Abstract
In locally advanced rectal cancer patients (LARC), preoperative chemoradiation improves local control and sphincter preservation. The response rate to treatment varies substantially between 20 and 30%, and it is an important prognostic factor. Indeed, nonresponsive patients are subjected to higher rates of local and distant metastases, and worse survival compared to patients with complete response. In the search of predictive biomarkers for response prediction to therapy in LARC patients, we found increased plasma tryptophan levels in nonresponsive patients. On the basis of plasma levels of 5-hydroxy-tryptophan and kynurenine, the activities of tryptophan 5-hydroxylase 1 (TPH1) and indoleamine-2,3-dioxygenases 1 (IDO1)/tryptophan-2,3-dioxygenase (TDO2) have been obtained and data have been correlated with gene expression profiles. We demonstrated that TDO2 overexpression in nonresponsive patients correlates with kynurenine plasma levels. Finally, through the gene expression and targeted metabolomic analysis in paired healthy mucosa-rectal cancer tumor samples, we evaluated the impact of tryptophan catabolism at tissue level in responsive and nonresponsive patients.
Highlights
Cancer is a major cause of death in industrialized countries, and colorectal cancer (CRC) is one of the most common tumors in both male and female [1]
We already demonstrated that TRP catabolism increases more in people affected by colon cancer than those affected by rectal cancer
This decrease underlines a possible involvement of serotonin pathway in tumor response, while the IDO1/TDO2 activity, which is an estimation of kynurenine pathway, shows only a nonstatistically significant increasing trend (Figure 2B, box-plots)
Summary
Cancer is a major cause of death in industrialized countries, and colorectal cancer (CRC) is one of the most common tumors in both male and female [1]. In the most advanced stages of the disease, the tumor delocalizes and begins its proliferation in areas of the body different from the one in which it arose. Due to the different blood and lymph node ducts to which they are connected, colon cancer mainly develops liver metastases while rectal cancer develops, in addition to the liver ones, thoracic metastases. Prevention and diagnosis strategies for rectal and colon cancer are mostly the same; the planned therapy, is shared only for some traits. Preoperative chemoradiotherapy (pCRT) is worldwide accepted as a standard treatment for locally advanced rectal cancer (LARC) with stage II and III aiming at improving local tumor control, and inducing tumor downsizing and downstaging [2].
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