Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool.

Abstract

BACKGROUND & AIMS:

Adenomatous polyps are precursors to colorectal cancer (CRC), whereas hyperplastic polyps (HPPs) have low risk of progression to CRC. Mutations in KRAS are found in ∼40% of CRCs and large adenomas and a subset of HPPs. We investigated the reasons why HPPs with KRAS mutations lack malignant potential and compared the effects of Kras/KRAS activation with those of Apc/APC inactivation, which promotes adenoma formation.

METHODS:

We activated a KrasG12D mutant allele or inactivated Apc alleles in mouse colon epithelium and analyzed phenotypes and expression of selected genes and proteins. The mouse data were validated using samples of human HPPs and adenomas. Signaling pathways and factors contributing to Kras/KRAS-induced phenotypes were studied in intestinal epithelial cells.

RESULTS:

Activation of Kras led to hyperplasia and serrated crypt architecture akin to that observed in human HPPs. We also observed loss of Paneth cells and increases in goblet cell numbers. Abnormalities in Kras-mediated differentiation and proliferation required mitogen-activated protein kinase signaling and were linked to activation of the Hes1 transcription factor. Human HPPs also had activation of HES1. In contrast to Apc/APC inactivation, Kras/KRAS activation did not increase expression of crypt stem cell markers in colon epithelium or colony formation in vitro. Kras/KRAS activation was not associated with substantial induction of p16(INK4a) protein expression in mouse colon epithelium or human HPPs.

CONCLUSIONS:

Although Kras/KRAS mutation promotes serrated and hyperplastic morphologic features in colon epithelium, it is not able to initiate adenoma development, perhaps in part because activated Kras/KRAS signaling does not increase the number of presumptive stem cells in affected crypts.

• Authors: Ying Feng, Guido T Bommer, Jenny Zhao, Maranne Green, Evan Sands, Yali Zhai, Kelly Brown, Aaron Burberry, Kathleen R Cho, Eric R Fearon
• Journal: Gastroenterology (Gastroenterology) Vol. 141 Issue 3 Pg. 1003-1013.e1-10 (Sep 2011) ISSN: 1528-0012 [Electronic] United States
• PMID: 21699772 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Hes1 protein, mouse
• Homeodomain Proteins
• Transcription Factor HES-1
• HES1 protein, human
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Adenoma (pathology, physiopathology)
• Animals
• Basic Helix-Loop-Helix Transcription Factors (physiology)
• Cell Differentiation (physiology)
• Cell Line
• Cell Proliferation
• Colon (pathology, physiology)
• Colonic Polyps (pathology, physiopathology)
• Colorectal Neoplasms (pathology, physiopathology)
• Disease Models, Animal
• Disease Progression
• Homeodomain Proteins (physiology)
• Humans
• Hyperplasia
• Intestinal Mucosa (pathology, physiology)
• Mice
• Mice, Transgenic
• Mutation (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics, physiology)
• Signal Transduction (physiology)
• Stem Cells (pathology)
• Transcription Factor HES-1