N-methylnitrosourea aggravates gastrointestinal polyposis in Lkb1+/- mice

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.