Current understanding concerning intestinal stem cells

World Journal of Gastroenterology

Volumn 22, Issue 31, 2016, Pages 7099-7110

  Cui, Shuang ^a   Chang, Peng Yu ^a  

^a THE FIRST HOSPITAL OF JILIN UNIVERSITY   (China)

Author keywords

Cell development; Colorectal cancer; Intestinal stem cell

Indexed keywords

APC PROTEIN; BETA CATENIN; CELL SURFACE MARKER; K RAS PROTEIN; MICRORNA; SMAD4 PROTEIN; G PROTEIN COUPLED RECEPTOR; LGR5 PROTEIN, HUMAN;

CARCINOGENESIS; CELL DIFFERENTIATION; CELL HETEROGENEITY; CELL PROLIFERATION; COLORECTAL CANCER; EXOSOME; EXPERIMENTAL COLITIS; HUMAN; INTESTINAL STEM CELL; INTESTINE CRYPT; INTESTINE MALFORMATION; INTESTINE VILLUS; MYOFIBROBLAST; NONHUMAN; PANETH CELL; REVIEW; SIGNAL TRANSDUCTION; STEM CELL EXPANSION; STEM CELL NICHE; STEM CELL TRANSPLANTATION; STOMACH ULCER; WNT SIGNALING PATHWAY; ANIMAL; COLORECTAL NEOPLASMS; CYTOLOGY; INFLAMMATORY BOWEL DISEASES; INTESTINE MUCOSA; PHYSIOLOGY; STEM CELL;

ANIMALS; COLORECTAL NEOPLASMS; HUMANS; INFLAMMATORY BOWEL DISEASES; INTESTINAL MUCOSA; RECEPTORS, G-PROTEIN-COUPLED; STEM CELL TRANSPLANTATION; STEM CELLS; STOMACH ULCER;

EID: 84982132579     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v22.i31.7099     Document Type: Review

References (109)

1. van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 2009; 71: 241-260 [PMID: 18808327 DOI: 10.1146/annurev. physiol.010908.163145]
2. Umar S. Intestinal stem cells. Curr Gastroenterol Rep 2010; 12: 340-348 [PMID: 20683682 DOI: 10.1007/s11894-010-0130-3]
3. van Es JH, Jay P, Gregorieff A, van Gijn ME, Jonkheer S, Hatzis P, Thiele A, van den Born M, Begthel H, Brabletz T, Taketo MM, Clevers H. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol 2005; 7: 381-386 [PMID: 15778706 DOI: 10.1038/ncb1240]
4. Li L, Clevers H. Coexistence of quiescent and active adult stem cells in mammals. Science 2010; 327: 542-545 [PMID: 20110496 DOI: 10.1126/science.1180794]
5. Jung P, Sato T, Merlos-Suárez A, Barriga FM, Iglesias M, Rossell D, Auer H, Gallardo M, Blasco MA, Sancho E, Clevers H, Batlle E, Isolation and in vitro expansion of human colonic stem cells. Nat Med 2011; 17: 1225-1227 [PMID: 21892181 DOI: 10.1038/nm.2470]
6. + stem cell. Nat Med 2012; 18: 618-623 [PMID: 22406745 DOI: 10.1038/nm.2695]
7. Sato T, Clevers H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 2013; 340: 1190-1194 [PMID: 23744940 DOI: 10.1126/science.1234852]
8. Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M, Barker N, Shroyer NF, van de Wetering M, Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 2011; 469: 415-418 [PMID: 21113151 DOI: 10.1038/nature09637]
9. Hirokawa Y, Yip KH, Tan CW, Burgess AW. Colonic myofibroblast cell line stimulates colonoid formation. Am J Physiol Gastrointest Liver Physiol 2014; 306: G547-G556 [PMID: 24481605 DOI: 10.1152/ajpgi.00267.2013]
10. Lei NY, Jabaji Z, Wang J, Joshi VS, Brinkley GJ, Khalil H, Wang F, Jaroszewicz A, Pellegrini M, Li L, Lewis M, Stelzner M, Dunn JC, Martín MG. Intestinal subepithelial myofibroblasts support the growth of intestinal epithelial stem cells. PLoS One 2014; 9: e84651 [PMID: 24400106 DOI: 10.1371/journal.pone.0084651]
