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From the Department of Pathology,*
Academic Medical
Center, University of Amsterdam, Amsterdam, the Department of Human
Genetics,
Leiden University Medical Center,
Leiden, and the Department of Immunology,
University Hospital, Utrecht, The Netherlands
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 ß-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 ß-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 ß-catenin/Tcf-4 signaling pathway and suggest a role for CD44 in the generation and turnover of epithelial cells.
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D. R. Schwartz, R. Wu, S. L. R. Kardia, A. M. Levin, C.-C. Huang, K. A. Shedden, R. Kuick, D. E. Misek, S. M. Hanash, J. M. G. Taylor, et al. Novel Candidate Targets of {beta}-Catenin/T-cell Factor Signaling Identified by Gene Expression Profiling of Ovarian Endometrioid Adenocarcinomas Cancer Res., June 1, 2003; 63(11): 2913 - 2922. [Abstract] [Full Text] [PDF]
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C. Gilles, M. Polette, M. Mestdagt, B. Nawrocki-Raby, P. Ruggeri, P. Birembaut, and J.-M. Foidart Transactivation of Vimentin by {beta}-Catenin in Human Breast Cancer Cells Cancer Res., May 15, 2003; 63(10): 2658 - 2664. [Abstract] [Full Text] [PDF]
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Y. Xu and Q. Yu E-cadherin Negatively Regulates CD44-Hyaluronan Interaction and CD44-mediated Tumor Invasion and Branching Morphogenesis J. Biol. Chem., February 28, 2003; 278(10): 8661 - 8668. [Abstract] [Full Text] [PDF]
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P. M. Campbell and M. Szyf Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway Carcinogenesis, January 1, 2003; 24(1): 17 - 24. [Abstract] [Full Text] [PDF]
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J R Jass, M Barker, L Fraser, M D Walsh, V L J Whitehall, B Gabrielli, J Young, and B A Leggett APC mutation and tumour budding in colorectal cancer J. Clin. Pathol., January 1, 2003; 56(1): 69 - 73. [Abstract] [Full Text] [PDF]
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E. M. J. Boon, R. van der Neut, M. van de Wetering, H. Clevers, and S. T. Pals Wnt Signaling Regulates Expression of the Receptor Tyrosine Kinase Met in Colorectal Cancer Cancer Res., September 15, 2002; 62(18): 5126 - 5128. [Abstract] [Full Text] [PDF]
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G. F. Weber, R. T. Bronson, J. Ilagan, H. Cantor, R. Schmits, and T. W. Mak Absence of the CD44 Gene Prevents Sarcoma Metastasis Cancer Res., April 1, 2002; 62(8): 2281 - 2286. [Abstract] [Full Text] [PDF]
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N. A. C. S. Wong and M. Pignatelli {beta}-Catenin--A Linchpin in Colorectal Carcinogenesis? Am. J. Pathol., February 1, 2002; 160(2): 389 - 401. [Abstract] [Full Text] [PDF]
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T. Zhang, T. Otevrel, Z. Gao, Z. Gao, S. M. Ehrlich, J. Z. Fields, and B. M. Boman Evidence That APC Regulates Survivin Expression: A Possible Mechanism Contributing to the Stem Cell Origin of Colon Cancer Cancer Res., December 1, 2001; 61(24): 8664 - 8667. [Abstract] [Full Text] [PDF]
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F. Hlubek, A. Jung, N. Kotzor, T. Kirchner, and T. Brabletz Expression of the Invasion Factor Laminin {gamma}2 in Colorectal Carcinomas Is Regulated by {beta}-Catenin Cancer Res., November 1, 2001; 61(22): 8089 - 8093. [Abstract] [Full Text] [PDF]
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T. Brabletz, A. Jung, S. Reu, M. Porzner, F. Hlubek, L. A. Kunz-Schughart, R. Knuechel, and T. Kirchner Variable beta -catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment PNAS, August 28, 2001; 98(18): 10356 - 10361. [Abstract] [Full Text] [PDF]
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V. J. M. Wielenga, R. van der Voort, T. E. I. Taher, L. Smit, E. A. Beuling, C. van Krimpen, M. Spaargaren, and S. T. Pals Expression of c-Met and Heparan-Sulfate Proteoglycan Forms of CD44 in Colorectal Cancer Am. J. Pathol., November 1, 2000; 157(5): 1563 - 1573. [Abstract] [Full Text] [PDF]
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T. Brabletz, K. Herrmann, A. Jung, G. Faller, and T. Kirchner Expression of Nuclear {beta}-Catenin and c-myc Is Correlated with Tumor Size but Not with Proliferative Activity of Colorectal Adenomas Am. J. Pathol., March 1, 2000; 156(3): 865 - 870. [Abstract] [Full Text] [PDF]
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H. G. Palmer, J. M. Gonzalez-Sancho, J. Espada, M. T. Berciano, I. Puig, J. Baulida, M. Quintanilla, A. Cano, A. G. de Herreros, M. Lafarga, et al. Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of {beta}-catenin signaling J. Cell Biol., July 23, 2001; 154(2): 369 - 388. [Abstract] [Full Text] [PDF]
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