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PMID: 10027409 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway.

The American journal of pathology ·Vol. 154 ·No. 2 ·1999-02-00 ·Pages 515-23

Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R, Clevers H, Pals ST

Abstract

Overexpression of cell surface glycoproteins of the CD44 family is an early event in the colorectal adenoma-carcinoma sequence. This suggests a link with disruption of APC tumor suppressor protein-mediated regulation of beta-catenin/Tcf-4 signaling, which is crucial in initiating tumorigenesis. To explore this hypothesis, we analyzed CD44 expression in the intestinal mucosa of mice and humans with genetic defects in either APC or Tcf-4, leading to constitutive activation or blockade of the beta-catenin/Tcf-4 pathway, respectively. We show that CD44 expression in the non-neoplastic intestinal mucosa of Apc mutant mice is confined to the crypt epithelium but that CD44 is strongly overexpressed in adenomas as well as in invasive carcinomas. This overexpression includes the standard part of the CD44 (CD44s) as well as variant exons (CD44v). Interestingly, deregulated CD44 expression is already present in aberrant crypt foci with dysplasia (ACFs), the earliest detectable lesions of colorectal neoplasia. Like ACFs of Apc-mutant mice, ACFs of familial adenomatous polyposis (FAP) patients also overexpress CD44. In sharp contrast, Tcf-4 mutant mice show a complete absence of CD44 in the epithelium of the small intestine. This loss of CD44 concurs with loss of stem cell characteristics, shared with adenoma cells. Our results indicate that CD44 expression is part of a genetic program controlled by the beta-catenin/Tcf-4 signaling pathway and suggest a role for CD44 in the generation and turnover of epithelial cells.

MeSH Terms
Adenoma/metabolism,pathology Adenomatous Polyposis Coli/genetics,metabolism,pathology Adult Animals Carcinoma/metabolism,pathology Cytoskeletal Proteins/genetics,metabolism DNA Primers/chemistry DNA, Neoplasm/analysis Female Fluorescent Antibody Technique, Indirect Genes, APC/genetics Humans Hyaluronan Receptors/analysis,biosynthesis Intestinal Mucosa/metabolism,pathology Intestinal Neoplasms/metabolism,pathology Male Mice Mice, Inbred C57BL Mice, Mutant Strains Proto-Oncogene Proteins/metabolism RNA, Messenger/biosynthesis Reverse Transcriptase Polymerase Chain Reaction Signal Transduction TCF Transcription Factors Trans-Activators Transcription Factor 7-Like 2 Protein Transcription Factors/genetics Wnt Proteins Zebrafish Proteins beta Catenin
Chemicals
CTNNB1 protein, human CTNNB1 protein, mouse Cytoskeletal Proteins DNA Primers DNA, Neoplasm Hyaluronan Receptors Proto-Oncogene Proteins RNA, Messenger TCF Transcription Factors TCF7L2 protein, human Tcf7l2 protein, mouse Trans-Activators Transcription Factor 7-Like 2 Protein Transcription Factors Wnt Proteins Zebrafish Proteins beta Catenin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Wielenga V J
Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
Smits R
Korinek V
Smit L
Kielman M
Fodde R
Clevers H
Pals S T
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)65297-2
Published
1999-02-00
Pages
515-23
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1850011
Subset
IM
External Links
PubMed source DOI: 10.1016/S0002-9440(10)65297-2 PMC Full Text View journal details
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