This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Preston, S. L. Articles by Wright, N. A. Search for Related Content PubMed PubMed Citation Articles by Preston, S. L. Articles by Wright, N. A.

Bottom-up Histogenesis of Colorectal Adenomas

Origin in the Monocryptal Adenoma and Initial Expansion by Crypt Fission

Histopathology Unit, London Research Institute, Cancer Research UK, London WC2A 3PX, United Kingdom [S. L. P., R. P., R. J., R. A. G., N. M., G. E., N. A. W.]; Department of Histopathology, Barts and the London, Queen Mary’s School of Medicine and Dentistry, London E1 2AD, United Kingdom [S. L. P., N. A. W.]; Department of Medicine, Queen Mary Hospital, Hong Kong [W-M. W., A. O-O. C.]; Department of Histopathology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom [M. N.]; Cancer and Immunogenetics Laboratory, Cancer Research UK, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, United Kingdom [W. F. B.]; Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, United Kingdom [I. P. T.]; and Colorectal Unit, Cancer Research UK, St. Mark’s Hospital, Harrow, Middlesex HA1 3UI, United Kingdom [I. P. T.]

The adenoma:carcinoma sequence is well established. Understanding the molecular pathology of the adenoma is therefore important. There is great controversy within the field. The Vogelstein group champions the "top-down" theory (colorectal adenomas arise and grow across the mucosal surface and down into the crypts), whereas other studies, including our own, propose "bottom-up" spread. Serial sections of 40 small (<3 mm) sporadic colorectal adenomas were stained with H&E, MIB-1, and for ß-catenin. 10 early adenomas were Feulgen-stained and microdissected. We also examined the flat mucosa of three patients who had undergone colectomies for familial adenomatous polyposis (FAP) and specimens from a XO/XY individual with FAP, the latter using in situ hybridization for the Y chromosome. In the earliest sporadic adenomas, there were crypts entirely filled with adenomatous epithelium, which showed proliferative activity and nuclear localization of ß-catenin. There was a sharp cutoff between crypt epithelial cells showing nuclear ß-catenin and surface cells with membrane staining. In slightly larger lesions, adenomatous spread from above was seen. Microdissected adenomas showed multiple fission events, with proliferation distributed equally throughout. In FAP tissue, numerous isolated monocryptal adenomas, which were clonal in origin, were seen. Examination of adenomas in the XO/XY individual showed no instances of XY or XO adenomatous epithelium growing down into crypts of the other genotype. Both sporadic and FAP adenomas start as a unicryptal adenomas and grow initially by crypt fission—a bottom-up pattern. Later, in sporadic adenomas, there is evidence of growth down into adjacent crypts (top-down).

This article has been cited by other articles:

				A. Milicic, L.-A. Harrison, R. A. Goodlad, R. G. Hardy, A. M. Nicholson, M. Presz, O. Sieber, S. Santander, J. H. Pringle, N. Mandir, et al. Ectopic Expression of P-Cadherin Correlates with Promoter Hypomethylation Early in Colorectal Carcinogenesis and Enhanced Intestinal Crypt Fission In vivo Cancer Res., October 1, 2008; 68(19): 7760 - 7768. [Abstract] [Full Text] [PDF]

				A. Bilger, R. Sullivan, A. J. Prunuske, L. Clipson, N. R. Drinkwater, and W. F. Dove Widespread hyperplasia induced by transgenic TGF{alpha} in ApcMin mice is associated with only regional effects on tumorigenesis Carcinogenesis, September 1, 2008; 29(9): 1825 - 1830. [Abstract] [Full Text] [PDF]

				L Ricci-Vitiani, A Pagliuca, E Palio, A Zeuner, and R De Maria Colon cancer stem cells Gut, April 1, 2008; 57(4): 538 - 548. [Full Text] [PDF]

				S J Leedham and N A Wright Expansion of a mutated clone: from stem cell to tumour J. Clin. Pathol., February 1, 2008; 61(2): 164 - 171. [Abstract] [Full Text] [PDF]