11. Peiris D, Pacheco I, Spencer C, MacLeod RJ. The extracellular calcium-sensing receptor reciprocally regulates the secretion of BMP-2 and the BMP antagonist Noggin in colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol 2007; 292: G753-G766 [PMID: 17138967 DOI: 10.1152/ajpgi.00225.2006]
12. Roth S, Fodde R. The nature of intestinal stem cells' nurture. EMBO Rep 2011; 12: 483-484 [PMID: 21566649 DOI: 10.1038/embor.2011.97]
13. Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D, Boutros M, Cruciat CM, Niehrs C. LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO Rep 2011; 12: 1055-1061 [PMID: 21909076 DOI: 10.1038/embor.2011.175]
14. Binnerts ME, Kim KA, Bright JM, Patel SM, Tran K, Zhou M, Leung JM, Liu Y, Lomas WE, Dixon M, Hazell SA, Wagle M, Nie WS, Tomasevic N, Williams J, Zhan X, Levy MD, Funk WD, Abo A. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proc Natl Acad Sci USA 2007; 104: 14700-14705 [PMID: 17804805 DOI: 10.1073/pnas.0702305104]
15. Mustata RC, Van Loy T, Lefort A, Libert F, Strollo S, Vassart G, Garcia MI. Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo. EMBO Rep 2011; 12: 558-564 [PMID: 21508962 DOI: 10.1038/embor.2011.52]
16. Holmberg J, Genander M, Halford MM, Annerén C, Sondell M, Chumley MJ, Silvany RE, Henkemeyer M, Frisén J. EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 2006; 125: 1151-1163 [PMID: 16777604 DOI: 10.1016/j.cell.2006.04.030]
17. Pellegrinet L, Rodilla V, Liu Z, Chen S, Koch U, Espinosa L, Kaestner KH, Kopan R, Lewis J, Radtke F. Dll1-and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 2011; 140: 1230-1240.e1-7 [PMID: 21238454 DOI: 10.1053/j.gastro.2011.01.005]
18. He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, Tian Q, Zeng X, He X, Wiedemann LM, Mishina Y, Li L. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 2004; 36: 1117-1121 [PMID: 15378062 DOI: 10.1038/ng1430]
19. Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 2001; 294: 2155-2158 [PMID: 11739954 DOI: 10.1126/science.1065718]
20. Suzuki K, Fukui H, Kayahara T, Sawada M, Seno H, Hiai H, Kageyama R, Okano H, Chiba T. Hes1-deficient mice show precocious differentiation of Paneth cells in the small intestine. Biochem Biophys Res Commun 2005; 328: 348-352 [PMID: 15670790 DOI: 10.1016/j.bbrc.2004.12.174]
21. Barker N, van Oudenaarden A, Clevers H. Identifying the stem cell of the intestinal crypt: strategies and pitfalls. Cell Stem Cell 2012; 11: 452-460 [PMID: 23040474 DOI: 10.1016/j.stem.2012.09.009]
22. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449: 1003-1007 [PMID: 17934449 DOI: 10.1038/nature06196]
23. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009; 459: 262-265 [PMID: 19329995 DOI: 10.1038/nature07935]
24. Hua G, Thin TH, Feldman R, Haimovitz-Friedman A, Clevers H, Fuks Z, Kolesnick R. Crypt base columnar stem cells in small intestines of mice are radioresistant. Gastroenterology 2012; 143: 1266-1276 [PMID: 22841781 DOI: 10.1053/j.gastro.2012.07.106]
25. Schepers AG, Vries R, van den Born M, van de Wetering M, Clevers H. Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. EMBO J 2011; 30: 1104-1109 [PMID: 21297579 DOI: 10.1038/emboj.2011.26]
26. Maria Cambuli F, Rezza A, Nadjar J, Plateroti M. Brief report: musashi1-eGFP mice, a new tool for differential isolation of the intestinal stem cell populations. Stem Cells 2013; 31: 2273-2278 [PMID: 23712573 DOI: 10.1002/stem.1428]
