title: Colonic crypt changes during adenoma development in familial adenomatous polyposis: immunohistochemical evidence for expansion of the crypt base cell population.
abstract: Familial adenomatous polyposis patients, who have a germline APC mutation, develop adenomas in normal-appearing colonic mucosa, and in the process usually acquire a mutation in the other APC allele as well. Nonetheless, the cellular mechanisms that link these initiating genetic changes with the earliest tissue changes (upward shift in the labeling index) in colon tumorigenesis are unclear. Based on the tenet that colorectal cancer originates from crypt stem cells (SCs) and on our kinetic modeling, we hypothesized that overpopulation of mutant colonic SCs is the missing link. Directly testing this hypothesis requires measuring changes in the size of the SC population, but specific markers for human colonic SCs are lacking. Hence, we used immunohistochemical mapping to study crypt base cells, of which SCs are a subset. Using colectomy specimens from 16 familial adenomatous polyposis and 11 control cases, we determined the topographic profiles of various cell populations along the crypt axis and the proportions of each cell type. In the formation of adenomatous crypts, the distribution of cells expressing crypt base cell markers (MSH2, Bcl-2, survivin) expanded toward the crypt surface and showed the greatest proportional increase (fivefold to eightfold). Cells expressing a marker for the upper crypt (p27(kip1)) shifted to the crypt bottom and showed the smallest increase. This suggests that: 1) during adenoma development, APC mutations cause expansion of the crypt base cell population, including crypt SCs; 2) SC overpopulation can explain the shifts in pattern of proliferative crypt cell populations in early colon tumorigenesis, and 3) mutant crypt SCs clonally expand to form colonic adenomas and carcinomas.
authors.affiliation: Division of Genetic and Preventive Medicine, Kimmel Cancer Center, 1100 Walnut St., Suite 400, Thomas Jefferson University, Philadelphia PA 19107, USA. bruce.boman@mail.tju.edu
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Boman
authors.forename: Rhonda
authors.initials: R
authors.lastname: Walters
authors.forename: Jeremy Z
authors.initials: JZ
authors.lastname: Fields
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kovatich
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Isenberg
authors.forename: Scott D
authors.initials: SD
authors.lastname: Goldstein
authors.forename: Juan P
authors.initials: JP
authors.lastname: Palazzo
mesh_terms: D000236:Adenoma / Q000473:pathology*; D011125:Adenomatous Polyposis Coli / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D014408:Biomarkers, Tumor; D002277:Carcinoma / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D003106:Colon / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27