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Top-down morphogenesis of colorectal tumors
I M Shih1, T L Wang, G Traverso
1The Howard Hughes Medical Institute, Johns Hopkins Oncology Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Summary
Colorectal adenomas develop via a top-down mechanism, challenging the traditional stem cell origin theory. Genetically altered cells spread downwards, replacing normal cells in colon crypts.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- Tumorigenesis is fundamentally linked to stem cells, typically localized at the base of colon crypts.
- Early colorectal adenomas show dysplastic cells at the luminal surface, contrasting with normal-appearing cells at the crypt base.
Purpose of the Study:
- To investigate the discrepancy in cell morphology and genetic status between the top and base of crypts in early colorectal adenomas.
- To elucidate the mechanism of adenomatous polyp development in the colon.
Main Methods:
- Isolation and molecular characterization of cells from the bases and orifices of crypts in small colorectal adenomas.
- Analysis of genetic alterations, including adenomatous polyposis coli (APC) gene mutations, and gene expression patterns.
Main Results:
- Dysplastic cells at the crypt orifices exhibited APC gene alterations and neoplasia-associated gene expression.
- Cells at the crypt base lacked these genetic alterations and were not clonally related to the dysplastic cells above.
- Evidence suggests a top-down progression model for adenomatous polyp development.
Conclusions:
- Colorectal adenoma development may not originate from stem cells at the crypt base as traditionally believed.
- A top-down mechanism is proposed, where genetically altered superficial cells spread and replace normal crypts.
- This finding redefines the understanding of early colorectal tumorigenesis and colon stem cell function.