Inflammatory cues acting on the adult intestinal stem cells and the early onset of cancer (Review)

De Lerma Barbaro,A.; Perletti,G.; Bonapace,I. M.; Monti,E.

doi:10.3892/ijo.2014.2490

Inflammatory cues acting on the adult intestinal stem cells and the early onset of cancer (Review)

Authors:
- A. De Lerma Barbaro
- G. Perletti
- I. M. Bonapace
- E. Monti
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Affiliations: Biomedical Research Division, Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio, Varese, Italy
Published online on: June 10, 2014 https://doi.org/10.3892/ijo.2014.2490
Pages: 959-968
Copyright: © De Lerma Barbaro et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The observation that cancer often arises at sites of chronic inflammation has prompted the idea that carcinogenesis and inflammation are deeply interwoven. In fact, the current literature highlights a role for chronic inflammation in virtually all the steps of carcinogenesis, including tumor initiation, promotion and progression. The aim of the present article is to review the current literature on the involvement of chronic inflammation in the initiation step and in the very early phases of tumorigenesis, in a type of cancer where adult stem cells are assumed to be the cells of origin of neoplasia. Since the gastrointestinal tract is regarded as the best-established model system to address the liaison between chronic inflammation and neoplasia, the focus of this article will be on intestinal cancer. In fact, the anatomy of the intestinal epithelial lining is uniquely suited to study adult stem cells in their niche, and the bowel crypt is an ideal developmental biology system, as proliferation, differentiation and cell migration are all distributed linearly along the long axis of the crypt. Moreover, crypt stem cells are regarded today as the most likely targets of neoplastic transformation in bowel cancer. More specifically, the present review addresses the molecular mechanisms whereby a state of chronic inflammation could trigger the neoplastic process in the intestine, focusing on the generation of inflammatory cues evoking enhanced proliferation in cells not initiated but at risk of neoplastic transformation because of their stemness. Novel experimental approaches, based on triggering an inflammatory stimulus in the neighbourhood of adult intestinal stem cells, are warranted to address some as yet unanswered questions. A possible approach, the targeted transgenesis of Paneth cells, may be aimed at ‘hijacking’ the crypt stem cell niche from a status characterized by the maintenance of homeostasis to local chronic inflammation, with the prospect of initiating neoplastic transformation in that site.

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1	Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
2	Thun MJ, Henley SJ and Gansler T: Inflammation and cancer: an epidemiological perspective. Novartis Found Symp. 256:6–21. 2004. View Article : Google Scholar
3	Allavena P, Garlanda C, Borrello MG, Sica A and Mantovani A: Pathways connecting inflammation and cancer. Curr Opin Genet Dev. 18:3–10. 2008. View Article : Google Scholar
4	Colotta F, Allavena P, Sica A, Garlanda C and Mantovani A: Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 30:1073–1081. 2009. View Article : Google Scholar
5	Grivennikov SI, Greten FR and Karin M: Immunity, inflammation, and cancer. Cell. 140:883–899. 2010. View Article : Google Scholar
6	Trinchieri G: Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol. 30:677–706. 2012. View Article : Google Scholar : PubMed/NCBI
7	Boland C, Luciani M, Gasche C and Goel A: Infection, inflammation, and gastrointestinal cancer. Gut. 54:1321–1331. 2005. View Article : Google Scholar : PubMed/NCBI
8	Potten CS, Gandara R, Mahida YR, Loeffler M and Wright NA: The stem cells of small intestinal crypts: Where are they? Cell Prolif. 42:731–750. 2009. View Article : Google Scholar : PubMed/NCBI
9	Barker N, Ridgway RA, van Es JH, et al: Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 457:608–611. 2009. View Article : Google Scholar : PubMed/NCBI
10	Sangiorgi E and Capecchi MR: Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet. 40:915–920. 2008. View Article : Google Scholar : PubMed/NCBI
11	Dyson JK and Rutter MD: Colorectal cancer in inflammatory bowel disease: what is the real magnitude of the risk? World J Gastroenterol. 18:3839–3848. 2012. View Article : Google Scholar : PubMed/NCBI
12	Eaden JA, Abrams KR and Mayberry JF: The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 48:526–535. 2001. View Article : Google Scholar : PubMed/NCBI
13	Canavan C, Abrams KR and Mayberry J: Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn’s disease. Aliment Pharmacol Ther. 23:1097–1104. 2006.
