Year: 2011
Type: article
Abstract: Colitis associated cancer is an important complication of the human inflammatory bowel diseases (IBD). Indoleamine 2,3 Dioxygenase-1 (IDO), the rate limiting enzyme in tryptophan catabolism, is over-expressed in the epithelium of active IBD and some colon cancers. Specific inhibitors of IDO1, including 1-methyl tryptophan (1-mT), are under investigation for their ability to break tumor-induced immune tolerance induced by IDO1 mediated suppression of T-effector cell responses. IDO inhibition in acute colitis also reduces regenerative epithelial cell proliferation. Examine the role of the IDO enzyme in a mouse model of colitis associated cancer using a genetic deletion model and pharmacologic inhibition. Comparison groups were WT vs IDO−/− as well as Rag1−/− vs DbKO (Rag1−/− x IDO−/−, Double KO), all on the C57Bl/6 background. 1-mT was administered to WT mice via an implanted time release capsule. Co-caging was used in all experiments. Colitis associated cancer induction used a standardized protocol of azoxymethane (AOM: 10mg/kg) IP prior to 3 week-long cycles of 2.5% dextran sodium sulfate (DSS). Clinical Disease Activity Index (DAI) was followed and histology examined. Immunohistochemistry was used to assess IDO and β-catenin expression as well as epithelial proliferation (via BrDU incorporation). High IDO expression was identified in the malignant epithelium by IHC and RT-PCR. Over the 60 day AOM/DSS protocol, IDO−/− vs WT mice had higher disease activity index (3 vs 6.4, p<.05) and more significant weight loss (-11% vs -21%, p<.01)during the first DSS cycle. This difference was attenuated for the second and absent during the third DSS cycle.. At sacrifice tumor number (4.1 vs 7.5, p<0.01) and total tumor area (13.7 vs 31.2 sq mm, p=0.017) were lower in IDO−/− vs WT mice. Correspondingly, the adenoma epithelial proliferation index was lower in IDO−/− vs WT mice (20.2% vs 41%, p=0.04) while cytoplasmic B-catenin staining was stronger in the WT than IDO−/− mice. WT mice given the IDO1 inhibitor 1-mT after the first cycle of DSS demonstrated significantly fewer visible tumors (3.00 vs 5.57, p<.04) and smaller total tumor area per mouse (15.3 vs 25 sq mm, p<.05). Finally, in mice lacking intact adaptive immunity (Rag1−/− vs DbKO), deletion of IDO resulted in no difference in DAI scores or histology. Surprisingly however, the reduced tumor phenotype persisted with DbKO mice developing fewer (avg # 5.4 vs 14, p<.001) and smaller (17.9 vs 39.1 sq mm, p=.001) tumors than Rag1−/− mice. These data show that the IDO enzyme is an important regulator of colitis associated cancer progression where dual roles of promoting tolerance from the adaptive immune system and facilitated cancer cell proliferation are implicated. While IDO blockade worsens acute colitis severity in this model, its effects in chronic colitis are less pronounced. Pharmacologic inhibition of IDO may be an effective therapeutic strategy for colon cancer, particularly inflammation associated colon cancer.
Source: Inflammatory Bowel Diseases
Institution: Washington University in St. Louis
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4231139682