Lucarelli Giuseppe, Rutigliano Monica, Ferro Matteo, Giglio Andrea, Intini Angelica, Triggiano Francesco, Palazzo Silvano, Gigante Margherita, Castellano Giuseppe, Ranieri Elena, Buonerba Carlo, Terracciano Daniela, Sanguedolce Francesca, Napoli Anna, Maiorano Eugenio, Morelli Franco, Ditonno Pasquale, Battaglia Michele
Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy.
Urol Oncol. 2017 Jul;35(7):461.e15-461.e27. doi: 10.1016/j.urolonc.2017.02.011. Epub 2017 Mar 28.
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.
研究犬尿氨酸（KYN）途径成分的表达以及KYN与色氨酸比值（KTR）在一组透明细胞肾细胞癌（ccRCC）患者中的预后作用。
通过基于组织芯片的免疫组织化学、间接免疫荧光和共聚焦显微镜分析，研究100例ccRCC病例和30例正常肾样本中KYN途径成分的表达。评估该途径在维持癌细胞增殖、迁移和化疗耐药性方面的作用。此外，使用夹心酶联免疫吸附测定法测量195例ccRCC患者血清中的色氨酸和KYN浓度及其比值。评估KTR作为ccRCC癌症特异性生存（CSS）和无进展生存（PFS）预后因素的作用。
基于组织芯片的免疫组织化学和间接免疫荧光染色显示ccRCC中KYN途径成分的信号增加。Kaplan-Meier曲线显示高KTR组与低KTR组患者在CSS和PFS方面存在显著差异。特别是，KTR值高的患者5年生存率为76.9%，而低水平患者为92.3%（P<0.0001）。PFS也观察到类似结果（5年时分别为72.8%和96.8%）。多因素分析中，KTR是CSS（风险比=1.24，P=0.001）和PFS（风险比=1.14，P=0.001）的独立不良预后因素。
KYN途径酶和代谢产物参与ccRCC是通过免疫和非免疫机制。我们的数据表明，KTR可作为ccRCC侵袭性的标志物以及CSS和PFS的预后因素。
