Tryptophan metabolism in melanomas: What do the microenvironment cells tell us?

Abstract

Tryptophan (TRP) metabolism occurs by kynurenine pathway (KYN pathway) and by serotoninergic pathway (SER pathway). KYN pathway generates kynurenine (KYN) and a lot of secondary products and, when it is conducted by indoleamine 2,3 dioxygenase enzyme (IDO), it contributes to tolerance phenomena and tumor cells immune escape. SER pathway produces serotonin (SER) which can generate melatonin (MLT) and other metabolites with immunomodulatory effects. In cancer regards, there are evidences that these compounds can control tumor growth. Giving the great importance on biochemical pathways of TRP metabolism in tumors, the initial aim of this project is to develop, standardize and validate new protocols for identification and quantification of metabolites from TRP metabolic pathways, especially tending to protocols that will allow us to obtain a large number of synchronic information and sensitivity. Subsequently, we will identify the different TRP metabolites in human melanoma tumor lineages, melanocytes and clinical samples of melanoma. In tumor lineages we will evaluate IFN-³ and 1-methyl-tryptophan (1-MT) effects; respectively an inductor and a competitive inhibitor of IDO. In clinical samples, KYN and SER pathways metabolites will be correlated to tumor development stage and to treatment response. From the data collected in this study, we intend to recognize what is the impact of one pathway over the other and the TRP metabolism on the neoplasic process, especially, in melanomas.