title: BMP pathway suppression is an early event in inflammation-driven colon neoplasmatogenesis of uPA-deficient mice.
abstract: The suppression of the bone morphogenetic protein (BMP) signaling pathway has been recently shown to promote adenoma-to-carcinoma transition in sporadic colon cancer. However, its role in the evolution of early preneoplastic changes to neoplasia remains elusive. In the present study, we aimed to investigate the gene expression levels of multiple extracellular BMP family constituents, including BMP ligands/receptors and inhibitors, during the early stages of inflammation-associated colon carcinogenesis. For that, we used the recently developed urokinase-type plasminogen activator (uPA)-deficient mouse model of colonic polypoidogenesis, in which adenomatous polyps arise several months after the induction of dextran sodium sulfate (DSS) colitis. In DSS-treated wild-type mice, the preneoplastic lesions which did not eventually evolve to adenomas resided in a colitic microenvironment characterized by a balanced upregulation of both BMP ligands, i.e., Bmp4/7 and BMP inhibitors, such as chordin, noggin, and gremlin-1. In the uPA-deficient tumor-promoting inflammatory microenvironment, however, there was a clear evidence for BMP pathway suppression. By contrast to DSS-treated wild-type controls, the inflammation-associated Bmp4 upregulation was abolished, and the BMP signaling suppression was further enhanced by a particularly high increase of gremlin-1 expression. These findings propose that BMP pathway suppression in colon cancer could be associated with very early stages of the preneoplasia-to-neoplasia sequence of events.
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA.
authors.forename: George S
authors.initials: GS
authors.lastname: Karagiannis
authors.affiliation: Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Hara
authors.initials: H
authors.lastname: Afaloniati
authors.affiliation: Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.|Department of Cardiovasular Sciences, Cardiovascular Research Centre, Glenfield General Hospital, University of Leicester, Leicester, UK.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Karamanavi
authors.affiliation: Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Theofilos
authors.initials: T
authors.lastname: Poutahidis
authors.affiliation: Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece. kangelop@vet.auth.gr.
authors.forename: Katerina
authors.initials: K
authors.lastname: Angelopoulou
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D011230:Precancerous Conditions / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency
chemical_list: D019485:Bone Morphogenetic Proteins; D014568:Urokinase-Type Plasminogen Activator
keywords: BMP; Colitis; Colorectal cancer; GREM1; Mouse; uPA