27. Formeister EJ, Sionas AL, Lorance DK, Barkley CL, Lee GH, Magness ST. Distinct SOX9 levels differentially mark stem/progenitor populations and enteroendocrine cells of the small intestine epithelium. Am J Physiol Gastrointest Liver Physiol 2009; 296: G1108-G1118 [PMID: 19228882 DOI: 10.1152/ajpgi.00004.2009]
28. van der Flier LG, van Gijn ME, Hatzis P, Kujala P, Haegebarth A, Stange DE, Begthel H, van den Born M, Guryev V, Oving I, van Es JH, Barker N, Peters PJ, van de Wetering M, Clevers H. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 2009; 136: 903-912 [PMID: 19269367 DOI: 10.1016/j.cell.2009.01.031]
29. Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, van Es JH, Mohammed S, Heck AJ, Maurice MM, Clevers H. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 2012; 488: 665-669 [PMID: 22895187 DOI: 10.1038/nature11308]
30. Koo BK, van Es JH, van den Born M, Clevers H. Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43; Znrf3-mutant neoplasia. Proc Natl Acad Sci USA 2015; 112: 7548-7550 [PMID: 26023187 DOI: 10.1073/pnas.1508113112]
31. VanDussen KL, Carulli AJ, Keeley TM, Patel SR, Puthoff BJ, Magness ST, Tran IT, Maillard I, Siebel C, Kolterud Å, Grosse AS, Gumucio DL, Ernst SA, Tsai YH, Dempsey PJ, Samuelson LC. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 2012; 139: 488-497 [PMID: 22190634 DOI: 10.1242/dev.070763]
32. Van Limbergen J, Geddes K, Henderson P, Russell RK, Drummond HE, Satsangi J, Griffiths AM, Philpott DJ, Wilson DC. Paneth cell marker CD24 in NOD2 knockout organoids and in inflammatory bowel disease (IBD). Gut 2015; 64: 353-354 [PMID: 23704317 DOI: 10.1136/gutjnl-2013-305077]
33. Zeilstra J, Joosten SP, van Andel H, Tolg C, Berns A, Snoek M, van de Wetering M, Spaargaren M, Clevers H, Pals ST. Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling. Oncogene 2014; 33: 665-670 [PMID: 23318432 DOI: 10.1038/onc.2012.611]
34. Snippert HJ, van Es JH, van den Born M, Begthel H, Stange DE, Barker N, Clevers H. Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine. Gastroenterology 2009; 136: 2187-2194.e1 [PMID: 19324043 DOI: 10.1053/j.gastro.2009.03.002]
35. Levin TG, Powell AE, Davies PS, Silk AD, Dismuke AD, Anderson EC, Swain JR, Wong MH. Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract. Gastroenterology 2010; 139: 2072-2082.e5 [PMID: 20826154 DOI: 10.1053/j.gastro.2010.08.053]
36. Potten CS. Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos Trans R Soc Lond B Biol Sci 1998; 353: 821-830 [PMID: 9684279 DOI: 10.1098/rstb.1998.0246]
37. Potten CS, Owen G, Booth D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 2002; 115: 2381-2388 [PMID: 12006622]
38. Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD, Clevers H. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 2010; 143: 134-144 [PMID: 20887898 DOI: 10.1016/j.cell.2010.09.016]
39. Lopez-Garcia C, Klein AM, Simons BD, Winton DJ. Intestinal stem cell replacement follows a pattern of neutral drift. Science 2010; 330: 822-825 [PMID: 20929733 DOI: 10.1126/science.1196236]
40. Zhu Y, Huang YF, Kek C, Bulavin DV. Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations. Cell Stem Cell 2013; 12: 298-303 [PMID: 23415913 DOI: 10.1016/j.stem.2013.01.003]
