Abstract
Somatic mutations of the adenomatous polyposis coli (APC) gene are initiating events in the majority of sporadic colon cancers. A common characteristic of such tumors is reduction in the number of goblet cells that produce the mucin MUC2, the principal component of intestinal mucus. Consistent with these observations, we showed that Muc2 deficiency results in the spontaneous development of tumors along the entire gastrointestinal tract, independently of deregulated Wnt signaling. To dissect the complex interaction between Muc2 and Apc in intestinal tumorigenesis and to elucidate the mechanisms of tumor formation in Muc2-/- mice, we crossed the Muc2 -/- mouse with two mouse models, Apc1638N/+ and Apc Min/+, each of which carries an inactivated Apc allele. The introduction of mutant Muc2 into Apc1638N/+ and ApcMin/+ mice greatly increased transformation induced by the Apc mutation and significantly shifted tumor development toward the colon as a function of Muc2 gene dosage. Furthermore, we showed that in compound double mutant mice, deregulation of Wnt signaling was the dominant mechanism of tumor formation. The increased tumor burden in the distal colon of Muc2/Apc double mutant mice was similar to the phenotype observed in ApcMin/+ mice that are challenged to mount an inflammatory response, and consistent with this, gene expression profiles of epithelial cells from flat mucosa of Muc2-deficient mice suggested that Muc2 deficiency was associated with low levels of subclinical chronic inflammation. We hypothesize that Muc2-/- tumors develop through an inflammation-related pathway that is distinct from and can complement mechanisms of tumorigenesis in Apc+/- mice.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 7313-7322 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 68 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 15 2008 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Interaction of Muc2 and Apc on Wnt signaling and in intestinal tumorigenesis : Potential role of chronic inflammation. / Yang, Kan; Popova, Natalia V.; Wan, Cai Yang; Lozonschi, Ioanna; Tadesse, Selam; Kent, Scott; Bancroft, Laura; Matise, Ilze; Cormier, Robert T.; Scherer, Stefan J.; Edelmann, Winfried; Lipkin, Martin; Augenlicht, Leonard H.; Velcich, Anna.
In: Cancer Research, Vol. 68, No. 18, 15.09.2008, p. 7313-7322.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Interaction of Muc2 and Apc on Wnt signaling and in intestinal tumorigenesis
T2 - Potential role of chronic inflammation
AU - Yang, Kan
AU - Popova, Natalia V.
AU - Wan, Cai Yang
AU - Lozonschi, Ioanna
AU - Tadesse, Selam
AU - Kent, Scott
AU - Bancroft, Laura
AU - Matise, Ilze
AU - Cormier, Robert T.
AU - Scherer, Stefan J.
AU - Edelmann, Winfried
AU - Lipkin, Martin
AU - Augenlicht, Leonard H.
AU - Velcich, Anna
PY - 2008/9/15
Y1 - 2008/9/15
N2 - Somatic mutations of the adenomatous polyposis coli (APC) gene are initiating events in the majority of sporadic colon cancers. A common characteristic of such tumors is reduction in the number of goblet cells that produce the mucin MUC2, the principal component of intestinal mucus. Consistent with these observations, we showed that Muc2 deficiency results in the spontaneous development of tumors along the entire gastrointestinal tract, independently of deregulated Wnt signaling. To dissect the complex interaction between Muc2 and Apc in intestinal tumorigenesis and to elucidate the mechanisms of tumor formation in Muc2-/- mice, we crossed the Muc2 -/- mouse with two mouse models, Apc1638N/+ and Apc Min/+, each of which carries an inactivated Apc allele. The introduction of mutant Muc2 into Apc1638N/+ and ApcMin/+ mice greatly increased transformation induced by the Apc mutation and significantly shifted tumor development toward the colon as a function of Muc2 gene dosage. Furthermore, we showed that in compound double mutant mice, deregulation of Wnt signaling was the dominant mechanism of tumor formation. The increased tumor burden in the distal colon of Muc2/Apc double mutant mice was similar to the phenotype observed in ApcMin/+ mice that are challenged to mount an inflammatory response, and consistent with this, gene expression profiles of epithelial cells from flat mucosa of Muc2-deficient mice suggested that Muc2 deficiency was associated with low levels of subclinical chronic inflammation. We hypothesize that Muc2-/- tumors develop through an inflammation-related pathway that is distinct from and can complement mechanisms of tumorigenesis in Apc+/- mice.
AB - Somatic mutations of the adenomatous polyposis coli (APC) gene are initiating events in the majority of sporadic colon cancers. A common characteristic of such tumors is reduction in the number of goblet cells that produce the mucin MUC2, the principal component of intestinal mucus. Consistent with these observations, we showed that Muc2 deficiency results in the spontaneous development of tumors along the entire gastrointestinal tract, independently of deregulated Wnt signaling. To dissect the complex interaction between Muc2 and Apc in intestinal tumorigenesis and to elucidate the mechanisms of tumor formation in Muc2-/- mice, we crossed the Muc2 -/- mouse with two mouse models, Apc1638N/+ and Apc Min/+, each of which carries an inactivated Apc allele. The introduction of mutant Muc2 into Apc1638N/+ and ApcMin/+ mice greatly increased transformation induced by the Apc mutation and significantly shifted tumor development toward the colon as a function of Muc2 gene dosage. Furthermore, we showed that in compound double mutant mice, deregulation of Wnt signaling was the dominant mechanism of tumor formation. The increased tumor burden in the distal colon of Muc2/Apc double mutant mice was similar to the phenotype observed in ApcMin/+ mice that are challenged to mount an inflammatory response, and consistent with this, gene expression profiles of epithelial cells from flat mucosa of Muc2-deficient mice suggested that Muc2 deficiency was associated with low levels of subclinical chronic inflammation. We hypothesize that Muc2-/- tumors develop through an inflammation-related pathway that is distinct from and can complement mechanisms of tumorigenesis in Apc+/- mice.
UR - http://www.scopus.com/inward/record.url?scp=54649084868&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=54649084868&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-0598
DO - 10.1158/0008-5472.CAN-08-0598
M3 - Article
C2 - 18794118
AN - SCOPUS:54649084868
VL - 68
SP - 7313
EP - 7322
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 18
ER -