Tumor M2 Pyruvate Kinase Research Articles

Pyruvate kinase isoenzyme M2 is not of diagnostic relevance as a marker for oral cancer

Increased aerobic glycolysis is one of the most common abnormalities occurring in the metabolism of tumour cells with pyruvate kinase as one of the key glycolytic enzymes. The dimeric form of M2-pyruvate kinase, found predominantly in tumour cells, is designated as tumour M2-pyruvate kinase (TuM2-PK). The aim of the present, prospective study was to evaluate the diagnostic relevance of TuM2-PK in detecting oral squamous cell carcinoma (OSCC). TuM2-PK concentration was analysed in ethylene diaminetetraacetic acid plasma of 80 untreated patients with histologically confirmed OSCC stages T3 and T4, whilst 90 patients with non-malignant diseases served as controls. The analysis was done using a sandwich enzyme-linked immunosorbent assay (ScheBo Biotech AG, Giessen, Germany). Immunohistochemical detection of TuM2-PK was performed by specific mouse monoclonal antibody DF-4. The median TuM2-PK concentration was 22.92U/ml in the tumour group and 10.00U/ml in the control group (p<0.001). Using 15U/ml as a cut-off yielded a sensitivity of 63% and a specificity of 59%. Moreover, the positive and negative predictive values were 57% and 64%, respectively. Immunohistochemical staining of tissue sections showed that TuM2-PK was not selectively expressed in tumour cells but also in non-malignant cells, particularly in more regenerative ones. Low sensitivity and specificity for stages T3 and T4 OSCC render the TuM2-PK test unsuitable as a tool for detecting OSCC, particularly in an early stage. Thus, routine clinical and radiological follow-up is indispensable after treatment of OSCC.

Tumor M2-Pyruvate Kinase as Tumor Marker in Exocrine Pancreatic Cancer A Meta-Analysis

Tumor M2-pyruvate kinase, a tumor-associated dimeric form of enzyme pyruvate kinase, is commonly elevated in pancreatic cancers. This meta-analysis aimed to evaluate its diagnostic utility in comparison to carbohydrate antigen 19-9 (CA19-9) in pancreatic cancer. A literature search was conducted for entries from 1951 to 2006 using PubMed, Embase, Central, and SCI Expanded databases using M2 pyruvate kinase AND pancreatic cancer/s OR tumor/s as keywords. A total of 258 references were retrieved. Of these, 118 duplicates were removed and 132 references were excluded. All studies comparing TuM2-PK with CA19-9 in pancreatic cancer were included. Full text was obtained for 8 references of 7 included studies. Diagnostic odds ratio (DOR) and 95% confidence interval (CI) was calculated from the available specificity and sensitivity for each study and were pooled to give overall DOR and 95% CI for TuM2-PK and CA19-9. Receiver operator characteristic curve was calculated to give overall specificity and sensitivity for TuM2-PK. The diagnostic performance of TuM2-PK (DOR, 35; 95% CI, 19.7-62.3) was similar to those of CA19-9 (DOR, 44; 95% CI, 26.5-73.1). The overall specificity for TuM2-PK was 60% with corresponding sensitivity of 95%. Efficacy of TuM2-PK as a tumor marker is similar to that of CA19-9. Further trials are needed to use it alone or in combination with CA19-9 in patients with suspected pancreatic cancer.

Diagnostic and Prognostic Value of Plasma Tumor M2 Pyruvate Kinase in Periampullary Cancer