41. Sangiorgi E, Capecchi MR. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 2008; 40: 915-920 [PMID: 18536716 DOI: 10.1038/ng.165]
42. Takeda N, Jain R, LeBoeuf MR, Wang Q, Lu MM, Epstein JA. Interconversion between intestinal stem cell populations in distinct niches. Science 2011; 334: 1420-1424 [PMID: 22075725 DOI: 10.1126/science.1213214]
43. Powell AE, Wang Y, Li Y, Poulin EJ, Means AL, Washington MK, Higginbotham JN, Juchheim A, Prasad N, Levy SE, Guo Y, Shyr Y, Aronow BJ, Haigis KM, Franklin JL, Coffey RJ. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 2012; 149: 146-158 [PMID: 22464327 DOI: 10.1016/j.cell.2012.02.042]
44. Montgomery RK, Carlone DL, Richmond CA, Farilla L, Kranendonk ME, Henderson DE, Baffour-Awuah NY, Ambruzs DM, Fogli LK, Algra S, Breault DT. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci USA 2011; 108: 179-184 [PMID: 21173232 DOI: 10.1073/pnas.1013004108]
45. Tian H, Biehs B, Warming S, Leong KG, Rangell L, Klein OD, de Sauvage FJ. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 2011; 478: 255-259 [PMID: 21927002 DOI: 10.1038/nature10408]
46. Yan KS, Chia LA, Li X, Ootani A, Su J, Lee J Y, Su N, Luo Y, Heilshorn SC, Amieva MR, Sangiorgi E, Capecchi MR, Kuo CJ. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci USA 2012; 109: 466-471 [PMID: 22190486 DOI: 10.1073/pnas.1118857109]
47. Metcalfe C, Kljavin NM, Ybarra R, de Sauvage FJ. Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 2014; 14: 149-159 [PMID: 24332836 DOI: 10.1016/j.stem.2013.11.008]
48. van Es JH, Sato T, van de Wetering M, Lyubimova A, Nee AN, Gregorieff A, Sasaki N, Zeinstra L, van den Born M, Korving J, Martens AC, Barker N, van Oudenaarden A, Clevers H. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 2012; 14: 1099-1104 [PMID: 23000963 DOI: 10.1038/ncb2581]
49. Buczacki SJ, Zecchini HI, Nicholson AM, Russell R, Vermeulen L, Kemp R, Winton DJ. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 2013; 495: 65-69 [PMID: 23446353 DOI: 10.1038/nature11965]
50. Clevers H. Stem Cells: A unifying theory for the crypt. Nature 2013; 495: 53-54 [PMID: 23446347 DOI: 10.1038/nature11958]
51. von Furstenberg RJ, Gulati AS, Baxi A, Doherty JM, Stappenbeck TS, Gracz AD, Magness ST, Henning SJ. Sorting mouse jejunal epithelial cells with CD24 yields a population with characteristics of intestinal stem cells. Am J Physiol Gastrointest Liver Physiol 2011; 300: G409-G417 [PMID: 21183658 DOI: 10.1152/ajpgi.00453.2010]
52. Chang PY, Jin X, Jiang YY, Wang LX, Liu YJ, Wang J. Mensenchymal stem cells can delay radiation-induced crypt death: impact on intestinal CD44(+) fragments. Cell Tissue Res 2016; 364: 331-344 [PMID: 26613604 DOI: 10.1007/s00441-015-2313-6]
53. Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S, Van Houdt WJ, Pronk A, Van Gorp J, Siersema PD, Clevers H. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 2011; 141: 1762-1772 [PMID: 21889923 DOI: 10.1053/j.gastro.2011.07.050]
54. Gracz AD, Ramalingam S, Magness ST. Sox9 expression marks a subset of CD24-expressing small intestine epithelial stem cells that form organoids in vitro. Am J Physiol Gastrointest Liver Physiol 2010; 298: G590-G600 [PMID: 20185687 DOI: 10.1152/ajpgi.00470.2009]
