The development of duodenal microadenomas in FAP patients: the human correlate of the Min mouse.
The morphological changes associated with the adenoma-carcinoma sequence are well documented in the colorectum. Small intestinal carcinogenesis is thought to progress through a similar adenoma-to-carcinoma pathway, but there is a relative dearth of studies examining the associated morphological changes. The best-known mouse model of intestinal neoplasia, the multiple intestinal neoplasia (Min) mouse, has been criticized as a genetic model of intestinal neoplasia, as the majority of its tumours occur in the small intestine. We examined pancreatico-duodenal resection specimens from seven familial adenomatous polyposis (FAP) patients. Serial sections of these were stained with haematoxylin and eosin for beta-catenin and its downstream target CD44, for BMPR1a, lysozyme, carbonic anhydrase II, and with MIB-1. Individual dysplastic crypts were isolated and mutations in the FAP (APC) gene compared between the top and bottom of the crypt. We found that: (a) duodenal microadenomas are extremely common in FAP patients; (b) these grow in the core of duodenal villi, forming lesions similar to those described in the Min mouse; (c) many lesions arise as monocryptal adenomas and grow by a process of crypt fission and branching; (d) migrating adenomatous cells lose their dysplastic phenotype as they migrate up the crypt villous axis; and (e) Paneth cells lose positional information.


CONCLUSIONS
(a) the morphological similarity of adenomas in the Min mouse and human suggest the Min mouse is a good model of FAP; (b) duodenal adenomas in FAP originate in monocryptal adenomas and follow the 'bottom-up' rather than the 'top-down' model of morphogenesis; (c) early microadenomas show evidence of cellular differentiation; (d) defects in the positioning of Paneth cells suggests disruption of the EphB2:EphB3 receptor system.
Preston
S L
SL
Histopathology Unit, London Research Institute, Cancer Research UK, London, UK.
Leedham
S J
SJ
Oukrif
D
D
Deheregoda
M
M
Goodlad
R A
RA
Poulsom
R
R
Alison
M R
MR
Wright
N A
NA
Novelli
M
M
D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D004379:Duodenal Neoplasms / Q000235:genetics / Q000473:pathology*; D015870:Gene Expression; D017491:Genes, APC; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009154:Mutation; D019879:Paneth Cells / Q000473:pathology; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000473:pathology; D013194:Staining and Labeling; D051176:beta Catenin / Q000032:analysis
D018960:Hyaluronan Receptors; D051176:beta Catenin