14	Rubio CA, Befrits R, Ljung T, Jaramillo E and Slezak P: Colorectal carcinoma in ulcerative colitis is decreasing in Scandinavian countries. Anticancer Res. 21:2921–2924. 2001.
15	Jess T, Loftus EV Jr, Velayos FS, et al: Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted county, Minnesota. Gastroenterology. 130:1039–1046. 2006. View Article : Google Scholar
16	Winther KV, Jess T, Langholz E, Munkholm P and Binder V: Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County. Clin Gastroenterol Hepatol. 2:1088–1095. 2004. View Article : Google Scholar : PubMed/NCBI
17	Loftus EV Jr: Epidemiology and risk factors for colorectal dysplasia and cancer in ulcerative colitis. Gastroenterol Clin North Am. 35:517–531. 2006. View Article : Google Scholar : PubMed/NCBI
18	Ullman TA and Itzkowitz SH: Intestinal inflammation and cancer. Gastroenterology. 140:1807–1816. 2011. View Article : Google Scholar : PubMed/NCBI
19	Harpaz N and Polydorides AD: Colorectal dysplasia in chronic inflammatory bowel disease: pathology, clinical implications, and pathogenesis. Arch Pathol Lab Med. 134:876–895. 2010.
20	Riddell RH, Goldman H, Ransohoff DF, et al: Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol. 14:931–968. 1983. View Article : Google Scholar
21	Friedlich MS, Guindi M and Stern HS: The management of dysplasia associated with ulcerative colitis: colectomy versus continued surveillance. Can J Surg. 4:212–214. 2004.PubMed/NCBI
22	Kulaylat MN and Dayton MT: Ulcerative colitis and cancer. J Surg Oncol. 101:706–712. 2010. View Article : Google Scholar
23	Grivennikov SI and Karin M: Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev. 20:65–71. 2010. View Article : Google Scholar : PubMed/NCBI
24	Grivennikov S: Inflammation and colorectal cancer: colitisassociated neoplasia. Semin Immunopathol. 35:229–244. 2013. View Article : Google Scholar : PubMed/NCBI
25	Fearon ER and Vogelstein B: A genetic model for colorectal tumorigenesis. Cell. 61:759–767. 1990. View Article : Google Scholar : PubMed/NCBI
26	Xie J and Itzkowitz SH: Cancer in inflammatory bowel disease. World J Gastroenterol. 14:378–389. 2008. View Article : Google Scholar
27	Terzić J, Grivennikov S, Karin E and Karin M: Inflammation and colon cancer. Gastroenterology. 138:2101–2114. 2010.
28	Itzkowitz SH and Harpaz N: Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroenterology. 126:1634–1648. 2004. View Article : Google Scholar : PubMed/NCBI
29	Taylor BA, Pemberton JH, Carpenter HA, et al: Dysplasia in chronic ulcerative colitis: implications for colonoscopic surveillance. Dis Colon Rectum. 35:950–956. 1992. View Article : Google Scholar : PubMed/NCBI
30	Gorfine SR, Bauer JJ, Harris MT and Kreel I: Dysplasia complicating chronic ulcerative colitis: is immediate colectomy warranted? Dis Colon Rectum. 43:1575–1581. 2000. View Article : Google Scholar : PubMed/NCBI
31	Bernstein CN, Shanahan F and Weinstein WM: Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet. 343:71–74. 1994. View Article : Google Scholar : PubMed/NCBI
32	Rutter MD, Saunders BP, Wilkinson KH, et al: Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology. 130:1030–1038. 2006.PubMed/NCBI
33	Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB and Wilkinson KH: Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology. 107:934–944. 1994.PubMed/NCBI
34	Melville DM, Jass JR, Morson BC, et al: Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome. Hum Pathol. 20:1008–1014. 1989. View Article : Google Scholar
35	Sjöqvist U: Dysplasia in ulcerative colitis - clinical consequences? Langenbecks Arch Surg. 389:354–360. 2004.PubMed/NCBI
36	Deans C and Wigmore SJ: Systemic inflammation, cachexia and prognosis in patients with cancer. Curr Opin Clin Nutr Metab Care. 8:265–269. 2005. View Article : Google Scholar : PubMed/NCBI
37	Philip M, Rowley DA and Schreiber H: Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol. 14:433–439. 2004. View Article : Google Scholar : PubMed/NCBI
38	DeNardo DG, Johansson M and Coussens LM: Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev. 27:11–18. 2008. View Article : Google Scholar : PubMed/NCBI
39	Kalluri R: EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest. 119:1417–1419. 2009. View Article : Google Scholar : PubMed/NCBI
40	Luo Y, Yu M and Grady WM: Field cancerization in the colon: a role for aberrant DNA methylation? Gastroenterol Rep. 2:16–20. 2014.(Epub ahead of print).
