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Review
, 167 (1), 67-79

Therapeutic Targeting of Inflammation and Tryptophan Metabolism in Colon and Gastrointestinal Cancer

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Review

Therapeutic Targeting of Inflammation and Tryptophan Metabolism in Colon and Gastrointestinal Cancer

Srikanth Santhanam et al. Transl Res.

Abstract

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.

Conflict of interest statement

CONFLICT OF INTEREST: The authors declare that no conflicts of interest to disclose and all authors have read the journal's policy on disclosure of potential conflicts of interest.

Figures

Figure 1
Figure 1. Tryptophan metabolism along the kynurenine pathway
The principle enzymes (IDO1, IDO2 and TDO) are shown. The bioactive metabolites downstream of kynurenine are shown with the respectively required enzymes. KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KYNU, kynureninase; 3-HAAO, 3-hydroxyanthranillic acid oxygenase; ACMS, 2-Amino-3-carboxymuconate semialdehyde; ACMSD, Aminocarboxymuconate-semialdehyde decarboxylase; QPRT, quinolinic acid phosphoribosyl transferase. NAD+, nicotinamide adenine dinucleotide (oxidized form)
Figure 2
Figure 2. Schematic of confirmed and postulated roles and interactions of IDO1 in colorectal cancer
IDO1 modulates signaling pathways in both cell autonomous and non-autonomous fashion. Solid lines represent interactions demonstrated in colorectal cancer, while dotted lines represent interactions extrapolated from other cell or tissue contexts.

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