Activation of Notch signaling in human colon adenocarcinoma.
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.
Reedijk
Michael
M
Program in Developmental Biology and Stem Cell Research, The Hospital for Sick Children, MaRS East Tower, Ontario M5G 1L7, Canada.
Odorcic
Silvia
S
Zhang
Hui
H
Chetty
Runjan
R
Tennert
Carsten
C
Dickson
Brendan C
BC
Lockwood
Gina
G
Gallinger
Steven
S
Egan
Sean E
SE
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005858:Germany; D016695:Glycosyltransferases / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000235:genetics; D009864:Ontario; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D051881:Receptor, Notch1 / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics*; D012042:Registries; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics*; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D016695:Glycosyltransferases; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C497761:NOTCH1 protein, human; C078493:HES1 protein, human; C498393:LFNG protein, human