Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients

Sara Crotti; Alessandra Fraccaro; Chiara Bedin; Antonella Bertazzo; Valerio Di Marco; Salvatore Pucciarelli; Marco Agostini

doi:10.3389/fonc.2020.583228

Tryptophan Catabolism and Response to Therapy in Locally Advanced Rectal Cancer (LARC) Patients

Front Oncol. 2020 Oct 15:10:583228. doi: 10.3389/fonc.2020.583228. eCollection 2020.

Authors

Sara Crotti¹, Alessandra Fraccaro², Chiara Bedin¹, Antonella Bertazzo³, Valerio Di Marco², Salvatore Pucciarelli⁴, Marco Agostini^{1

4}

Affiliations

¹ Nano-Inspired Biomedicine Laboratory, Institute of Paediatric Research-Città della Speranza, Padua, Italy.
² Department of Chemical Sciences, University of Padua, Padua, Italy.
³ Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
⁴ First Surgical Clinic Section, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padua, Italy.

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.

Keywords: IDO1; TDO2; TPH1; kynurenine pathway; rectal cancer; serotonin pathway; tryptophan.