This prospective study examines the diagnostic and prognostic use of tumor-M2-pyruvate kinase (Tu-M2-PK) used in conjunction with carbohydrate antigen (CA) 19-9 in patients with subsequently histologically confirmed periampullary malignancy. Plasma Tu-M2-PK and serum CA 19-9 levels were measured at admission in a cohort of patients with suspected pancreatic cancer. Values for Tu-M2-PK and serum CA 19-9 were compared with a control group comprising jaundiced patients in whom malignancy was excluded by endoscopic retrograde cholangiopancreatography and nonjaundiced individuals undergoing laparoscopic cholecystectomy. The mean (SD) plasma Tu-M2-PK level for patients with histologically proven malignancy was 40.5 (26.4) U/mL and for noncancer patients, 29.9 (20.9) U/mL (Mann-Whitney U = 1163, P = 0.006). Tumor-M2-pyruvate kinase had an area under the curve of 0.623 on receiver operating characteristic curve analysis, and at optimal cutoff of 27 U/mL, sensitivity is 66%, and specificity is 58%.However, on multivariate Cox regression modeling, elevated Tu-M2-PK (>27 U/mL) was strongly correlated with the subsequent finding of poorly differentiated cancer and/or metastatic disease and strongly predicted survival on Kaplan-Meier analysis. An elevated Tu-M2-PK more than 27 U/mL measured on admission in suspected periampullary cancer is a predictor of adverse prognosis in periampullary cancer.

Tumour M2-pyruvate kinase: a gastrointestinal cancer marker

Gastrointestinal cancer tumour markers are valuable in the detection of recurrence following resection or in monitoring response to chemotherapy. CEA, CA19-9, CA-50 and CA72-4 are currently available but are nonspecific and have a low sensitivity. 'Tumour M2-pyruvate kinase' was described by Eigenbrodt around 1985. In cancers the active tetrameric form of the M2 isoenzyme of pyruvate kinase converted to an inactive dimeric form by direct interaction with oncoproteins to channel glucose carbons into DNA synthesis. This review summarizes the current knowledge of this unique tumour marker with regard to its biochemistry, assay and potential use as a diagnostic and screening tool in gastrointestinal cancer. A literature search was conducted for entries from 1980 to 2005 using PubMed and NeLH databases using tumour M2-pyruvate kinase, faecal tumour M2-pyruvate kinase, tumour metabolism, tumour markers and carcinoembryonic antigen as keywords. A total of 56 references relevant to tumour M2-pyruvate kinase were retrieved. Eighteen references were clinical studies involving plasma/faecal tumour M2-pyruvate kinase and gastrointestinal cancer. The remaining 38 references were clinical/nonclinical trials and reviews on tumour metabolism and plasma/faecal tumour M2-pyruvate kinase assay. Seven of the 18 clinical studies involved faecal M2-pyruvate kinase. Three of the 11 plasma tumour M2-pyruvate kinase studies were non-English language and were excluded. The sensitivity, specificity, positive predictive and negative predictive value for plasma/serum tumour M2-pyruvate kinase in the detection of gastrointestinal cancer was determined for each of the remaining eight studies. Data for gastrointestinal cancer M2-pyruvate kinase were compared with other gastrointestinal cancer markers. Data from three of the eight studies using a diagnostic cut-off value of 15 U/ml for ethylenediaminetetraacetic acid (EDTA) plasma tumour M2-pyruvate kinase were analysed together as a small meta-analysis. At a diagnostic cut-off value of 15 U/ml for tumour M2-pyruvate kinase in EDTA plasma the sensitivity, specificity, positive predictive and negative predictive value was 57.3, 89, 85.7 and 64.8%, respectively, for colorectal cancers, 62.1, 89, 88 and 64%, respectively, for gastric/oesophageal cancers and 72.5, 89, 58 and 94%, respectively, for pancreatic cancers. As a faecal marker for colorectal cancers, faecal tumour M2-pyruvate kinase has a sensitivity of 73-92% at a cut-off value of 4 U/ml as against 50% sensitivity for Guaiac faecal test. Circulating tumour M2-pyruvate kinase is more commonly elevated in oesophageal, gastric and colorectal cancer patients than conventional tumour markers. Faecal M2-pyruvate kinase is a sensitive marker of colorectal cancer. The clinical role of tumour M2-pyruvate kinase in gastrointestinal cancer management should be investigated in large-scale clinical trials.

