Colonic crypt changes during adenoma development in familial adenomatous polyposis: immunohistochemical evidence for expansion of the crypt base cell population - PubMed (original) (raw)

Colonic crypt changes during adenoma development in familial adenomatous polyposis: immunohistochemical evidence for expansion of the crypt base cell population

Bruce M Boman et al. Am J Pathol. 2004 Nov.

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.

PubMed Disclaimer

Figures

Figure 1

Immunostaining of normal crypts from control (non-FAP) patients (A, D, G, J) versus normal-appearing crypts from FAP patients (B, E, H, K) versus adenomatous crypts from FAP patients (C, F, I, L). Staining patterns are shown for hMSH2 (A–C), survivin (D–F), Ki67 (G–I), and p27 (J–L).

Figure 2

Immunostaining of normal colonic crypts (A, C, E) versus adenomatous crypts (B, D, F) from FAP patients for Bcl-2 (A, B); topoisomerase II (C, D), and p21WAF1/C1P1 (E, F).

Figure 3

Changes in proportions of different kinds of cells based on differential staining between normal control crypts (gray bars), normal-appearing FAP crypts (black bars), and adenomatous mucosa (white bars) from FAP patients. The proportion of cells expressing markers for the crypt base (where SCs reside) shows the greatest increase in adenomatous crypts relative to normal-appearing crypts.

Cited by

Stochastic model for cell population dynamics quantifies homeostasis in colonic crypts and its disruption in early tumorigenesis.
Mamis K, Zhang R, Bozic I. Mamis K, et al. Proc Biol Sci. 2023 Oct 25;290(2009):20231020. doi: 10.1098/rspb.2023.1020. Epub 2023 Oct 18. Proc Biol Sci. 2023. PMID: 37848058
Expression of Stem Cell Markers in High-LET Space Radiation-Induced Intestinal Tumors in _Apc_1638N/+ Mouse Intestine.
Kwiatkowski E, Suman S, Kallakury BVS, Datta K, Fornace AJ Jr, Kumar S. Kwiatkowski E, et al. Cancers (Basel). 2023 Aug 24;15(17):4240. doi: 10.3390/cancers15174240. Cancers (Basel). 2023. PMID: 37686516 Free PMC article.
The v8-10 variant isoform of CD44 is selectively expressed in the normal human colonic stem cell niche and frequently is overexpressed in colon carcinomas during tumor development.
Boman BM, Viswanathan V, Facey COB, Fields JZ, Stave JW. Boman BM, et al. Cancer Biol Ther. 2023 Dec 31;24(1):2195363. doi: 10.1080/15384047.2023.2195363. Cancer Biol Ther. 2023. PMID: 37005380 Free PMC article.
High Variability in Cellular Proliferation, Gene Expression, and Cytokine Production in the Nonneoplastic Colonic Epithelium of Young Apc+/Min-FCCC Mice.
Leystra AA, Harvey KN, Kaunga E, Hensley H, Vanderveer LA, Devarajan K, Clapper ML. Leystra AA, et al. Front Oncol. 2021 Aug 27;11:705562. doi: 10.3389/fonc.2021.705562. eCollection 2021. Front Oncol. 2021. PMID: 34513688 Free PMC article.
Retinoids as Chemo-Preventive and Molecular-Targeted Anti-Cancer Therapies.
Hunsu VO, Facey COB, Fields JZ, Boman BM. Hunsu VO, et al. Int J Mol Sci. 2021 Jul 20;22(14):7731. doi: 10.3390/ijms22147731. Int J Mol Sci. 2021. PMID: 34299349 Free PMC article. Review.

References

1. Bach SP, Renehan AG, Potten CS. Stem cells: the intestinal stem cell as a paradigm. Carcinogenesis. 2000;21:469–476. - PubMed
1. Potter JD. Colorectal cancer: molecules and populations. J Natl Cancer Inst. 1999;91:916–932. - PubMed
1. Moser AR, Dove WF, Roth KA, Gordon JI. The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol. 1992;116:1517–1526. - PMC - PubMed
1. Pierce GB, Stevens LC, Nakane PK. Ultrastructural comparison of differentiation of stem cells of adenocarcinomas of colon and breast with their normal counterparts. J Natl Cancer Inst. 1967;39:755–773. - PubMed
1. Boman BM, Fields JZ, Bonham-Carter O, Runquist OA. Computer modeling implicates stem cell overproduction in colon cancer initiation. Cancer Res. 2001;61:8408–8411. - PubMed

Colonic crypt changes during adenoma development in familial adenomatous polyposis: immunohistochemical evidence for expansion of the crypt base cell population - PubMed (original) (raw)