41	Kaler P, Godasi BN, Augenlicht L and Klampfer L: The NFkappaB/AKT-dependent induction of Wnt signaling in colon cancer cells by macrophages and IL-1beta. Cancer Microenviron. 2:69–80. 2009. View Article : Google Scholar
42	Lee G, Goretsky T, Managlia E, et al: Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis. Gastroenterology. 139:869–881. 2010. View Article : Google Scholar
43	Oguma K, Oshima H, Aoki M, et al: Activated macrophages promote Wnt signalling through tumor necrosis factor-alpha in gastric tumor cells. EMBO J. 27:1671–1681. 2008. View Article : Google Scholar : PubMed/NCBI
44	Castellone MD, Teramoto H, Williams BO, Druey KM and Gutkind JS: Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science. 310:1504–1510. 2005. View Article : Google Scholar : PubMed/NCBI
45	Corvinus FM, Orth C, Moriggl R, et al: Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia. 7:545–555. 2005. View Article : Google Scholar : PubMed/NCBI
46	Yu H, Kortylewski M and Pardoll D: Crosstalk between cancer and immune cells: role of STAT3 in the tumor microenvironment. Nature Rev Immunol. 7:41–51. 2007. View Article : Google Scholar : PubMed/NCBI
47	Van Immerseel F, Ducatelle R, De Vos M, et al: Butyric acid-producing anaerobic bacteria as a novel probiotic treatment approach for inflammatory bowel disease. J Med Microbiol. 59:141–143. 2010.
48	Van der Sluis M, De Koning BA, De Bruijn AC, et al: Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 131:117–129. 2006.
49	Velcich A, Yang W, Heyer J, et al: Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 295:1726–1729. 2002. View Article : Google Scholar : PubMed/NCBI
50	Petersson J, Schreiber O, Hansson GC, et al: Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am J Physiol Gastrointest Liver Physiol. 300:G327–G333. 2011. View Article : Google Scholar : PubMed/NCBI
51	Arthur JC, Perez-Chanona E, Mühlbauer M, et al: Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 338:120–123. 2012. View Article : Google Scholar : PubMed/NCBI
