Marker for renal cell carcinoma (RCC): the dimeric form of pyruvate kinase type M2 (Tu M2-PK).

ABSTRACT

OBJECTIVE: The evaluate a potential tumor marker for RCC. Tumor formation is generally linked to an expansion of glycolytic phosphometabolite pools and aerobic glycolyticflux rates. To achieve this, tumor cells generally overexpress a special glycolytic isoenzyme, termed pyruvate kinase type M2. To establish the expansion of phosphometabolite pools pyruvate kinase switches between a tetrameric form with high phosphoenol-pyruvate (PEP) affinity and a dimeric form with a lower PEP affinity. The dimeric form is predominant in all tumors that have been investigated and has been termed TuM2Pk. MATERIALS AND METHODS: We studied a) the expression of TuM2Pk in RCC by immunohistochemistry using a monoclonal antibody recognizing only the mono- or dimeric form of pyruvate kinase, b) the stability of TuM2Pk in serum by measuring TuM2Pk in 3 patients at different times after taking blood with a two-site immunometric assay, c) the a circadiane rhythm of TuM2Pk in blood by measuring levels every 4 hours in 5 patients, d) TuM2Pk- expression in serum (see 2.) in 5 patients by taking blood from tumor-side vena renalis compared to peripherally blood, e) TuM2Pk (see point 2.) in 40 RCC-patients comparing the results with 39 healthy persons and clinical data of RCC, f) the influence of wound healing to TuM2Pk by measuring serum-levels during a period of more than 12 weeks in 6 patients, g) the individual follow up of 4 patients with RCC stage Robson III for more than 2 years. Comparing TuM2Pk-levels to findings of staging by computed tomography. RESULTS: The isoenzyme TuM2Pk could be demonstrated in RCC and their metastases by immunohistochemistry with a monoclonal antibody specific for pyruvate kinase type M2. In normal kidney cells pyruvate kinase type M2 is not detectable. The stability of TuM2Pk was studied in the serum within 30 minutes. No circadian rhythm was found. Most serum TuM2Pk comes from tumor. Serum evaluation in 39 healthy persons was used to determine normal values, with an upper concentration of 28 U/ml of TuM2Pk (95% percentile of normal healthy persons). Serum evaluation in 40 RCC showed a significant difference to healthy persons and a positive correlation with Robson stage and grading No correlation of TuM2Pk was found with histopathological cell type of tumor diameter. After radical nephrectomy normalization of TuM2Pk level was found within 11 weeks in all localized RCC. Continuously elevated serum levels were seen in metastatic RCC. Individual follow-up seems to be possible. CONCLUSION: Initial discrimination is not possible between localized and metastasized RCC using TuM2PK; however, it is possible to differentiate between benign and malignant renal processes; the specificity under these circumstances is 75%. After successful surgery of localized RCC, an elevated TuM2Pk will be normalized within 11 weeks, and will be remain elevated or will increase again in case of RCC-relapse or metastasis. Thus TuM2Pk would appear to be a useful marker for RCC detection and follow-up.