Investigation of CCL18 and A1AT as potential urinary biomarkers for bladder cancer detection.

Makito Miyake,Adrienne Lawton,Yunfeng Dai,Evan Gomes Giacoia,Steve Goodison,Myron Chang,Lourdes Mengual,Shanti Ross,Charles J Rosser,Antonio Alcaraz

doi:10.1186/1471-2490-13-42

Abstract

BackgroundIn this study, we further investigated the association of two biomarkers, CCL18 and A1AT, with bladder cancer (BCa) and evaluated the influence of potentially confounding factors in an experimental model.MethodsIn a cohort of 308 subjects (102 with BCa), urinary concentrations of CCL18 and A1AT were assessed by enzyme-linked immunosorbent assay (ELISA). In an experimental model, benign or cancerous cells, in addition to blood, were added to urines from healthy controls and analyzed by ELISA. Lastly, immunohistochemical staining for CCL18 and A1AT in human bladder tumors was performed.ResultsMedian urinary protein concentrations of CCL18 (52.84 pg/ml vs. 11.13 pg/ml, p < 0.0001) and A1AT (606.4 ng/ml vs. 120.0 ng/ml, p < 0.0001) were significantly elevated in BCa subjects compared to controls. Furthermore, the addition of whole blood to pooled normal urine resulted in a significant increase in both CCL18 and A1AT. IHC staining of bladder tumors revealed CCL18 immunoreactivity in inflammatory cells only, and there was no significant increase in these immunoreactive cells within benign and cancerous tissue and no association with BCa grade nor stage was noted. A1AT immunoreactivity was observed in the cytoplasm of epithelia cells and intensity of immunostaining increased with tumor grade, but not tumor stage.ConclusionsFurther development of A1AT as a diagnostic biomarker for BCa is warranted.

Highlights

In this study, we further investigated the association of two biomarkers, CCL18 and A1AT, with bladder cancer (BCa) and evaluated the influence of potentially confounding factors in an experimental model
Two single-protein biomarker urinebased assays, bladder tumor antigen (BTA) test and nuclear matrix protein-22 (NMP-22) test, have been developed and FDA approved for use in this context
Through genomic and proteomic profiling of urine components, we have previously identified a panel of biomarkers that can outperform current urine-based biomarkers for the non-invasive detection of BCa [11,12,13,14]

Summary

Introduction

We further investigated the association of two biomarkers, CCL18 and A1AT, with bladder cancer (BCa) and evaluated the influence of potentially confounding factors in an experimental model. Non-invasive urine tests for the early detection or postsurgical surveillance of bladder cancer (BCa) are highly desirable for both the patient and the healthcare system. Voided urinary cytology (VUC) is the most widely used non-invasive urine test, with reported specificities ranging from 85-100% and sensitivities ranging from 13-75% [1,2]. Two single-protein biomarker urinebased assays, bladder tumor antigen (BTA) test and nuclear matrix protein-22 (NMP-22) test, have been developed and FDA approved for use in this context. The BTA tests (BTA statTM and BTA TRAKTM (Polymedco Inc. Cortlandt Manor, NY, USA) have diagnostic sensitivities ranging from 29-83% and specificities ranging from 56-86%

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