5-ASA and Carcinogenesis in IBD

Transcription

1 5-ASA and Carcinogenesis in IBD Maikel P. Peppelenbosch

2 Typical lunch table at the Peppelenbosch residence This seminar takes place at a most awkward time: People would rather munch their lunch in peace rather as being confronted with more scientific discussion

3 The Gastro-intestinal tract, the most interesting structure in the human body Extreme mechanical stress Extreme microbiological load

4 Typical lunch table at the Peppelenbosch residence Especially myself, I enjoy a rather copious meal accompanied by substantial quantities of wine and thus subject the lining of my Gut to severe stress

5 Thus after such a meal the epithelia in my tractus face two opposing challenges: Severe mechanical stress. Biology usually solves this by forming multilayer, sometimes cornified, squamous epithelia Efficient resorption ot nutrients and water. Biology usually solves this by forming columnar epithelia

6 In the intestine, efficient replacement of a monolayer of cells, before wear and tear compromises the functionality of epithelium, deals with these challenges.

7 Despite relentless proliferation, differentiation, apoptosis and shedding of cells in the lumen, histostability is the norm in the intestine. Highly active morphogen signalling

8 Wnt signalling represents a developmentally relevant signalling pathway. Wnt signalling maintains stem cell phenotype in the crypt Mutations in the Wnt/APC pathway underlie most often colorectal cancer ( 90 % of all cases).

9 BMP is a developmentally active molecule BMP-signalling induces apoptosis at the top of the villus Defects in BMP signalling cause juvenile polyposis

10 Maybe the surprise is that with all this differentiation and cell division cancer in the tractus is not more prevalent. Balancing act Dutch Cancer Registry

11 Even small attenuations of the DNA repair machinery dramatically increase the risk of contracting colorectal cancer

12 Strong increase >50 years of age Populationwide screens Further shows the tight balance between proand antioncogenic processes in the gut

13 Typical lunch table in the Peppelenbosch residence Thus the interplay of morphogens explains the histostability in my Gut. My kitchen, however, is not particularly clean, causing a serious microbiological challenge to my intestines

14 Our Gut is home to approximately bacteria, placing unusual constraints on the mucosal immune system

15 Thus our mucosal immune system has to sail between Scylla and Charybdis, adequately attacking pathogenic micro organisms but tolerating harmless bacteria Artist impression of Ulysses sailing between Scylla and Charybdis.

16 An extensive network of pro- and anti-inflammatory signals performs this balancing act This network is in inbalance in IBD Chronic inflammation Disturbs the tight equilibrium between pro- and anti-oncogenic influences antigen presenting cell bacteria IL-12 IL-18 IL-10 CD4 CD4 regulatory T cell apoptosis activation CD4 IFNγ Lumen TNF

17 Interleukin-10 mediates antigen-specific tolerance in the gut Interleukin-10 -/- animals develop spontaneous colitis Interleukin-10 -/- animals develop spontaneous adenomacarcinoma

18 IBD increases CRC risk ( 20-fold ) Little difference Crohn/UC adenoma carcinoma sequence becomes inflammation dysplasia carcinoma sequence Cumulative risk for CRC (%) Years after onset of UC meta-analysis of 116 publications in the English language

19 5-aminosalicyclic acid (5-ASA) : Regular 5-aminosalicylic acid (5-ASA) therapy reduces colon cancer risk in UC by 81% (OR 0.19, 95% CI: , P=0.006)* Mechanism of action? Wnt/APC pathway most often responsible for colorectal cancer *Eaden J, Abrams K, Ekbom A, Jackson E, Mayberry J. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther :

20 Firefly luciferase Wnt/Apc Responsive promoter 5-ASA reduces expression of target genes the prooncogenic Wnt/APC pathway Carina Bos James Hardwick

21 β-cat 5-ASA β-cat (active) Wnt signalling Translocation of β- catenin is crucial for oncogenic Wnt signalling 5-ASA blocks β-catenin accumulation in the nucleus of colon cancer cells Further studies were done

22 I am a bit of nerd and I like this kind of thing, but most people here are fairly normal. And come on, its weekend! So I skip all the intricate results

23 . Crunch, crunch -Cat Mr proteasome β-cat P β-cat. No Wnt signalling Mr PP2a 5-ASA By inhibiting dephosphorylation of β-catenin 5-ASA stimulates β-catenin breakdown and thus prevents its accumulation in nucleus

24 5-ASA antagonises the most important prooncogenic pathway in the colon 5-ASA is well-tolerated and has little systemic side effects (contrast with aspirin) 5-ASA may become an interesting candidate for the chemoprevention of colorectal cancer

25 Typical lunch table in the Peppelenbosch residence Thus it may well be that in the future it may be considered good manners to offer a tablet of 5- ASA to your guest when giving an intestinechallenging lunch