Objective: 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). Materials and methods: 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. Results: 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 5. y). 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). Conclusions: 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.

Activation of the kynurenine pathway predicts poor outcome in patients with clear cell renal cell carcinoma

LUCARELLI, GIUSEPPE;RUTIGLIANO, MONICA;GIGLIO, ANDREA;INTINI, ANGELICA;PALAZZO, SILVANO;GIGANTE, MARGHERITA;CASTELLANO, GIUSEPPE;NAPOLI, Anna;MAIORANO, Eugenio;DITONNO, Pasquale;BATTAGLIA, Michele
2017-01-01

Abstract

Objective: 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). Materials and methods: 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. Results: 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 5. y). 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). Conclusions: 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.
File in questo prodotto:
File Dimensione Formato  
UrOnc2017 (3).pdf

non disponibili

Tipologia: Documento in Versione Editoriale
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 5.14 MB
Formato Adobe PDF
5.14 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/192718
Citazioni
  • ???jsp.display-item.citation.pmc??? 33
  • Scopus 95
  • ???jsp.display-item.citation.isi??? 83
social impact