Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice
| العنوان: | Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice |
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| المؤلفون: | Matthew G. Davidson, E. Scott Seeley, Justin A. Kenkel, Luis A. Zuniga, Jinshan Wang, Hweixian Leong Penny, Reetesh K. Pai, Fionna Sun, Edgar G. Engleman, Lei Shen, Nupur Bhattacharya, Lorna L. Tolentino, Tyler R. Prestwood, Joseph L. Napoli, Okmi Choi |
| المصدر: | Cancer immunology research, vol 4, iss 11 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Adenoma, 0301 basic medicine, Cancer Research, Genes, APC, Oncology and Carcinogenesis, Immunology, Retinoic acid, Antineoplastic Agents, Tretinoin, Inflammation, Biology, Cell Transformation, medicine.disease_cause, Article, Familial adenomatous polyposis, Mice, 03 medical and health sciences, CYP26A1, chemistry.chemical_compound, 0302 clinical medicine, Immune system, medicine, Animals, Humans, Vitamin A, Neoplastic, Lamina propria, Enterocolitis, Vitamin A Deficiency, Cancer, Pharmacology and Pharmaceutical Sciences, Dendritic Cells, medicine.disease, APC, Tumor Burden, Cell Transformation, Neoplastic, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Genes, Adenomatous Polyposis Coli, chemistry, 030220 oncology & carcinogenesis, Th17 Cells, medicine.symptom, Colorectal Neoplasms, Carcinogenesis |
| الوصف: | Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APCMin/+ mice, a model that recapitulates FAP in most respects. We also investigated the impact of intestinal RA repletion and depletion on tumorigenesis and inflammation in APCMin/+ mice. Tumors from both FAP patients and APCMin/+ mice displayed striking alterations in RA metabolism that resulted in reduced intestinal RA. APCMin/+ mice placed on a vitamin A–deficient diet exhibited further reductions in intestinal RA with concomitant increases in inflammation and tumor burden. Conversely, restoration of RA by pharmacologic blockade of the RA-catabolizing enzyme CYP26A1 attenuated inflammation and diminished tumor burden. To investigate the effect of RA deficiency on the gut immune system, we studied lamina propria dendritic cells (LPDC) because these cells play a central role in promoting tolerance. APCMin/+ LPDCs preferentially induced Th17 cells, but reverted to inducing Tregs following restoration of intestinal RA in vivo or direct treatment of LPDCs with RA in vitro. These findings demonstrate the importance of intestinal RA deficiency in tumorigenesis and suggest that pharmacologic repletion of RA could reduce tumorigenesis in FAP patients. Cancer Immunol Res; 4(11); 917–26. ©2016 AACR. |
| وصف الملف: | application/pdf |
| تدمد: | 2326-6074 2326-6066 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::748ebda131b3963fa1023132a188c906Test https://doi.org/10.1158/2326-6066.cir-15-0038Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....748ebda131b3963fa1023132a188c906 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23266074 23266066 |
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