title: Activation of the kynurenine pathway predicts poor outcome in patients with clear cell renal cell carcinoma.
abstract: To investigate the expression of the kynurenine (KYN) pathway components and the prognostic role of the KYN-to-tryptophan ratio (KTR) in a cohort of patients with clear cell renal cell carcinoma (ccRCC).
  
  
  
  The expression of KYN pathway components was investigated by tissue microarray-based immunohistochemistry, indirect immunofluorescence, and confocal microscopy analysis in 100 ccRCC cases and 30 normal renal samples. The role of this pathway in sustaining cancer cell proliferation, migration, and chemoresistance was evaluated. In addition, tryptophan and KYN concentrations and their ratio were measured in serum of 195 patients with ccRCC using a sandwich enzyme-linked immunosorbent assay. The role of KTR as a prognostic factor for ccRCC cancer-specific survival (CSS) and progression-free survival (PFS) was assessed.
  
  
  
  Tissue microarray-based immunohistochemistry and indirect immunofluorescence staining showed an increased signal for KYN pathway components in ccRCC. Kaplan-Meier curves showed significant differences in CSS and PFS among groups of patients with high vs. low KTR. In particular, patients with high KTR values had a 5-year survival rate of 76.9% as compared with 92.3% for subjects with low levels (P  < 0.0001). Similar findings were observed for PFS (72.8% vs. 96.8% at 5y). At multivariate analysis, KTR was an independent adverse prognostic factor for CSS (hazard ratio  = 1.24, P  =  0.001), and PFS (hazard ratio  =  1.14, P  =  0.001).
  
  
  
  The involvement of the KYN pathway enzymes and catabolites in ccRCC occurs via both immune and nonimmune mechanisms. Our data suggest that KTR could serve as a marker of ccRCC aggressiveness and as a prognostic factor for CSS and PFS.
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy. Electronic address: giuseppe.lucarelli@inwind.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lucarelli
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Rutigliano
authors.affiliation: Department of Urology, European Institute of Oncology, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Ferro
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giglio
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Intini
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Triggiano
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Palazzo
authors.affiliation: Department of Emergency and Organ Transplantation-Nephrology, Dialysis and Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Gigante
authors.affiliation: Department of Emergency and Organ Transplantation-Nephrology, Dialysis and Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Department of Medical and Surgical Sciences, Clinical Pathology Unit, University of Foggia, Foggia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ranieri
authors.affiliation: Department of Clinical Medicine, Medical Oncology Unit, Federico II University, Naples, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Buonerba
authors.affiliation: Department of Translational Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Terracciano
authors.affiliation: Department of Pathology, University of Foggia, Foggia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanguedolce
authors.affiliation: Department of Pathology, University of Bari, Bari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Napoli
authors.affiliation: Department of Pathology, University of Bari, Bari, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Maiorano
authors.affiliation: Casa Sollievo della Sofferenza Hospital, Medical Oncology Unit, San Giovanni Rotondo, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Morelli
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Ditonno
authors.affiliation: Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Battaglia
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D007737:Kynurenine / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D007737:Kynurenine
keywords: Aryl hydrocarbon receptor; Cancer metabolism; Indoleamine 2,3-dioxygenase; Kynurenine; Renal cell carcinoma