title: Reduced intestinal tumorigenesis in APCmin mice lacking melanin-concentrating hormone.
abstract: BACKGROUND
  Melanin-concentrating hormone (MCH) is an evolutionary conserved hypothalamic neuropeptide that in mammals primarily regulates appetite and energy balance. We have recently identified a novel role for MCH in intestinal inflammation by demonstrating attenuated experimental colitis in MCH deficient mice or wild type mice treated with an anti-MCH antibody. Therefore, targeting MCH has been proposed for the treatment of inflammatory bowel disease. Given the link between chronic intestinal inflammation and colorectal cancer, in the present study we sought to investigate whether blocking MCH might have effects on intestinal tumorigenesis that are independent of inflammation.
  
  
  METHODS
  Tumor development was evaluated in MCH-deficient mice crossed to the APCmin mice which develop spontaneously intestinal adenomas. A different cohort of MCH-/- and MCH+/+ mice in the APCmin background was treated with dextran sodium sulphate (DSS) to induce inflammation-dependent colorectal tumors. In Caco2 human colorectal adenocarcinoma cells, the role of MCH on cell survival, proliferation and apoptosis was investigated.
  
  
  RESULTS
  APCmin mice lacking MCH developed fewer, smaller and less dysplastic tumors in the intestine and colon which at the molecular level are characterized by attenuated activation of the wnt/beta-catenin signaling pathway and increased apoptotic indices. Form a mechanistic point of view, MCH increased the survival of colonic adenocarcinoma Caco2 cells via inhibiting apoptosis, consistent with the mouse studies.
  
  
  CONCLUSIONS
  In addition to modulating inflammation, MCH was found to promote intestinal tumorigenesis at least in part by inhibiting epithelial cell apoptosis. Thereby, blocking MCH as a therapeutic approach is expected to decrease the risk for colorectal cancer.
authors: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Jutta M
authors: JM
authors: Nagel
authors: Brenda M
authors: BM
authors: Geiger
authors: Apostolos K A
authors: AK
authors: Karagiannis
authors: Beatriz
authors: B
authors: Gras-Miralles
authors: David
authors: D
authors: Horst
authors: Robert M
authors: RM
authors: Najarian
authors: Dimitrios C
authors: DC
authors: Ziogas
authors: Xinhua
authors: X
authors: Chen
authors: Efi
authors: E
authors: Kokkotou
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000009:adverse effects; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007028:Hypothalamic Hormones / Q000172:deficiency*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008543:Melanins / Q000172:deficiency*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010907:Pituitary Hormones / Q000172:deficiency*; D017481:Receptors, Somatostatin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D007028:Hypothalamic Hormones; C491209:Mchr1 protein, mouse; D008543:Melanins; D010907:Pituitary Hormones; D017481:Receptors, Somatostatin; D051153:Wnt Proteins; D051176:beta Catenin; C019463:melanin-concentrating hormone; D016264:Dextran Sulfate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3