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.
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Authors | Lina Udd, Yajing Gao, Ari P Ristimäki, Tomi P Mäkelä |
Journal | Carcinogenesis
(Carcinogenesis)
Vol. 34
Issue 10
Pg. 2409-14
(Oct 2013)
ISSN: 1460-2180 [Electronic] England |
PMID | 23722652
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Carcinogens
- Cyclooxygenase 2 Inhibitors
- Pyrazoles
- Sulfonamides
- Methylnitrosourea
- Protein Serine-Threonine Kinases
- Stk11 protein, mouse
- AMP-Activated Protein Kinases
- Celecoxib
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Topics |
- AMP-Activated Protein Kinases
- Animals
- Carcinogenesis
(drug effects, genetics)
- Carcinogens
(administration & dosage, toxicity)
- Celecoxib
- Cyclooxygenase 2 Inhibitors
(pharmacology)
- Disease Models, Animal
- Female
- Gastric Mucosa
(metabolism, pathology)
- Gastrointestinal Neoplasms
(chemically induced, genetics, pathology)
- Methylnitrosourea
(administration & dosage, toxicity)
- Mice
- Mice, Knockout
- Peutz-Jeghers Syndrome
(genetics, mortality, pathology)
- Protein Serine-Threonine Kinases
(genetics)
- Pyrazoles
(pharmacology)
- Sulfonamides
(pharmacology)
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