55. Gracz AD, Fuller MK, Wang F, Li L, Stelzner M, Dunn JC, Martin MG, Magness ST. Brief report: CD24 and CD44 mark human intestinal epithelial cell populations with characteristics of active and facultative stem cells. Stem Cells 2013; 31: 2024-2030 [PMID: 23553902 DOI: 10.1002/stem.1391]
56. Hou NY, Yang K, Chen T, Chen XZ, Zhang B, Mo XM, Hu JK. CD133+ CD44+ subgroups may be human small intestinal stem cells. Mol Biol Rep 2011; 38: 997-1004 [PMID: 20526812 DOI: 10.1007/s11033-010-0195-y]
57. Wang F, Scoville D, He XC, Mahe MM, Box A, Perry JM, Smith NR, Lei NY, Davies PS, Fuller MK, Haug JS, McClain M, Gracz AD, Ding S, Stelzner M, Dunn JC, Magness ST, Wong MH, Martin MG, Helmrath M, Li L. Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology 2013; 145: 383-95.e1-21 [PMID: 23644405 DOI: 10.1053/j.gastro.2013.04.050]
58. Li VS, Clevers H. In vitro expansion and transplantation of intestinal crypt stem cells. Gastroenterology 2012; 143: 30-34 [PMID: 22613623 DOI: 10.1053/j.gastro.2012.05.017]
59. Huch M, Dorrell C, Boj SF, van Es JH, Li VS, van de Wetering M, Sato T, Hamer K, Sasaki N, Finegold MJ, Haft A, Vries RG, Grompe M, Clevers H. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 2013; 494: 247-250 [PMID: 23354049 DOI: 10.1038/nature11826]
60. Huch M, Bonfanti P, Boj SF, Sato T, Loomans CJ, van de Wetering M, Sojoodi M, Li VS, Schuijers J, Gracanin A, Ringnalda F, Begthel H, Hamer K, Mulder J, van Es JH, de Koning E, Vries RG, Heimberg H, Clevers H. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J 2013; 32: 2708-2721 [PMID: 24045232 DOI: 10.1038/emboj.2013.204]
61. Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom R, Clevers H. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 2010; 6: 25-36 [PMID: 20085740 DOI: 10.1016/j.stem.2009.11.013]
62. Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H, Toda S, Sugihara H, Fujimoto K, Weissman IL, Capecchi MR, Kuo CJ. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med 2009; 15: 701-706 [PMID: 19398967 DOI: 10.1038/nm.1951]
63. Yin X, Farin HF, van Es JH, Clevers H, Langer R, Karp JM. Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny. Nat Methods 2014; 11: 106-112 [PMID: 24292484 DOI: 10.1038/nmeth.2737]
64. Clevers H. At the crossroads of inflammation and cancer. Cell 2004; 118: 671-674 [PMID: 15369667 DOI: 10.1016/j.cell.2004.09.005]
65. Zeuner A, Todaro M, Stassi G, De Maria R. Colorectal cancer stem cells: from the crypt to the clinic. Cell Stem Cell 2014; 15: 692-705 [PMID: 25479747 DOI: 10.1016/j.stem.2014.11.012]
66. Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, Canli O, Heijmans J, Huels DJ, Moreaux G, Rupec RA, Gerhard M, Schmid R, Barker N, Clevers H, Lang R, Neumann J, Kirchner T, Taketo MM, van den Brink GR, Sansom OJ, Arkan MC, Greten FR. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 2013; 152: 25-38 [PMID: 23273993 DOI: 10.1016/j.cell.2012.12.012]
67. Westphalen CB, Asfaha S, Hayakawa Y, Takemoto Y, Lukin DJ, Nuber AH, Brandtner A, Setlik W, Remotti H, Muley A, Chen X, May R, Houchen CW, Fox JG, Gershon MD, Quante M, Wang TC. Long-lived intestinal tuft cells serve as colon cancer-initiating cells. J Clin Invest 2014; 124: 1283-1295 [PMID: 24487592 DOI: 10.1172/JCI73434]
68. Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 2009; 457: 608-611 [PMID: 19092804 DOI: 10.1038/nature07602]
69. Adams PD, Jasper H, Rudolph KL. Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer. Cell Stem Cell 2015; 16: 601-612 [PMID: 26046760 DOI: 10.1016/j.stem.2015.05.002]
70. Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015; 347: 78-81 [PMID: 25554788 DOI: 10.1126/science.1260825]
71. Biswas S, Davis H, Irshad S, Sandberg T, Worthley D, Leedham S. Microenvironmental control of stem cell fate in intestinal homeostasis and disease. J Pathol 2015; 237: 135-145 [PMID: 25974319 DOI: 10.1002/path.4563]
72. Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R, Clevers H, Pals ST. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol 1999; 154: 515-523 [PMID: 10027409 DOI: 10.1016/S0002-9440(10)65297-2]
73. Davidson LA, Callaway ES, Kim E, Weeks BR, Fan YY, Allred CD, Chapkin RS. Targeted Deletion of p53 in Lgr5-Expressing Intestinal Stem Cells Promotes Colon Tumorigenesis in a Preclinical Model of Colitis-Associated Cancer. Cancer Res 2015; 75: 5392-5397 [PMID: 26631266 DOI: 10.1158/0008-5472.CAN-15-1706]
74. Drost J, van Jaarsveld RH, Ponsioen B, Zimberlin C, van Boxtel R, Buijs A, Sachs N, Overmeer RM, Offerhaus GJ, Begthel H, Korving J, van de Wetering M, Schwank G, Logtenberg M, Cuppen E, Snippert HJ, Medema JP, Kops GJ, Clevers H. Sequential cancer mutations in cultured human intestinal stem cells. Nature 2015; 521: 43-47 [PMID: 25924068 DOI: 10.1038/nature14415]
75. Liu Z, Dai W, Jiang L, Cheng Y. Over-expression of LGR5 correlates with poor survival of colon cancer in mice as well as in patients. Neoplasma 2014; 61: 177-185 [PMID: 24063790 DOI: 10.4149/neo-2014-016]
76. Demidov ON, Timofeev O, Lwin HN, Kek C, Appella E, Bulavin DV. Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine. Cell Stem Cell 2007; 1: 180-190 [PMID: 18371349 DOI: 10.1016/j.stem.2007.05.020]
77. Barry ER, Morikawa T, Butler BL, Shrestha K, de la Rosa R, Yan KS, Fuchs CS, Magness ST, Smits R, Ogino S, Kuo CJ, Camargo FD. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 2013; 493: 106-110 [PMID: 23178811 DOI: 10.1038/nature11693]
78. Gregorieff A, Liu Y, Inanlou MR, Khomchuk Y, Wrana JL. Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer. Nature 2015; 526: 715-718 [PMID: 26503053 DOI: 10.1038/nature15382]
79. Merlos-Suárez A, Barriga FM, Jung P, Iglesias M, Céspedes M V, Rossell D, Sevillano M, Hernando-Momblona X, da Silva-Diz V, Muñoz P, Clevers H, Sancho E, Mangues R, Batlle E. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 2011; 8: 511-524 [PMID: 21419747 DOI: 10.1016/j.stem.2011.02.020]
80. Sagiv E, Starr A, Rozovski U, Khosravi R, Altevogt P, Wang T, Arber N. Targeting CD24 for treatment of colorectal and pancreatic cancer by monoclonal antibodies or small interfering RNA. Cancer Res 2008; 68: 2803-2812 [PMID: 18413748 DOI: 10.1158/0008-5472.CAN-07-6463]
81. Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, Apuzzo T, Sperduti I, Volpe S, Cocorullo G, Gulotta G, Dieli F, De Maria R, Stassi G. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 2014; 14: 342-356 [PMID: 24607406 DOI: 10.1016/j.stem.2014.01.009]
82. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445: 111-115 [PMID: 17122771 DOI: 10.1038/nature05384]
83. Zhang SS, Han ZP, Jing YY, Tao SF, Li TJ, Wang H, Wang Y, Li R, Yang Y, Zhao X, Xu XD, Yu ED, Rui YC, Liu HJ, Zhang L, Wei LX. CD133(+)CXCR4(+) colon cancer cells exhibit metastatic potential and predict poor prognosis of patients. BMC Med 2012; 10: 85 [PMID: 22871210 DOI: 10.1186/1741-7015-10-85]
84. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, Clarke MF. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 2007; 104: 10158-10163 [PMID: 17548814 DOI: 10.1073/pnas.0703478104]
85. Pang R, Law WL, Chu AC, Poon JT, Lam CS, Chow AK, Ng L, Cheung LW, Lan XR, Lan HY, Tan VP, Yau TC, Poon RT, Wong BC. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 2010; 6: 603-615 [PMID: 20569697 DOI: 10.1016/j.stem.2010.04.001]
86. Gao W, Chen L, Ma Z, Du Z, Zhao Z, Hu Z, Li Q. Isolation and phenotypic characterization of colorectal cancer stem cells with organ-specific metastatic potential. Gastroenterology 2013; 145: 636-646.e5 [PMID: 23747337 DOI: 10.1053/j.gastro.2013.05.049]
87. Nakanishi Y, Seno H, Fukuoka A, Ueo T, Yamaga Y, Maruno T, Nakanishi N, Kanda K, Komekado H, Kawada M, Isomura A, Kawada K, Sakai Y, Yanagita M, Kageyama R, Kawaguchi Y, Taketo MM, Yonehara S, Chiba T. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat Genet 2013; 45: 98-103 [PMID: 23202126 DOI: 10.1038/ng.2481]
88. Goessling W, North TE, Loewer S, Lord AM, Lee S, Stoick-Cooper CL, Weidinger G, Puder M, Daley GQ, Moon RT, Zon LI. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell 2009; 136: 1136-1147 [PMID: 19303855 DOI: 10.1016/j.cell.2009.01.015]
89. Wang D, Fu L, Sun H, Guo L, DuBois RN. Prostaglandin E2 Promotes Colorectal Cancer Stem Cell Expansion and Metastasis in Mice. Gastroenterology 2015; 149: 1884-1895.e4 [PMID: 26261008 DOI: 10.1053/j.gastro.2015.07.064]
90. Chang PY, Qu YQ, Wang J, Dong LH. The potential of mesenchymal stem cells in the management of radiation enteropathy. Cell Death Dis 2015; 6: e1840 [PMID: 26247725 DOI: 10.1038/cddis.2015.189]
91. Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, Sevillano M, Palomo-Ponce S, Tauriello D V, Byrom D, Cortina C, Morral C, Barceló C, Tosi S, Riera A, Attolini CS, Rossell D, Sancho E, Batlle E. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet 2015; 47: 320-329 [PMID: 25706628 DOI: 10.1038/ng.3225]
92. Huynh PT, Beswick EJ, Coronado YA, Johnson P, O'Connell MR, Watts T, Singh P, Qiu S, Morris K, Powell DW, Pinchuk IV. CD90(+) stromal cells are the major source of IL-6, which supports cancer stem-like cells and inflammation in colorectal cancer. Int J Cancer 2016; 138: 1971-1981 [PMID: 26595254 DOI: 10.1002/ijc.29939]
93. Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, Gantt GA, Sukhdeo K, DeVecchio J, Vasanji A, Leahy P, Hjelmeland AB, Kalady MF, Rich JN. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med 2013; 210: 2851-2872 [PMID: 24323355 DOI: 10.1084/jem.20131195]
94. Zubeldia IG, Bleau AM, Redrado M, Serrano D, Agliano A, Gil-Puig C, Vidal-Vanaclocha F, Lecanda J, Calvo A. Epithelial to mesenchymal transition and cancer stem cell phenotypes leading to liver metastasis are abrogated by the novel TGFβ1-targeting peptides P17 and P144. Exp Cell Res 2013; 319: 12-22 [PMID: 23153552 DOI: 10.1016/j.yexcr.2012.11.004]