				K. Mimori, K. Nishida, Y. Nakamura, K. Ieta, Y. Yoshikawa, A. Sasaki, H. Ishii, M. A. Alonso, and M. Mori Loss of MAL Expression in Precancerous Lesions of the Esophagus Ann. Surg. Oncol., May 1, 2007; 14(5): 1670 - 1677. [Abstract] [Full Text] [PDF]

				M. D. Johnston, C. M. Edwards, W. F. Bodmer, P. K. Maini, and S. J. Chapman Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer PNAS, March 6, 2007; 104(10): 4008 - 4013. [Abstract] [Full Text] [PDF]

				R. Leggett, J. Harrison, and A. Phipps Reliability of the ICRP'S dose coefficients for members of the public: IV. basis of the human alimentary tract model and uncertainties in model predictions Radiat Prot Dosimetry, February 1, 2007; 123(2): 156 - 170. [Abstract] [Full Text] [PDF]

				H. K. Roy, Y. L. Kim, Y. Liu, R. K. Wali, M. J. Goldberg, V. Turzhitsky, J. Horwitz, and V. Backman Risk Stratification of Colon Carcinogenesis through Enhanced Backscattering Spectroscopy Analysis of the Uninvolved Colonic Mucosa Clin. Cancer Res., February 1, 2006; 12(3): 961 - 968. [Abstract] [Full Text] [PDF]

				L. C. Greaves, S. L. Preston, P. J. Tadrous, R. W. Taylor, M. J. Barron, D. Oukrif, S. J. Leedham, M. Deheragoda, P. Sasieni, M. R. Novelli, et al. Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission PNAS, January 17, 2006; 103(3): 714 - 719. [Abstract] [Full Text] [PDF]

				R. Chen, P. S. Rabinovitch, D. A. Crispin, M. J. Emond, M. P. Bronner, and T. A. Brentnall The initiation of colon cancer in a chronic inflammatory setting Carcinogenesis, September 1, 2005; 26(9): 1513 - 1519. [Abstract] [Full Text] [PDF]

				F. Radtke and H. Clevers Self-Renewal and Cancer of the Gut: Two Sides of a Coin Science, March 25, 2005; 307(5717): 1904 - 1909. [Abstract] [Full Text] [PDF]

				P. Andreu, S. Colnot, C. Godard, S. Gad, P. Chafey, M. Niwa-Kawakita, P. Laurent-Puig, A. Kahn, S. Robine, C. Perret, et al. Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine Development, March 15, 2005; 132(6): 1443 - 1451. [Abstract] [Full Text] [PDF]

				T. Chiu, C. Santiskulvong, and E. Rozengurt EGF receptor transactivation mediates ANG II-stimulated mitogenesis in intestinal epithelial cells through the PI3-kinase/Akt/mTOR/p70S6K1 signaling pathway Am J Physiol Gastrointest Liver Physiol, February 1, 2005; 288(2): G182 - G194. [Abstract] [Full Text] [PDF]

				L. W. Slice, T. Chiu, and E. Rozengurt Angiotensin II and Epidermal Growth Factor Induce Cyclooxygenase-2 Expression in Intestinal Epithelial Cells through Small GTPases Using Distinct Signaling Pathways J. Biol. Chem., January 14, 2005; 280(2): 1582 - 1593. [Abstract] [Full Text] [PDF]

				B. M. Boman, R. Walters, J. Z. Fields, A. J. Kovatich, T. Zhang, G. A. Isenberg, S. D. Goldstein, and J. P. Palazzo Colonic Crypt Changes during Adenoma Development in Familial Adenomatous Polyposis: Immunohistochemical Evidence for Expansion of the Crypt Base Cell Population Am. J. Pathol., November 1, 2004; 165(5): 1489 - 1498. [Abstract] [Full Text] [PDF]

				M Brittan and N A Wright STEM CELL IN GASTROINTESTINAL STRUCTURE AND NEOPLASTIC DEVELOPMENT Gut, June 1, 2004; 53(6): 899 - 910. [Full Text] [PDF]

				Abstracts Gut, April 1, 2004; 53(suppl_3): a1 - a123. [Full Text] [PDF]