52	Sharma S, Kelly TK and Jones PA: Epigenetics in cancer. Carcinogenesis. 31:27–36. 2010. View Article : Google Scholar
53	Suvà ML, Riggi N and Bernstein BE: Epigenetic reprogramming in cancer. Science. 339:1567–1570. 2013.
54	Chiba T, Marusawa H and Ushijima T: Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology. 143:550–563. 2012. View Article : Google Scholar
55	Niwa T and Ushijima T: Induction of epigenetic alterations by chronic inflammation and its significance on carcinogenesis. Adv Genet. 71:41–56. 2010. View Article : Google Scholar : PubMed/NCBI
56	Robertson KD: DNA methylation and human disease. Nat Rev Genet. 6:597–610. 2005. View Article : Google Scholar : PubMed/NCBI
57	Hahn MA, Hahn T, Lee DH, et al: Methylation of polycomb target genes in intestinal cancer is mediated by inflammation. Cancer Res. 68:10280–10289. 2008. View Article : Google Scholar : PubMed/NCBI
58	Cirri P and Chiarugi P: Cancer-associated-fibroblasts and tumor cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 31:195–208. 2012. View Article : Google Scholar
59	Achyut BR, Bader DA, Robles AI, et al: Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling. PLoS Genet. 9:e10032512013.PubMed/NCBI
60	El-Omar EM, Carrington M, Chow WH, et al: Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 404:398–402. 2000. View Article : Google Scholar : PubMed/NCBI
61	El-Omar EM, Carrington M, Chow WH, et al: The role of interleukin-1 polymorphisms in the pathogenesis of gastric cancer. Nature. 412:992001. View Article : Google Scholar : PubMed/NCBI
62	Chan AO, Chu KM, Huang C, et al: Association between Helicobacter pylori infection and interleukin 1beta polymorphism predispose to CpG island methylation in gastric cancer. Gut. 56:595–597. 2007.
63	Niwa T, Tsukamoto T, Toyoda T, et al: Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 70:1430–1440. 2010.
64	McLaughlan JM, Seth R, Vautier G, et al: Interleukin-8 and inducible nitric oxide synthase mRNA levels in inflammatory bowel disease at first presentation. J Pathol. 181:87–92. 1997. View Article : Google Scholar
65	Yoshida T, Yamashita S, Takamura-Enya T, et al: Alu and Satα hypomethylation in Helicobacter pylori-infected gastric mucosae. Int J Cancer. 128:33–39. 2011.
66	Semenza G: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar
67	Giles RH, Lolkema MP, Snijckers CM, et al: Interplay between VHL/HIF1alpha and Wnt/beta-catenin pathways during colorectal tumorigenesis. Oncogene. 25:3065–3070. 2006. View Article : Google Scholar
68	Shah YM, Ito S, Morimura K, Chen C, et al: Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology. 134:2036–2048. 2008. View Article : Google Scholar : PubMed/NCBI
69	Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, et al: Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 120:2699–2714. 2010. View Article : Google Scholar
70	Chaturvedi MM, Sung B, Yadav VR, Kannappan R and Aggarwal BB: NF-κB addiction and its role in cancer: ‘one size does not fit all’. Oncogene. 30:1615–1630. 2011.
71	Colgan SP, Curtis VF and Campbell EL: The inflammatory tissue microenvironment in IBD. Inflamm Bowel Dis. 19:2238–2244. 2013. View Article : Google Scholar : PubMed/NCBI
72	Colgan SP and Taylor CT: Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol. 7:281–287. 2010. View Article : Google Scholar : PubMed/NCBI
73	Clambey ET, McNamee EN, Westrich JA, et al: Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA. 109:E2784–E2793. 2012. View Article : Google Scholar
74	Olaru AV, Selaru FM, Mori Y, et al: Dynamic changes in the expression of MicroRNA-31 during inflammatory bowel disease-associated neoplastic transformation. Inflamm Bowel Dis. 17:221–231. 2011. View Article : Google Scholar : PubMed/NCBI
75	Gillies RJ and Gatenby RA: Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev. 26:311–317. 2007. View Article : Google Scholar : PubMed/NCBI
76	Covello KL, Kehler J, Yu H, et al: HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 20:557–570. 2006. View Article : Google Scholar : PubMed/NCBI
77	Edwards RA, Witherspoon M, Wang K, et al: Epigenetic repression of DNA mismatch repair by inflammation and hypoxia in inflammatory bowel disease-associated colorectal cancer. Cancer Res. 69:6423–6429. 2009. View Article : Google Scholar : PubMed/NCBI
78	Clevers H and Batlle E: SnapShot: the intestinal crypt. Cell. 152:1198. 2013. View Article : Google Scholar : PubMed/NCBI
79	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. View Article : Google Scholar : PubMed/NCBI
80	Barker N, van de Wetering M and Clevers H: The intestinal stem cell. Genes Dev. 22:1856–1864. 2008. View Article : Google Scholar
81	Li L and Clevers H: Coexistence of quiescent and active adult stem cells in mammals. Science. 327:542–545. 2010. View Article : Google Scholar : PubMed/NCBI
82	Shih IM, Wang TL, Traverso G, et al: Top-down morphogenesis of colorectal tumors. Proc Natl Acad Sci USA. 98:2640–2645. 2001. View Article : Google Scholar : PubMed/NCBI
83	Preston SL, Wong WM, Chan AO, et al: Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission. Cancer Res. 63:3819–3825. 2003.
