of epithelial cell kinetic parameters of human colonic epithelium isolated from surgical and biopsy specimens. Gastroenterology　86：78-85，1984

3) Potten CS, Kellett M, Rew DA, et al:Proliferation in human gastrointestinal epithelium using bromodeoxyuridine in vivo:data for different sites, proximity to a tumour, and polyposis coli. Gut　33：524-529，1992

4) Radtke F, Clevers H:Self-renewal and cancer of the gut:two sides of a coin. Science　307：1904-1909，2005

5) Fevr T, Robine S, Louvard D, et al:Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol Cell Biol　27：7551-7559，2007

6) Kosinski C, Li VS, Chan AS, et al:Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A　104：15418-15423，2007

7) Batlle E, Henderson JT, Beghtel H, et al:Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell　111：251-263，2002

8) Crosnier C, Stamataki D, Lewis J:Organizing cell renewal in the intestine:stem cells, signals and combinatorial control. Nat Rev Genet　7：349-359，2006

9) van Es JH, Clevers H:Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol Med　11：496-502，2005

10) Cheng H, Leblond CP:Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. Am J Anat　141：537-561，1974

11) Cheng H, Leblond CP:Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. I. Columnar cell. Am J Anat　141：461-479，1974

12) Cheng H, Leblond CP:Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Entero-endocrine cells. Am J Anat　141：503-519，1974

13) Cotsarelis G, Sun TT, Lavker RM:Label-retaining cells reside in the bulge area of pilosebaceous unit:implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell　61：1329-1337，1990

14) Kiel MJ, He S, Ashkenazi R, et al:Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature　449：238-242，2007

15) Nishimura S, Wakabayashi N, Toyoda K, et al:Expression of Musashi-1 in human normal colon crypt cells:a possible stem cell marker of human colon epithelium. Dig Dis Sci　48：1523-1529，2003

16) Kayahara T, Sawada M, Takaishi S, et al:Candidate markers for stem and early progenitor cells, Musashi-1 and Hes1, are expressed in crypt base columnar cells of mouse small intestine. FEBS Lett　535：131-135，2003

17) Fujimoto K, Beauchamp RD, Whitehead RH:Identification and isolation of candidate human colonic clonogenic cells based on cell surface integrin expression. Gastroenterology　123：1941-1948，2002

18) Holmberg J, Genander M, Halford MM, et al:EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell　125：1151-1163，2006

19) Sangiorgi E, Capecchi MR:Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet　40：915-920，2008

20) Gregorieff A, Clevers H:Wnt signaling in the intestinal epithelium:from endoderm to cancer. Genes Dev　19：877-890，2005

21) Katoh M:WNT signaling pathway and stem cell signaling network. Clin Cancer Res　13：4042-4045，2007

22) Batlle E, Bacani J, Begthel H, et al:EphB receptor activity suppresses colorectal cancer progression. Nature　435：1126-1130，2005

23) Barker N, van Es JH, Kuipers J, et al:Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature　449：1003-1007，2007

24) Sato T, Vries RG, Snippert HJ, et al:Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature　459：262-265，2009

25) Bonnet D, Dick JE:Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med　3：730-737，1997

26) Ponti D, Costa A, Zaffaroni N, et al:Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res　65：5506-5511，2005

27) O'Brien CA, Pollett A, Gallinger S, et al:A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature　445：106-110，2007

28) Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al:Identification and expansion of human colon-cancer-initiating cells. Nature　445：111-115，2007

29) Vogelstein B, Fearon ER, Hamilton SR, et al:Genetic alterations during colorectal-tumor development. N Engl J Med　319：525-532，1988

30) Gostjeva EV, Zukerberg L, Chung D, et al:Bell-shaped nuclei dividing by symmetrical and asymmetrical nuclear fission have qualities of stem cells in human colonic embryogenesis and carcinogenesis. Cancer Genet Cytogenet　164：16-24，2006

31) Dalerba P, Dylla SJ, Park IK, et al:Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A　104：10158-10163，2007

metastatic colon cancer cells initiate tumors. J Clin Invest　118：2111-2120，2008

33) Huang EH, Hynes MJ, Zhang T, et al:Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res　69：3382-3389，2009

34) Horst D, Kriegl L, Engel J, et al:CD133 expression is an independent prognostic marker for low survival in colorectal cancer. Br J Cancer　99：1285-1289，2008

35) Horst D, Kriegl L, Engel J, et al:CD133 and nuclear beta-catenin:the marker combination to detect high risk cases of low stage colorectal cancer. Eur J Cancer　45：2034-2040，2009

36) Ishii H, Iwatsuki M, Ieta K, et al:Cancer stem cells and chemoradiation resistance. Cancer Sci　99：1871-1877，2008

37) Dylla SJ, Beviglia L, Park IK, et al:Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One　3：e2428，2008

38) Bao S, Wu Q, McLendon RE, et al:Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature　444：756-760，2006

39) Todaro M, Alea MP, Di Stefano AB, et al:Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell　1：389-402，2007

40) Todaro M, Francipane MG, Medema JP, et al:Colon cancer stem cells:promise of targeted therapy. Gastroenterology　138：2151-2162，2010

41) Todaro M, Perez Alea M, Scopelliti A, et al:IL-4-mediated drug resistance in colon cancer stem cells. Cell Cycle　7：309-313，2008