Agrawal Usha, Kumari Nitu, Mishra Ashwani K, Vasudeva Pawan, Kumar Anup, Mohanty Nayan K, Saxena Sunita
National Institute of Pathology, Indian Council of Medical Research, New Delhi, India; Symbiosis International University, Lavale, Pune, India.
National Institute of Pathology, Indian Council of Medical Research, New Delhi, India; BITS, Pilani, Rajasthan, India.
Urol Oncol. 2016 Sep;34(9):418.e17-26. doi: 10.1016/j.urolonc.2016.04.013.
Urothelial carcinoma (UC) is one of most common genitourinary malignancy and the spectrum of disease ranges from in situ lesions to muscle-invasive cancers. The non-muscle-invasive lesions have tendency to recur or progress to muscle-invasive disease. The study of the immune profile may identify immune determinants associated with high-grade, recurrence, and invasion in patients with UC.
Pathway-focused RT(2) profiler arrays were used to screen patients with UC for dysregulation of candidate genes of Th1-Th2-Th3 and NFκB pathways, which were then validated by real-time polymerase chain reaction on tumor samples and correlated with grade, recurrence, and invasion of tumors to identify their role in predicting behavior of the tumor. The cytokines found associated with recurrence were then validated in urine of patients with UC.
IFNγ, IL2, IL4, IL10, IL17, CCL7, CTLA4, and SPP1 of the cytokine pathway and TLR4, TLR3, RELA, NFκB1, and MYD88 of the NFκB pathway were found differentially expressed in patients with urothelial cancer by array and quantative real-time polymerase chain reaction. Among these, IL10 and SPP1 were found consistently up-regulated in high-grade, invasive, and recurrent cases and up-regulated IL10 and CTLA4 were found associated with a short recurrence-free survival time (P = 0.001 and P = 0.065). Urinary IL10 concentration was significantly higher in both patients with cancer and cystitis compared with healthy controls, but the difference in concentration between patients with cancer and cystitis patients was not statistically significant. However, urinary CTLA4 concentrations were found to be significantly higher in urothelial cancer patients compared with healthy controls and cystitis cases and found to be associated with poor recurrence-free survival.
The study indicates that high urinary CTLA4 concentration raises the index of suspicion of recurrence in a known case of urothelial cancer and may be used as a surveillance marker.
尿路上皮癌（UC）是最常见的泌尿生殖系统恶性肿瘤之一，疾病范围从原位病变到肌肉浸润性癌。非肌肉浸润性病变有复发或进展为肌肉浸润性疾病的倾向。免疫谱研究可能会识别出与UC患者的高级别、复发和浸润相关的免疫决定因素。
使用通路聚焦RT(2) Profiler阵列筛选UC患者中Th1-Th2-Th3和NFκB通路候选基因的失调情况，然后通过对肿瘤样本进行实时聚合酶链反应进行验证，并与肿瘤的分级、复发和浸润相关联，以确定它们在预测肿瘤行为中的作用。然后在UC患者的尿液中验证发现与复发相关的细胞因子。
通过阵列和定量实时聚合酶链反应发现，细胞因子通路的IFNγ、IL2、IL4、IL10、IL17、CCL7、CTLA4和SPP1以及NFκB通路的TLR4、TLR3、RELA、NFκB1和MYD88在尿路上皮癌患者中差异表达。其中，IL10和SPP1在高级别、浸润性和复发病例中持续上调，上调的IL10和CTLA4与无复发生存时间短相关（P = 0.001和P = 0.065）。与健康对照相比，癌症患者和膀胱炎患者的尿IL10浓度均显著更高，但癌症患者和膀胱炎患者之间的浓度差异无统计学意义。然而，发现尿路上皮癌患者的尿CTLA4浓度与健康对照和膀胱炎病例相比显著更高，并且与无复发生存不良相关。
该研究表明，尿CTLA4浓度高会增加已知尿路上皮癌病例复发的怀疑指数，可作为监测标志物。
