Soluble chemokine (C-X-C motif) ligand 16 (CXCL16) in urine as a novel biomarker candidate to identify high grade and muscle invasive urothelial carcinomas.

Kerstin Lang,Volker Harth,Sibylle Robens,Thomas Brüning,Andrea Tannapfel,Jan Hovanec,Joachim Noldus,Yu Chun Tam,Katharina Braun,Raimund Erbel,Thomas Behrens,Heiko Udo Käfferlein,Nadine Bonberg,Karl-Heinz Jöckel,Florian Roghmann,Thomas Deix

doi:10.18632/oncotarget.20737

Abstract

Information on biomarkers of urothelial carcinomas (UC) for clinical decision-making is limited. Here, we newly identified and verified CXCL16 as a promising novel biomarker in urine for high grade and muscle invasive UC in a cross-sectional cohort of 308 UC patients, 126 urological hospital controls, and 50 population controls using antibody arrays and ELISA. Median CXCL16 levels in urine was significantly higher in UC patients (273.2 pg/mg creatinine) compared to hospital (148.1 pg/mg) and population controls (85.1 pg/mg) with a particular preference for high grade (460.8 pg/mg), muscle invasive (535.7 pg/mg) and primary UC (327.8 pg/mg) (all p<0.0001). Group differences were confirmed after adjusting or stratifying for potential clinical and individual characteristics, such as leukocyte counts, haematuria, age, gender, and smoking status. In contrast, CXCL16 showed less discriminating power in low grade (244.3 pg/mg), non-muscle invasive (≤pT1, 251.2 pg/mg) and recurrent UC (203.9 pg/mg). In agreement with its function in immune defence, expression of CXCL16 in tissue samples of primary UC patients (n=53) showed only a weak or no immunoreactivity compared to urological hospital controls (n=32). Expression of CXCR6, the G-protein-coupled receptor of CXCL16, remained unchanged. Our findings suggest that evading the immune defence by shedding cell-surface CXCL16 and its increased elimination in urine is a molecular feature of high grade and muscle invasive UC. Therefore, urinary CXCL16 may serve as a useful, simple and non-invasive tool to identify high-risk UC with increased risk of progression at the molecular level.

Highlights

Urothelial carcinoma (UC) is one of the most prevalent types of cancer worldwide, with an estimated 386,000 primary cancer cases diagnosed each year
CXCL16 levels were intermediate to high in tissue samples from patients with low grade urothelial carcinomas (UC) and urocystitis, while its levels in urine were low. In this cross-sectional study with UC cases and two groups of controls, we identified CXCL16 as a novel biomarker candidate for UC with a preference for highgrade, muscle-invasive and primary UC
CXCL16 was excreted in about 4-fold higher concentrations in pretherapeutic urine samples from patients with high-grade UC compared to voided urine samples from hospital and population controls

Summary

Introduction

Urothelial carcinoma (UC) is one of the most prevalent types of cancer worldwide, with an estimated 386,000 primary (new) cancer cases diagnosed each year It is considerably more common in males than in females [1], and at the time of initial diagnosis, approximately 80% of patients present with non-muscle invasive cancer (i.e., pTa and pTis) [2]. The patient and the physician can make an informed decision, i.e., prior to using an invasive technique, such as cystoscopy which can be uncomfortable, especially in male patients. Such a biomarker should be able to predict any type of UC (general diagnostics). The results can be used by the pathologist to confirm the histological evaluation at the molecular level, and by the physician and patient to help plan the most appropriate treatment

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Conclusion