Therapeutic targeting of inflammation and tryptophan metabolism in colon and gastrointestinal cancer

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• 作者：Srikanth Santhanam ; David M. Alvarado ; Matthew A. Ciorba ; ^{mciorba@dom.wustl.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ACF ; aberrant crypt foci ; AHR ; aryl hydrocarbon receptor ; AOM ; azoxymethane ; APC ; adenomatous polyposis coli ; CAC ; colitis-associated cancer ; CD ; cluster of differentiation ; COX-2 ; cyclooxygenase 2 ; CRC ; colorectal cancer ; DC ; dendritic cell ; DNA ; deoxyribonucleic acid ; GCN2 ; general control nonderepressible 2 ; GSK-3β ; glycogen synthase kinase 3 beta ; IDO1 ; indoleamine 2 ; 3-dioxygenase 1 ; IDO2 ; indoleamine 2 ; 3-dioxygenase 2 ; IFN ; interferon ; IL ; interleukin ; iNOS ; inducible nitric oxide synthase
• 刊名：Translational Research
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：167
• 期：1
• 页码：67-79
• 全文大小：1146 K

文摘

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death in the United States. Cytotoxic therapies cause significant adverse effects for most patients and do not offer cure in many advanced cases of CRC. Immunotherapy is a promising new approach to harness the body's own immune system and inflammatory response to attack and clear the cancer. Tryptophan metabolism along the kynurenine pathway (KP) is a particularly promising target for immunotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) is the most well studied of the enzymes that initiate this pathway and it is commonly overexpressed in CRC. Herein, we provide an in-depth review of how tryptophan metabolism and KP metabolites shape factors important to CRC pathogenesis including the host mucosal immune system, pivotal transcriptional pathways of neoplastic growth, and luminal microbiota. This pathway's role in other gastrointestinal (GI) malignancies such as gastric, pancreatic, esophageal, and GI stromal tumors is also discussed. Finally, we highlight how currently available small molecule inhibitors and emerging methods for therapeutic targeting of IDO1 might be applied to colon, rectal, and colitis–associated cancer.