title: The neurotensin receptor-1 promotes tumor development in a sporadic but not an inflammation-associated mouse model of colon cancer.
abstract: Neurotensin receptor-1 (NTR-1) is overexpressed in colon cancers and colon cancer cell lines. Signaling through this receptor stimulates proliferation of colonocyte-derived cell lines and promotes inflammation and mucosal healing in animal models of colitis. Given the causal role of this signaling pathway in mediating colitis and the importance of inflammation in cancer development, we tested the effects of NTR-1 in mouse models of inflammation-associated and sporadic colon cancer using NTR-1-deficient (Ntsr1(-) (/-)) and wild-type (Ntsr1(+/+)) mice. In mice treated with azoxymethane (AOM) to model sporadic cancer, NTR-1 had a significant effect on tumor development with Ntsr1(+/+) mice developing over twofold more tumors than Ntsr1(-) (/-) mice (p = 0.04). There was no effect of NTR-1 on the number of aberrant crypt foci or tumor size, suggesting that NT/NTR-1 signaling promotes the conversion of precancerous cells to adenomas. Interestingly, NTR-1 status did not affect tumor development in an inflammation-associated cancer model where mice were treated with AOM followed by two cycles of 5% dextran sulfate sodium (DSS). In addition, colonic molecular and histopathologic analyses were performed shortly after a single cycle of DSS. NTR-1 status did not affect colonic myeloperoxidase activity or histopathologic scores for damage and inflammation. However, Ntsr1(-) (/-) mice were more resistant to DSS-induced mortality (p = 0.01) and had over twofold higher colonic expression levels of Il6 and Cxcl2 (p < 0.04), cytokines known to promote tumor development. These results represent the first direct demonstration that targeted disruption of the Ntsr1 gene reduces susceptibility to colon tumorigenesis.
authors.affiliation: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, Room 1240 MacDonald Research Laboratories, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Bugni
authors.forename: Leina Al-
authors.initials: LA
authors.lastname: Rabadi
authors.forename: Kevin
authors.initials: K
authors.lastname: Jubbal
authors.forename: Iordanis
authors.initials: I
authors.lastname: Karagiannides
authors.forename: Gregory
authors.initials: G
authors.lastname: Lawson
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D000818:Animals; D001397:Azoxymethane; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; D015850:Interleukin-6; D011720:Pyrazoles; D011804:Quinolines; D018028:Receptors, Neurotensin; C114947:SR 142948; D014409:Tumor Necrosis Factor-alpha; C114036:neurotensin type 1 receptor; D016264:Dextran Sulfate; D001397:Azoxymethane