84	Ward RJ and Dirks PB: Cancer stem cells: at the headwaters of tumor development. Annu Rev Pathol. 2:175–189. 2007. View Article : Google Scholar : PubMed/NCBI
85	Scheel C and Weinberg RA: Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells? Int J Cancer. 129:2310–2314. 2011. View Article : Google Scholar : PubMed/NCBI
86	Roskams T: Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene. 25:3818–3822. 2006. View Article : Google Scholar : PubMed/NCBI
87	El Marjou F, Janssen KP, Chang BH, et al: Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis. 39:186–193. 2004.PubMed/NCBI
88	Haigis KM, Hoff PD, White A, Shoemaker AR, Halberg RB and Dove WF: Tumor regionality in the mouse intestine reflects the mechanism of loss of Apc function. Proc Natl Acad Sci USA. 101:9769–9773. 2004. View Article : Google Scholar : PubMed/NCBI
89	Shaked H, Hofseth LJ, Chumanevich A, et al: Chronic epithelial NF-kappaB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation. Proc Natl Acad Sci USA. 109:14007–14012. 2012. View Article : Google Scholar : PubMed/NCBI
90	Kanneganti M, Mino-Kenudson M and Mizoguchi E: Animal models of colitis-associated carcinogenesis. J Biomed Biotechnol. 2011:3426372011. View Article : Google Scholar : PubMed/NCBI
91	Rowlatt C, Franks LM, Sheriff MU and Chesterman FC: Naturally occurring tumors and other lesions of the digestive tract in untreated C57BL mice. J Natl Cancer Inst. 43:1353–1364. 1969.PubMed/NCBI
92	Preston SL, Leedham SJ, Oukrif D, et al: The development of duodenal microadenomas in FAP patients: the human correlate of the Min mouse. J Pathol. 214:294–301. 2008. View Article : Google Scholar : PubMed/NCBI
93	Sato T, van Es JH, Snippert HJ, et al: Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 469:415–418. 2011. View Article : Google Scholar : PubMed/NCBI
94	Clevers HC and Bevins CL: Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol. 75:289–311. 2013. View Article : Google Scholar : PubMed/NCBI
95	Tu S, Bhagat G, Cui G, et al: Overexpression of interleukin 1β induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell. 14:408–419. 2008.
96	Sturlan S, Oberhuber G, Beinhauer BG, et al: Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. Carcinogenesis. 22:665–671. 2001. View Article : Google Scholar : PubMed/NCBI
97	Lala S, Ogura Y, Osborne C, et al: Crohn’s disease and the NOD2 gene: a role for Paneth cells. Gastroenterology. 125:47–57. 2003.
98	Medema JP and Vermeulen L: Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature. 474:318–326. 2011. View Article : Google Scholar : PubMed/NCBI
99	Scadden DT: The stem-cell niche as an entity of action. Nature. 441:1075–1079. 2006. View Article : Google Scholar
100	Barcellos-Hoff MH, Lyden D and Wang TC: The evolution of the cancer niche during multistage carcinogenesis. Nat Rev Cancer. 13:511–518. 2013. View Article : Google Scholar
101	Kemper K, Prasetyanti PR, De Lau W, Rodermond H, Clevers H and Medema JP: Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells. Stem Cells. 30:2378–2386. 2012. View Article : Google Scholar : PubMed/NCBI
102	Vaishnava S, Behrendt CL, Ismail AS, Eckmann L and Hooper LV: Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA. 105:20858–20863. 2008. View Article : Google Scholar
103	Gum JR Jr, Hicks JW, Gillespie AM, et al: Goblet cell-specific expression mediated by the MUC2 mucin gene promoter in the intestine of transgenic mice. Am J Physiol. 276:G666–G676. 1999.PubMed/NCBI