Tumor M2-Pyruvate Kinase, Matrix Carbonic Anhydrase IX, and Metalloproteinase 9 — Novel Prognostic Markers of Renal Cell Carcinoma

Abstract

The aim of the study was to assess the possibility of using plasma levels of tumor M2-pyruvate kinase (Tu M2-PK), matrix carbonic anhydrase IX (CA9), and matrix metalloproteinase 9 (MMP9) in patients with renal cell cancer as predictors of the disease course and the response to treatment. Materials and Methods. Samples of blood plasma or serum of 46 patients with clear cell renal cancer T 1-4 N 0-1 M 0-1 obtained before surgery and 8-9 days after surgery were tested. The control group consisted of 20 practically healthy individuals, comparable in age with the examined patients. Quantitative determination of Tu M2-PK in EDTA-added blood plasma was performed by enzyme-linked immunosorbent assay using a ScheBo Tumor M2-PK test (Germany). Determination of CA9 by ELISA was performed using a Human Carbonic Anhydrase IX Quantikine ELISA Kit (USA) and MMP9-using a Quantikine ELISA Kit (USA). Results. In patients with renal cell carcinoma, a statistically significant increase in the level of Tu M2-PK, CA9 and a statistically significant decrease in MMP9 in comparison with the control group were found. The level of Tu M2-PK in patients with localized kidney cancer was significantly lower than in patients with disseminated cancer. An increase in size of the primary tumor and a decrease in the degree of its differentiation correlated with an increase in Tu M2-PK, and decrease in CA9 and MMP9 in the blood serum. Performing surgery equivalent to nephrectomy did not change the Tu M2-PK levels in the early postoperative period, but caused a decrease in the levels of CA9 and MMP9. Conclusion. The results indicate a potential significance of Tu M2-PK, CA9, and MMP9 as biological markers for predicting the disease course in patients with renal cell carcinoma.

Posttranslational Modifications Pattern in Clear Cell Renal Cell Carcinoma

“…In patients with renal cell carcinomas, TuM2-PK levels were back to baseline from 6 to 11 weeks after surgical removal of the tumor when patients had no relapse, and were constantly higher in patients with relapse or metastasis [ 67 ]. Some studies report that high extracellular levels of TuM2-PK, a metabolic marker, are associated with ccRCC progression, strongly related to tumor stage and aggressivity, differentiation grade, accumulation of phosphometabolites, phospholipids and amino acids synthesis, all used by the tumoral cells [ 66 , 67 , 68 , 69 , 70 ]. Extracellular TuM2-PK stimulates tumoral increase, promotes tumoral angiogenesis, endothelial cells migration, and attachment to the extracellular matrix [ 69 , 107 ].…”

“…Some studies report that high extracellular levels of TuM2-PK, a metabolic marker, are associated with ccRCC progression, strongly related to tumor stage and aggressivity, differentiation grade, accumulation of phosphometabolites, phospholipids and amino acids synthesis, all used by the tumoral cells [66][67][68][69][70]. Extracellular TuM2-PK stimulates tumoral increase, promotes tumoral angiogenesis, endothelial cells migration, and attachment to the extracellular matrix [69,107]. In conclusion, TK-1 and TuM2-PK factors play a key role of enzymes involved in the highly proliferative cells in advanced RCC.…”

“…Its variation after repeated assessments was considered to show the remission or the relapse of the tumor [ 56 , 61 , 62 , 63 ]. Many tumoral cells are characterized by pyruvate-kinase overproduction [ 66 , 67 , 68 , 69 , 70 ]. Many isoforms of pyruvate-kinases were identified L-PK (liver, kidney), R-PK (erythrocytes), M1-PK (muscles, brain), and M2-PK (liver, tumoral cells).…”

“…TuM2-PK was determined in the blood of patients with renal cancer and other nephropathies (nephritis, diabetic nephropathy). The circulant level of this protein shows the activity and progression of the tumoral process and it is important in identifying metastatic disease, the tumoral relapse, and in monitoring therapeutic response [ 66 , 68 , 69 , 70 ].…”

“…Clear cell renal cell carcinoma (ccRCC) is the most frequent and studied kidney cancer. Some studies regarding PTMs in ccRCC were developed but only using immunohistochemical staining, and none in patients’ sera [ 5 , 6 , 61 , 66 , 67 , 68 , 69 , 70 ]. The aim of the present study was to determine the significance of posttranslational modifications in the pathogenesis of renal cell carcinoma.…”