TY - JOUR
T1 - Stromal Indian hedgehog signaling is required for intestinal adenoma formation in mice
AU - Büller, Nikè V J A
AU - Rosekrans, Sanne L.
AU - Metcalfe, Ciara
AU - Heijmans, Jarom
AU - Van Dop, Willemijn A.
AU - Fessler, Evelyn
AU - Jansen, Marnix
AU - Ahn, Christina
AU - Vermeulen, Jacqueline L M
AU - Westendorp, B. Florien
AU - Robanus-Maandag, Els C.
AU - Offerhaus, G. Johan
AU - Medema, Jan Paul
AU - D'Haens, Geert R A M
AU - Wildenberg, Manon E.
AU - De Sauvage, Frederic J.
AU - Muncan, Vanesa
AU - Van Den Brink, Gijs R.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - BACKGROUND & AIMS: Indian hedgehog (IHH) is an epithelial-derived signal in the intestinal stroma, inducing factors that restrict epithelial proliferation and suppress activation of the immune system. In addition to these rapid effects of IHH signaling, IHH is required to maintain a stromal phenotype in which myofibroblasts and smooth muscle cells predominate. We investigated the role of IHH signaling during development of intestinal neoplasia in mice. METHODS: Glioma-associated oncogene (Gli1)-CreERT2 and Patched (Ptch)-lacZ reporter mice were crossed with ApcMin mice to generate Gli1CreERT2-Rosa26-ZSGreen-ApcMin and Ptch-lacZ-ApcMin mice, which were used to identify hedgehog-responsive cells. Cyp1a1Cre-Apc (ApcHET) mice, which develop adenomas after administration of β-naphthoflavone, were crossed with mice with conditional disruption of Ihh in the small intestine epithelium. ApcMin mice were crossed with mice in which sonic hedgehog (SHH) was overexpressed specifically in the intestinal epithelium. Intestinal tissues were collected and analyzed histologically and by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction. We also analyzed levels of IHH messenger RNA and expression of IHH gene targets in intestinal tissues from patients with familial adenomatous polyposis (n = 18) or sessile serrated adenomas (n = 15) and normal colonic tissue from control patients (n = 12). RESULTS: Expression of IHH messenger RNA and its targets were increased in intestinal adenomas from patients and mice compared with control colon tissues. In mice, IHH signaling was exclusively paracrine, from the epithelium to the stroma. Loss of IHH from ApcHET mice almost completely blocked adenoma development, and overexpression of SHH increased the number and size of adenomas that developed. Loss of IHH from ApcHET mice changed the composition of the adenoma stroma; cells that expressed α-smooth muscle actin or desmin were lost, along with expression of cyclooxygenase-2, and the number of vimentin-positive cells increased. CONCLUSIONS: Apc mutant epithelial cells secrete IHH to maintain an intestinal stromal phenotype that is required for adenoma development in mice.
AB - BACKGROUND & AIMS: Indian hedgehog (IHH) is an epithelial-derived signal in the intestinal stroma, inducing factors that restrict epithelial proliferation and suppress activation of the immune system. In addition to these rapid effects of IHH signaling, IHH is required to maintain a stromal phenotype in which myofibroblasts and smooth muscle cells predominate. We investigated the role of IHH signaling during development of intestinal neoplasia in mice. METHODS: Glioma-associated oncogene (Gli1)-CreERT2 and Patched (Ptch)-lacZ reporter mice were crossed with ApcMin mice to generate Gli1CreERT2-Rosa26-ZSGreen-ApcMin and Ptch-lacZ-ApcMin mice, which were used to identify hedgehog-responsive cells. Cyp1a1Cre-Apc (ApcHET) mice, which develop adenomas after administration of β-naphthoflavone, were crossed with mice with conditional disruption of Ihh in the small intestine epithelium. ApcMin mice were crossed with mice in which sonic hedgehog (SHH) was overexpressed specifically in the intestinal epithelium. Intestinal tissues were collected and analyzed histologically and by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction. We also analyzed levels of IHH messenger RNA and expression of IHH gene targets in intestinal tissues from patients with familial adenomatous polyposis (n = 18) or sessile serrated adenomas (n = 15) and normal colonic tissue from control patients (n = 12). RESULTS: Expression of IHH messenger RNA and its targets were increased in intestinal adenomas from patients and mice compared with control colon tissues. In mice, IHH signaling was exclusively paracrine, from the epithelium to the stroma. Loss of IHH from ApcHET mice almost completely blocked adenoma development, and overexpression of SHH increased the number and size of adenomas that developed. Loss of IHH from ApcHET mice changed the composition of the adenoma stroma; cells that expressed α-smooth muscle actin or desmin were lost, along with expression of cyclooxygenase-2, and the number of vimentin-positive cells increased. CONCLUSIONS: Apc mutant epithelial cells secrete IHH to maintain an intestinal stromal phenotype that is required for adenoma development in mice.
KW - Colon Cancer
KW - COX2
KW - Mouse Model
KW - Prostaglandin
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UR - http://www.scopus.com/inward/citedby.url?scp=84922896060&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2014.10.006
DO - 10.1053/j.gastro.2014.10.006
M3 - Article
C2 - 25307863
AN - SCOPUS:84922896060
SN - 0016-5085
VL - 148
SP - 170-180.e6
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -