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. 1999 Feb;154(2):515-23.
doi: 10.1016/S0002-9440(10)65297-2.

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

V J Wielenga  1 , R Smits, V Korinek, L Smit, M Kielman, R Fodde, H Clevers, S T Pals
Affiliations

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

V J Wielenga et al. Am J Pathol. 1999 Feb.

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.

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Figures

Figure 1.
Figure 1.
A: Schematic representation of the CD44 gene. Open boxes indicate exons that can be alternatively spliced. TM, transmembrane region. B and C: Schematic representation of the CD44 protein with localizations of the epitopes that are recognized by the anti-human monoclonal antibodies VFF18 and Hermes-3 and the anti-mouse antibodies PGP-1, 10D1, and 9A4. v1 to v10, domains encoded by variant exons.
Figure 2.
Figure 2.
CD44 expression in the normal and neoplastic intestinal epithelium of the Apc+/Apc1638 mice. CD44v6 expression in non-neoplastic intestinal mucosa (A), in dysplastic ACF (B), in an adenomatous polyp (C), and in invasive carcinoma (D) of Apc+/Apc1638 mice.
Figure 3.
Figure 3.
CD44 mRNA expression in normal and neoplastic intestine of Apc+/Apc1638 mice. RT-PCR amplification products were generated with 5′ and 3′ CD44s primers, from specimens of normal mouse skin, normal mouse small intestine, and mouse intestinal tumor of Apc+/Apc1638 mice, respectively. Amplification products were analyzed on Southern blot by hybridization with 32P-labeled probes, specific for CD44s (A), CD44v3 (B), CD44v6 (C), and CD44v9 (D). *CD44v4-v10 plasmid does not contain exon v3 and therefore does not hybridize with the 32P-labeled exon v3 probe.
Figure 4.
Figure 4.
ACF with dysplasia in FAP patients overexpress CD44. Serial sections stained with either hematoxylin and eosin (A and C) or MAb VFF18 against human CD44v6 (B and D) in a dysplastic ACF in the colon of a FAP patient.
Figure 5.
Figure 5.
Tcf-4−/− mice lack CD44 expression in the epithelial lining of the small intestine. Staining with proliferation marker PCNA of small intestinal crypts and villi of a wild-type mouse (A) and of a Tcf-4−/− mouse (B) and CD44v6 staining of small intestinal crypts and villi of a wild-type mouse (C) and of a Tcf-4−/− mouse (D).
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