Heterogeneity of Jagged1 expression in human and mouse intestinal tumors

Implications for targeting Notch signaling

S. Guilmeau, M. Flandez, J. M. Mariadason, Leonard H. Augenlicht

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Inhibition of Notch signaling is effective in inhibiting colon tumorigenesis, but targeting specific components of the pathway may provide more effective strategies. Here we show that the expression of Jagged1, a ligand for canonical Notch signaling, was restricted to enteroendocrine cells or undetectable in the mucosa of the human small and large intestine, respectively. In contrast, increased expression characterized half of human colon tumors, although not all tumors with elevated Wnt signaling displayed elevated Jagged1. Increased Jagged1 was also present in intestinal tumors of Apc1638N/+ and ApcMin/+ mice, but to a higher level and more frequently in the former, and in 90% of mouse tumors Notch signaling was elevated when Jagged1 was elevated. In the human HT29Cl16E colonic carcinoma cell line, induction of goblet cell differentiation by contact inhibition of growth depended on the loss of Jagged1-mediated Notch activation, with signaling through Notch1 and Notch2 acting redundantly. Therefore, targeting of Jagged1 could be effective in downregulating Notch signaling in a subset of tumors, but may avoid the limiting gastrointestinal toxicity caused by pharmacological inhibition of Notch signaling.

Original languageEnglish (US)
Pages (from-to)992-1002
Number of pages11
JournalOncogene
Volume29
Issue number7
DOIs
StatePublished - Feb 2010
Externally publishedYes

Fingerprint

Neoplasms
Colon
Enteroendocrine Cells
Contact Inhibition
Goblet Cells
Large Intestine
Small Intestine
Cell Differentiation
Carcinogenesis
Mucous Membrane
Down-Regulation
Pharmacology
Ligands
Carcinoma
Cell Line
Growth

Keywords

  • Colon cancer
  • Jagged1
  • Notch signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Heterogeneity of Jagged1 expression in human and mouse intestinal tumors : Implications for targeting Notch signaling. / Guilmeau, S.; Flandez, M.; Mariadason, J. M.; Augenlicht, Leonard H.

In: Oncogene, Vol. 29, No. 7, 02.2010, p. 992-1002.

Research output: Contribution to journalArticle

@article{4f36e9cf7a2440d48da67493b9410dce,
title = "Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: Implications for targeting Notch signaling",
abstract = "Inhibition of Notch signaling is effective in inhibiting colon tumorigenesis, but targeting specific components of the pathway may provide more effective strategies. Here we show that the expression of Jagged1, a ligand for canonical Notch signaling, was restricted to enteroendocrine cells or undetectable in the mucosa of the human small and large intestine, respectively. In contrast, increased expression characterized half of human colon tumors, although not all tumors with elevated Wnt signaling displayed elevated Jagged1. Increased Jagged1 was also present in intestinal tumors of Apc1638N/+ and ApcMin/+ mice, but to a higher level and more frequently in the former, and in 90{\%} of mouse tumors Notch signaling was elevated when Jagged1 was elevated. In the human HT29Cl16E colonic carcinoma cell line, induction of goblet cell differentiation by contact inhibition of growth depended on the loss of Jagged1-mediated Notch activation, with signaling through Notch1 and Notch2 acting redundantly. Therefore, targeting of Jagged1 could be effective in downregulating Notch signaling in a subset of tumors, but may avoid the limiting gastrointestinal toxicity caused by pharmacological inhibition of Notch signaling.",
keywords = "Colon cancer, Jagged1, Notch signaling",
author = "S. Guilmeau and M. Flandez and Mariadason, {J. M.} and Augenlicht, {Leonard H.}",
year = "2010",
month = "2",
doi = "10.1038/onc.2009.393",
language = "English (US)",
volume = "29",
pages = "992--1002",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Heterogeneity of Jagged1 expression in human and mouse intestinal tumors

T2 - Implications for targeting Notch signaling

AU - Guilmeau, S.

AU - Flandez, M.

AU - Mariadason, J. M.

AU - Augenlicht, Leonard H.

PY - 2010/2

Y1 - 2010/2

N2 - Inhibition of Notch signaling is effective in inhibiting colon tumorigenesis, but targeting specific components of the pathway may provide more effective strategies. Here we show that the expression of Jagged1, a ligand for canonical Notch signaling, was restricted to enteroendocrine cells or undetectable in the mucosa of the human small and large intestine, respectively. In contrast, increased expression characterized half of human colon tumors, although not all tumors with elevated Wnt signaling displayed elevated Jagged1. Increased Jagged1 was also present in intestinal tumors of Apc1638N/+ and ApcMin/+ mice, but to a higher level and more frequently in the former, and in 90% of mouse tumors Notch signaling was elevated when Jagged1 was elevated. In the human HT29Cl16E colonic carcinoma cell line, induction of goblet cell differentiation by contact inhibition of growth depended on the loss of Jagged1-mediated Notch activation, with signaling through Notch1 and Notch2 acting redundantly. Therefore, targeting of Jagged1 could be effective in downregulating Notch signaling in a subset of tumors, but may avoid the limiting gastrointestinal toxicity caused by pharmacological inhibition of Notch signaling.

AB - Inhibition of Notch signaling is effective in inhibiting colon tumorigenesis, but targeting specific components of the pathway may provide more effective strategies. Here we show that the expression of Jagged1, a ligand for canonical Notch signaling, was restricted to enteroendocrine cells or undetectable in the mucosa of the human small and large intestine, respectively. In contrast, increased expression characterized half of human colon tumors, although not all tumors with elevated Wnt signaling displayed elevated Jagged1. Increased Jagged1 was also present in intestinal tumors of Apc1638N/+ and ApcMin/+ mice, but to a higher level and more frequently in the former, and in 90% of mouse tumors Notch signaling was elevated when Jagged1 was elevated. In the human HT29Cl16E colonic carcinoma cell line, induction of goblet cell differentiation by contact inhibition of growth depended on the loss of Jagged1-mediated Notch activation, with signaling through Notch1 and Notch2 acting redundantly. Therefore, targeting of Jagged1 could be effective in downregulating Notch signaling in a subset of tumors, but may avoid the limiting gastrointestinal toxicity caused by pharmacological inhibition of Notch signaling.

KW - Colon cancer

KW - Jagged1

KW - Notch signaling

UR - http://www.scopus.com/inward/record.url?scp=77149177354&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77149177354&partnerID=8YFLogxK

U2 - 10.1038/onc.2009.393

DO - 10.1038/onc.2009.393

M3 - Article

VL - 29

SP - 992

EP - 1002

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 7

ER -