Abstract
Notch and Wnt signaling function together to regulate colonic progenitor cell division and differentiation. Studies in mice have also shown that Notch signaling is required for adenoma formation in response to elevated Wnt-pathway signaling that occurs in the APCMin mouse model of human adenomatous polyposis coli. We therefore used in situ hybridization to analyze expression of Notch ligands, receptors and fringe genes, as well as the Notch target gene, HES1, in human colorectal cancer (CRC). In a small cohort of tumors, JAGGED ligands, NOTCH1, LFNG and HES1 were expressed at levels similar to, or higher than, levels observed in the crypt. To explore the possibility that Notch signaling may play a quantitative role in human CRC we next analyzed HES1 mRNA expression in 130 tumors, each associated with outcome data. The vast majority of these tumors expressed HES1, although at varying levels. Absolute expression levels did not correlate with patient survival. These results establish that JAG ligands and NOTCH1, as well as Notch receptor activation are consistent features of human CRC and support the notion that many of these tumors, like the APCMin mouse, may respond to anti-Notch therapeutic regimes.
Publication types
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Multicenter Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics*
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Adenocarcinoma / mortality
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Adenocarcinoma / pathology
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Calcium-Binding Proteins / genetics
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Cell Differentiation
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / mortality
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Colonic Neoplasms / pathology
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Gene Expression Regulation, Neoplastic*
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Germany
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Glycosyltransferases / genetics
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Homeodomain Proteins / genetics
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Humans
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In Situ Hybridization
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Intercellular Signaling Peptides and Proteins / genetics
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Jagged-1 Protein
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Kaplan-Meier Estimate
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Membrane Proteins / genetics
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Ontario
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Prognosis
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RNA, Messenger / analysis
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Receptor, Notch1 / genetics
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Receptors, Notch / genetics*
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Registries
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Serrate-Jagged Proteins
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Signal Transduction / genetics*
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Transcription Factor HES-1
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Calcium-Binding Proteins
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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NOTCH1 protein, human
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RNA, Messenger
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Receptor, Notch1
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Receptors, Notch
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Serrate-Jagged Proteins
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Transcription Factor HES-1
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HES1 protein, human
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Glycosyltransferases
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LFNG protein, human