NOTCH Signaling is Required for Formation and Self-renewal of Tumor-initiating Cells and for Repression of Secretory Cell Differentiation in Colon Cancer

Overview

Journal Cancer Res

Specialty Oncology

Date 2010 Feb 11

PMID 20145124

Citations 148

Authors

Shaheen S Sikandar

Kira T Pate

Scott Anderson

Diana Dizon

Robert A Edwards

Marian L Waterman

Steven M Lipkin

Affiliations

Soon will be listed here.

Abstract

NOTCH signaling is critical for specifying the intestinal epithelial cell lineage and for initiating colorectal adenomas and colorectal cancers (CRC). Based on evidence that NOTCH is important for the maintenance and self-renewal of cancer-initiating cells in other malignancies, we studied the role of NOTCH signaling in colon cancer-initiating cells (CCIC). Tumors formed by CCICs maintain many properties of the primary CRCs from which they were derived, such as glandular organization, cell polarity, gap junctions, and expression of characteristic CRC molecular markers. Furthermore, CCICs have the property of self-renewal. In this study, we show that NOTCH signaling is 10- to 30-fold higher in CCIC compared with widely used colon cancer cell lines. Using small-molecule inhibition and short hairpin RNA knockdown, we show that NOTCH prevents CCIC apoptosis through repression of cell cycle kinase inhibitor p27 and transcription factor ATOH1. NOTCH is also critical to intrinsic maintenance of CCIC self-renewal and the repression of secretory cell lineage differentiation genes such as MUC2. Our findings describe a novel human cell system to study NOTCH signaling in CRC tumor initiation and suggest that inhibition of NOTCH signaling may improve CRC chemoprevention and chemotherapy.

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References

Kinzler K, Vogelstein B . Lessons from hereditary colorectal cancer. Cell. 1996; 87(2):159-70. DOI: 10.1016/s0092-8674(00)81333-1. View

Dalerba P, Dylla S, Park I, Liu R, Wang X, Cho R . Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007; 104(24):10158-63. PMC: 1891215. DOI: 10.1073/pnas.0703478104. View

Zhang H, Ye Y, Bai Z, Wang S . The COX-2 selective inhibitor-independent COX-2 effect on colon carcinoma cells is associated with the Delta1/Notch1 pathway. Dig Dis Sci. 2008; 53(8):2195-203. DOI: 10.1007/s10620-007-0139-0. View

Ricci-Vitiani L, Lombardi D, Pilozzi E, Biffoni M, Todaro M, Peschle C . Identification and expansion of human colon-cancer-initiating cells. Nature. 2006; 445(7123):111-5. DOI: 10.1038/nature05384. View

Akiyoshi T, Nakamura M, Yanai K, Nagai S, Wada J, Koga K . Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. Gastroenterology. 2008; 134(1):131-44. DOI: 10.1053/j.gastro.2007.10.008. View

Reedijk M, Odorcic S, Zhang H, Chetty R, Tennert C, Dickson B . Activation of Notch signaling in human colon adenocarcinoma. Int J Oncol. 2008; 33(6):1223-9. PMC: 2739737. DOI: 10.3892/ijo_00000112. View

Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters P . Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 1998; 19(4):379-83. DOI: 10.1038/1270. View

Andreu P, Colnot S, Godard C, Gad S, Chafey P, Niwa-Kawakita M . Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine. Development. 2005; 132(6):1443-51. DOI: 10.1242/dev.01700. View

Giardiello F, Hamilton S, KRUSH A, Piantadosi S, Hylind L, Celano P . Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993; 328(18):1313-6. DOI: 10.1056/NEJM199305063281805. View

10.

Hemming M, Elias J, Gygi S, Selkoe D . Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements. PLoS Biol. 2008; 6(10):e257. PMC: 2570425. DOI: 10.1371/journal.pbio.0060257. View

11.

Garzia L, Andolfo I, Cusanelli E, Marino N, Petrosino G, De Martino D . MicroRNA-199b-5p impairs cancer stem cells through negative regulation of HES1 in medulloblastoma. PLoS One. 2009; 4(3):e4998. PMC: 2656623. DOI: 10.1371/journal.pone.0004998. View

12.

Takahashi Y, Hayashi I, Tominari Y, Rikimaru K, Morohashi Y, Kan T . Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation. J Biol Chem. 2003; 278(20):18664-70. DOI: 10.1074/jbc.M301619200. View

13.

Guilmeau S, Flandez M, Bancroft L, Sellers R, Tear B, Stanley P . Intestinal deletion of Pofut1 in the mouse inactivates notch signaling and causes enterocolitis. Gastroenterology. 2008; 135(3):849-60, 860.e1-6. PMC: 3207497. DOI: 10.1053/j.gastro.2008.05.050. View

14.

Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li Y . Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 2006; 66(15):7445-52. DOI: 10.1158/0008-5472.CAN-06-0858. View

15.

Heitzler P, Bourouis M, Ruel L, Carteret C, Simpson P . Genes of the Enhancer of split and achaete-scute complexes are required for a regulatory loop between Notch and Delta during lateral signalling in Drosophila. Development. 1996; 122(1):161-71. DOI: 10.1242/dev.122.1.161. View

16.

Cho R, Clarke M . Recent advances in cancer stem cells. Curr Opin Genet Dev. 2008; 18(1):48-53. DOI: 10.1016/j.gde.2008.01.017. View

17.

De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm J . A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999; 398(6727):518-22. DOI: 10.1038/19083. View

18.

Longman R, Douthwaite J, Sylvester P, Poulsom R, Corfield A, Thomas M . Coordinated localisation of mucins and trefoil peptides in the ulcer associated cell lineage and the gastrointestinal mucosa. Gut. 2000; 47(6):792-800. PMC: 1728152. DOI: 10.1136/gut.47.6.792. View

19.

Nugent K, Farmer K, Spigelman A, Williams C, Phillips R . Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg. 1993; 80(12):1618-9. DOI: 10.1002/bjs.1800801244. View

20.

Cammareri P, Lombardo Y, Francipane M, Bonventre S, Todaro M, Stassi G . Isolation and culture of colon cancer stem cells. Methods Cell Biol. 2008; 86:311-24. DOI: 10.1016/S0091-679X(08)00014-9. View