ReviewCurrent status of urinary diagnostic biomarkers for colorectal cancer
Introduction
Colorectal cancer (CRC) is one of the most frequent causes of cancer-related deaths worldwide with an incidence rate of 31.6 (male) and 21.2 (female)/100,000 person-years and a death rate of 15.5 (male) and 10.5 (female)/100,000 person-years [1]. Since patients with early stage CRC can be cured with minimally invasive therapy including endoscopic resection, it is very important to identify patients with early stage CRC by mass screening. Fecal occult blood test (FOBT) and flexible sigmoidoscopy have been established as screening methods and there is strong evidence that these methods can help reduce disease-specific morbidity and mortality in CRC [2,3]. The American Cancer Society recommends either stool-based tests (FOBT or DNA) or structural tests [colonoscopy or computed tomography colonography (CTC)] for adults aged 50 years and older [4]. However, FOBT is well known to have many false positives and is easily affected by non-specific bleeding, thus initiating unnecessary invasive examinations [5]. In addition to its invasiveness, colonoscopy is also costly and time consuming. These reasons make it difficult to disseminate colonoscopy globally as a method of medical checkup. Although CTC might be proposed for patients who refuse colonoscopy, benefits of CTC in terms of accuracy and comfortability are unclear [6,7].
Research for non-invasive detection of CRC has been conducted using various materials in serum/plasma, feces, and urine. Serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA19–9) are commonly used as less-invasive biomarkers in clinical practice; however, their sensitivities are very low, and they cannot accomplish early stage detection [8]. Despite the less-invasiveness, serum sample collection still needs special instruments and healthcare professionals to draw blood. Compared to reports regarding serum and fecal samples, there are much fewer reports using urine samples as a diagnostic biomarker of CRC. However, urine containing various components is considered to be an ideal sample for medical checkup because it can be collected completely non-invasively without requiring the patients to visit the clinic (Fig. 1) [9,10]. In addition, the urinary tract is so clean biologically that the materials in urine might be less affected by microorganisms than in feces. The discovery of urinary biomarker is thus desirable for the diagnoses of several malignancies including CRC. We have had longstanding interest in the discovery of urinary diagnostic biomarkers for gastrointestinal cancers including gastric cancer and CRC [[11], [12], [13], [14]]. In this review, we summarize and discuss urinary biomarkers that can be used for the detection of CRC.
Section snippets
Protein markers
Since excreted proteins are not abundant in urine, a small amount of urinary protein may be a disadvantage in the detection of CRC because it is sometimes difficult to identify these slight differences in the concentration of target proteins. On the other hand, this small amount of target protein is an advantage in the identification of reliable biomarkers because the urinary target protein that emerges after glomerular filtering and tubular resorption in kidney is not contaminated with large
Genetic markers
DNA methylation regulates transcription and its abnormality could cause carcinogenesis. Furthermore, DNA methylation is also expected to be useful as a diagnostic marker and therapeutic target for CRC [[25], [26], [27]]. It is possible that mutated DNAs that originate from cancer tissues are excreted into the urine either within enclosed microvesicles such as exosomes or in the naked form [28,29]. As shown in Table 2, there are several reports of urinary genetic markers using methylated or
Metabolomics
Since urinary metabolites are derived from glomerular filtration of serum and secretion in the renal tubule, it is possible that the metabolites secreted into the blood from cancer tissues are detected in urine of the patients with CRC. The development of metabolomics using nuclear magnetic resonance (NMR) and mass spectrometry (MS) has made it possible to analyze a large number of metabolites [37,38].
Table 3 lists the urinary metabolite biomarkers used in the detection of CRC. Notably, despite
Prostaglandin/reactive oxygen species
It has been reported that prostaglandin E2 (PGE2) plays crucial roles in promoting angiogenesis and carcinogenesis under the regulation of cyclooxygenase-2 (COX-2), consequently resulting in proliferation and metastasis [53,54]. Meanwhile, reactive oxygen species (ROS) generated by oxidative stress such as inflammation can induce nucleic acid damage and ROS are associated with carcinogenesis [[55], [56], [57]]. Based on these reports, some studies identified the diagnostic biomarkers related to
Other markers
Other specific biomarkers are summarized in Table 5. Hirotsu et al. reported a very unique method that used Caenorhabditis elegans (C. elegans) having chemotaxis to the urine from patients with CRC. Albeit a small sample size of CRC, C. elegans showed an excellent diagnostic performance with 100% sensitivity and 95% specificity [61]. There is another unique method that uses canine scent in the detection of CRC from breath and fecal samples with over 90% sensitivity and specificity [62].
Conclusions
The present review provided the candidates for urinary diagnostic biomarkers for the diagnosis of CRC. Although none of them have been clinically applied because of the lack of validation, accumulating evidence indicates the potency of urinary test as a screening tool for CRC. Although the fecal assays including FOBT and MT-sDNA are more advanced for CRC diagnosis, urine samples still have some advantages compared to faces and blood samples. First, as urine contains very few protein and
Declaration of Competing Interest
None of the authors declare any conflicts of interest. No financial support was received for this study.
Acknowledgements
The authors would like to thank Honyaku Center Inc. (https://www.honyakucenter.jp/) for the English language review. Financial support was not received for this study.
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