Validation of the diagnostic utility of urinary midkine for the detection of bladder cancer

Abstract

As it has been demonstrated previously that midkine (also known as neurite growth-promoting factor 2) protein levels in urine of bladder cancer (BCa) patients are increased compared to healthy controls, the present study validated the diagnostic utility of midkine in an independent patient cohort and compared the observed values with voided urine cytology (VUC), which is the current reference standard for non-invasive diagnosis of BCa. Voided urine samples were prospectively collected from 92 BCa patients and 70 control subjects. Protein levels of midkine were assessed using a commercially available enzyme-linked immunosorbent assay and normalized to urinary creatinine. The diagnostic performance of urinary midkine was evaluated by receiver operating characteristic curves. The best combinations of sensitivities and specificities were determined by Youden's Index. Midkine concentrations were significantly elevated in urine samples from BCa patients compared to controls (P<0.001; Mann-Whitney U Test). The level of midkine was associated with disease progression, with the highest concentrations in urine specimens of patients with pT1 and ≥pT2a, as well as high-grade tumors (P<0.001; Mann-Whitney U test). Sensitivities of urinary midkine and VUC were 69.7 and 87.6%, respectively. The corresponding specificities for midkine and VUC were 77.9 and 87.7%, respectively. The combined use of VUC and midkine improved the sensitivity to 93.3%, but reduced the specificity to 66.2%. Despite its reduced discriminatory power for low-grade and low-stage BCa, urinary midkine can be utilized for the identification of high-grade pT1 and ≥pT2a tumors. This means that midkine may potentially be suitable for the identification of patients with high risk BCa.

Prognostic value of Midkine expression in patients with solid tumors: a systematic review and meta-analysis

“…Serum and plasma levels of MDK are evidently correlated with diagnosis and prognosis in cancer patients (higher MDK level usually suggests tumor occurrence and worse prognosis). Furthermore, MDK was detected in urine, and its high expression in urine might be correlated with worse prognosis in patients with bladder cancer [ 15 , 33 ]. Moreover, MDK was associated with relapse free survival in patients with cancers [ 34 , 35 ].…”

“…In tumors, MDK can promote tumor cells differentiation, proliferation, anti-apoptosis, chemoresistance, transformation and epithelial-mesenchymal transition (EMT) [ 4 – 7 ]. High MDK protein expression has been reported in several cancer types and associated with the cancer progression, including gastric cancer [ 8 ], pancreatic cancer [ 9 ], lung cancer [ 10 ], breast cancer [ 11 ], colorectal carcinoma [ 12 ], esophageal cancer [ 13 ], hepatocellular carcinoma [ 14 ] and bladder cancer [ 15 ]. An important example, MDK is overexpressed in about 50% of pancreatic cancer patients, and participates in the tumor cells chemotherapy resistance through the Notch 2 signaling pathway [ 16 ].…”

The Role of Midkine in Arteriogenesis, Involving Mechanosensing, Endothelial Cell Proliferation, and Vasodilation

“…Yet, the cellular source of MK in the vascular system has not been fully elucidated. Elevated MK serum levels are found in patients with different tumor entities and have been shown to correlate with poor prognosis and recurrence after tumor removal [ 2 , 3 , 4 ]. The tumor cells may be the source of MK in this case, as malignant tissue often shows high MK expression [ 5 ].…”

“…However, multiple studies during the last three decades clearly indicated a functional impact of MK on the adult organism as well. By far, most of the studies on MK addressed its role in malignant diseases and suggested a detrimental effect for the host [ 2 , 3 , 4 , 5 ]. A significant part of the literature on MK has shown its ability to promote inflammatory responses.…”

Effect of midkine on gemcitabine resistance in biliary tract cancer

“…Midkine (MDK), a heparin-binding growth factor, was first identified as a highly expressed factor involved in embryonic development ( 12 ). MDK has been reported to have important roles in the survival, growth and migration of cells, which may contribute to oncogenesis and tumor progression in numerous types of cancer ( 13 – 18 ). Several studies have demonstrated that MDK mediates drug resistance.…”