Serum Exosomal Gamma-Glutamyltransferase Activity Increased in Patients with Renal Cell Carcinoma with Advanced Clinicopathological Features

Abstract

Background: There has been no clinically useful diagnostic or prognostic biomarker for renal cell carcinoma (RCC). Serum γ-glutamyltransferase (GGT) activity has been reported to be a prognostic marker for several types of cancer including RCC. Exosomes or small extracellular vesicles present in body fluids have potential as a biomarker. We have recently demonstrated that GGT activity on exosomes isolated from serum is useful for the differential diagnosis of prostate cancer and benign prostate hyperplasia. In this study, we aimed to examine if serum exosomal GGT activity could be a marker for RCC. Methods: We examined GGT1 expression and GGT activity in cell lysates and exosomes from culture medium of HK-2 proximal tubule epithelial and RCC cell lines. GGT activity was measured using a fluorescent probe for GGT, γ-glutamyl hydroxymethyl rhodamine green. Serum and serum exosomal GGT activities were measured in patients with RCC. GGT1 expression in RCC tissues was evaluated by immunohistochemical staining. Results: GGT1 levels in exosomes from KMRC-1, OS-RC-2 and 786-O cells were elevated compared with those from HK-2 cells. In exosomes, GGT1 expression correlated with GGT activity determined using a fluorescent probe for GGT. In RCC patients, serum exosomal GGT activity was elevated in those with advanced stages (III/IV vs. I/II, p = 0.037) and those with microvascular invasion (with vs. without, p = 0.034). Immunohistochemical analysis showed that membranous GGT1 expression was increased in RCC with microvascular invasion. Notably, preoperative serum exosomal GGT activity could predict the likelihood of having microvascular invasion diagnosed by pathological examination of surgically resected specimens. Conclusions: Our results suggest that serum exosomal GGT activity could be a clinically useful marker for advanced clinicopathological features of RCC patients, and its combined use with conventional diagnostic modalities may improve the diagnosis and treatment of patients.

Expression Status and Prognostic Significance of Gamma-Glutamyl Transpeptidase Family Genes in Hepatocellular Carcinoma

“…Further, its inhibition significantly decreased the migration of tumor cells, suggesting that GGT1 might be of therapeutic interest for patients with renal cancer (24). Another study further revealed that serum exosomal GGT1 could be a useful marker for advanced clinical features of patients with renal cancer (25). Kawakami et al (26) found that the activity of serum exosomal GGT1 was significantly higher in individuals with prostate cancer than those with benign prostatic hyperplasia.…”

“…Moreover, serum GGT combined with other serum biomarkers were effective diagnostic markers of AFP-negative HCC, especially in individuals with early stage, small size or good liver function (42). More researchers continue to assess the prognostic role of serum GGT in cervical cancer (43), esophageal squamous cell carcinoma (44), ovarian cancer (45), renal cell carcinoma (25), and HCC (46). By carrying out a clinical analysis, Zhang et al (15) found that a high concentration of serum GGT was positively associated with advanced TNM stage and large tumor size and was an independent element for predicting the OS rate of patients with primary HCC.…”

A Systematic Review of Serum γ-Glutamyltransferase as a Prognostic Biomarker in Patients with Genitourinary Cancer

“…Serum exosomal GGT activity has recently been reported as superior to serum total GGT activity as a biomarker for predicting the clinicopathological features of patients with RCC [99]. The authors of the study concluded that exosomal GGT reflected the characteristics of the original cancer cells and might indeed predict the likelihood of a microvascular invasion while the total serum GGT activity could not.…”

Proteomic analysis of extracellular vesicles identified PI3K pathway as a potential therapeutic target for cabazitaxel‐resistant prostate cancer

“…We have previously reported several EV markers in serum and urine that are useful for diagnosis and monitoring of several diseases including PC. [8][9][10][11][12][13][14] EV samples isolated from serum by conventional methods such as sequential centrifugation, polymer-based precipitation, gelfiltration, and immunoaffinity are not suitable for proteomic analysis, because they are heavily contaminated with serum proteins. Recently, a novel affinity-based method was reported in which highly purified EVs are isolated using T-cell immunoglobulin domain and mucin domain-containing protein 4 (hereinafter referred to as Tim4) that recognizes phosphatidylserine (PS) on EVs, allowing us to identify disease-associated proteins in serum EVs.…”

“…Since blood can be collected in a less invasive manner, EV markers in blood can be analyzed repeatedly. We have previously reported several EV markers in serum and urine that are useful for diagnosis and monitoring of several diseases including PC 8‐14 …”