title: N-methylnitrosourea aggravates gastrointestinal polyposis in Lkb1+/- mice.
abstract: Peutz-Jeghers patients develop hamartomatous polyps and carcinomas of the gastrointestinal tract. Cyclooxygenase-2 accelerates polyp growth in Lkb1 (+/-) mice modelling Peutz-Jeghers polyposis. In this study, we aimed to evaluate the effect of the mutagenic carcinogen N-methylnitrosourea (MNU) on gastrointestinal tumourigenesis in Lkb1 (+/-) mice and to investigate the role of cyclooxygenase-2 on the tumourigenesis. We treated 40 Lkb1 (+/-) and 51 wild-type mice with MNU, 10 mice from both groups received the cyclooxygenase-2 inhibitor celecoxib. Carcinogen-treated Lkb1 (+/-) mice displayed worse survival (60%) than treated wild-type (100%, P = 0.028) or untreated Lkb1 (+/-) mice (92%, P = 0.045). Also, the gastrointestinal tumour burden was almost 10-fold higher in carcinogen-treated (2181 mm(3)) than in untreated (237 mm(3), P = 0.00045) Lkb1 (+/-) mice. Celecoxib was much less efficient in reducing tumourigenesis in MNU-treated mice (by 23%; 1686 mm(3)) than in untreated mice (76%; 58 mm(3)). Surprisingly, the increase in tumour burden in MNU-treated mice was not accompanied by consistent histological changes, with only a single focus of epithelial dysplasia noted. This study suggests that MNU promotes Peutz-Jeghers polyposis independently from the acceleration by cyclooxygenase-2.
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland and.
authors.forename: Lina
authors.initials: L
authors.lastname: Udd
authors.forename: Yajing
authors.initials: Y
authors.lastname: Gao
authors.forename: Ari P
authors.initials: AP
authors.lastname: Ristimäki
authors.forename: Tomi P
authors.initials: TP
authors.lastname: Mäkelä
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005770:Gastrointestinal Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D008770:Methylnitrosourea / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D010580:Peutz-Jeghers Syndrome / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D008770:Methylnitrosourea; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D000068579:Celecoxib