95. Jung T, Gross W, Zöller M. CD44v6 coordinates tumor matrix-triggered motility and apoptosis resistance. J Biol Chem 2011; 286: 15862-15874 [PMID: 21372142 DOI: 10.1074/jbc.M110.208421]
96. Zhang C, Zhou C, Wu XJ, Yang M, Yang ZH, Xiong HZ, Zhou CP, Lu YX, Li Y, Li XN. Human CD133-positive hematopoietic progenitor cells initiate growth and metastasis of colorectal cancer cells. Carcinogenesis 2014; 35: 2771-2777 [PMID: 25269803 DOI: 10.1093/carcin/bgu192]
97. Varol U, Yildiz I, Salman T, Karabulut B, Uslu R. Markers to predict the efficacy of bevacizumab in the treatment of metastatic colorectal cancer. Tumori 2014; 100: 370-376 [PMID: 25296585 DOI: 10.1700/1636.17888]
98. Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014; 30: 255-289 [PMID: 25288114 DOI: 10.1146/annurev-cellbio-101512-122326]
99. Hu Y, Yan C, Mu L, Huang K, Li X, Tao D, Wu Y, Qin J. Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer. PLoS One 2015; 10: e0125625 [PMID: 25938772 DOI: 10.1371/journal.pone.0125625]
100. Hong BS, Cho JH, Kim H, Choi EJ, Rho S, Kim J, Kim JH, Choi DS, Kim YK, Hwang D, Gho YS. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells. BMC Genomics 2009; 10: 556 [PMID: 19930720 DOI: 10.1186/1471-2164-10-556]
101. The exosomes in tumor immunity. Oncoimmunology 2015; 4: e1027472 [PMID: 26405598 DOI: 10.1080/2162402X.2015.1027472]
102. Cha DJ, Franklin JL, Dou Y, Liu Q, Higginbotham JN, Demory Beckler M, Weaver AM, Vickers K, Prasad N, Levy S, Zhang B, Coffey RJ, Patton JG. KRAS-dependent sorting of miRNA to exosomes. Elife 2015; 4: e07197 [PMID: 26132860 DOI: 10.7554/eLife.07197]
103. Matsumura T, Sugimachi K, Iinuma H, Takahashi Y, Kurashige J, Sawada G, Ueda M, Uchi R, Ueo H, Takano Y, Shinden Y, Eguchi H, Yamamoto H, Doki Y, Mori M, Ochiya T, Mimori K. Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer 2015; 113: 275-281 [PMID: 26057451 DOI: 10.1038/bjc.2015.201]
104. Ogata-Kawata H, Izumiya M, Kurioka D, Honma Y, Yamada Y, Furuta K, Gunji T, Ohta H, Okamoto H, Sonoda H, Watanabe M, Nakagama H, Yokota J, Kohno T, Tsuchiya N. Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS One 2014; 9: e92921 [PMID: 24705249 DOI: 10.1371/journal.pone.0092921]
105. Watanabe M. Adult tissue stem cell therapy for gastrointestinal diseases. J Gastroenterol Hepatol 2014; Epub ahead of print [PMID: 24547965 DOI: 10.1111/jgh.12555]
106. Quetglas EG, Mujagic Z, Wigge S, Keszthelyi D, Wachten S, Masclee A, Reinisch W. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. World J Gastroenterol 2015; 21: 12519-12543 [PMID: 26640330 DOI: 10.3748/wjg.v21.i44.12519]
107. Zhong XY, Yu T, Zhong W, Li JY, Xia ZS, Yuan YH, Yu Z, Chen QK. Lgr5 positive stem cells sorted from small intestines of diabetic mice differentiate into higher proportion of absorptive cells and Paneth cells in vitro. Dev Growth Differ 2015; 57: 453-465 [PMID: 26122164 DOI: 10.1111/dgd.12226]
108. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Multiplex genome engineering using CRISPR/Cas systems. Science 2013; 339: 819-823 [PMID: 23287718 DOI: 10.1126/science.1231143]
109. Bhattacharjee T, Zehnder SM, Rowe KG, Jain S, Nixon RM, Sawyer WG, Angelini TE. Writing in the granular gel medium. Sci Adv 2015; 1: e1500655 [PMID: 26601274 DOI: 10.1126/sciadv.1500655]