Fecal tumor M2 pyruvate kinase is not a specific biomarker for colorectal cancer screening

Yogesh M Shastri, Jurgen Stein, Department of Medicine I-ZAFES, Division of Gastroenterology and Clinical Nutrition, Johann Wolfgang Goethe-University Hospital, Frankfurt am Main, Germany Correspondence to: Professor J Stein, MD, PhD, Medizinische Klinik I-ZAFES, J. W. Goethe-University Hospital, TheodorStern-Kai 7, 60590 Frankfurt/Main, Germany. j.stein@em.uni-frankfurt.de Telephone: +49-69-63016232 Fax: +49-69-63016246 Received: 2007-02-01 Accepted: 2007-03-26

Tumor M2 Pyruvate Kinase as a Stool Marker for Colorectal Cancer: Stability at Room Temperature and Implications for Application in the Screening Setting

Colorectal cancer (CRC) remains the third most common malignancy worldwide (1)(2). To improve noninvasive screening for CRC, various stool tests have been described based on tumor-associated markers (3). Among these is a test for fecal tumor M2 pyruvate kinase (M2-PK) activity (4). Tumor M2-PK, an isoform of PK, is found in proliferating tissues such as tumor cells (5). To date, the performance of this test has been evaluated only in small-scale investigations (4)(6). Regarding large-scale applications, the stability of tumor M2-PK, which would affect the handling of stool samples, is a critical issue. We investigated the average stability of tumor M2-PK in stool at room temperature to estimate the potential impact of its degradation on the sensitivity and specificity of the test. We collected stool specimens before bowel preparation for surgery from 20 patients with histologically confirmed CRC. Samples were kept at room temperature for 5 days. Immediately after sample collection and on each of the following days, the amount needed for duplicate …

Colorectal cancer screening by non-invasive metabolic biomarker fecal tumor M2-PK

To evaluate the utility of the innovative fecal tumor M2-Pyruvate kinase (M2-PK) test in our daily clinical routine, as a marker for the pre-selection of patients who should subsequently undergo colonoscopy for the diagnosis or exclusion of colorectal cancer. Fecal tumor M2-PK was measured in stool samples of 96 study participants (33 patients with colorectal cancer, 21 patients with rectal carcinoma and 42 controls) who all underwent total colonoscopy. In 39 of 42 individuals in the control group, fecal tumor M2-PK was below 4.0 kU/L (93% specificity). Colorectal tumors were accompanied by a highly significant increase (P < 0.001) in fecal tumor M2-PK levels (median: colon carcinoma, 23.1 kU/L; rectal carcinoma, 6.9 kU/L; colorectal carcinoma, 14.7 kU/L), which correlated with Duke's staging and T-classification. The overall sensitivity was 78% for colorectal cancer, increasing from 60% for stage T1 to 100% for stage T4 and from 60% for Duke's A to 90% for Duke's D tumors. Fecal tumor M2-PK is an appropriately sensitive tool to pre-select those patients requiring colonoscopy for the further diagnostic confirmation or exclusion of colorectal cancer.

Plasma levels of tumor M2-pyruvate kinase should not be used as a tumor marker for hematological malignancies and solid tumors

It has been reported that the dimeric isoform of the enzyme pyruvate kinase M2 was overexpressed in various solid tumor cells. Hence, it was suggested that circulating levels of the so-called tumor M2-pyruvate kinase (Tu M2-PK) could be used as a tumor marker for monitoring systemic therapies of various solid tumors. We analyzed its validity as a tumor marker by comparing plasma levels of Tu M2-PK in patients with different non-malignant diseases to levels in healthy individuals and in patients with hematological diseases. Plasma levels of Tu M2-PK were measured using an ELISA assay in a total of 284 patients. The mean Tu M2-PK concentration of 32 U/mL was significantly higher in the group of patients with hematological malignancies (n = 121) (p < 0.001). However, 37% of healthy individuals (n = 63) and 44% of patients with non-malignant diseases (n = 100), especially patients with an acute inflammatory reaction (67%), were found to have elevated levels of Tu M2-PK using a cutoff level of 15 U/mL. The specificity was 59% and the sensitivity was 51%. There was no significant correlation between the prevalence of a hematological malignancy and positive Tu M2-PK result. Thus, our data imply that Tu M2-PK is not a useful tumor marker for hematological malignancies and solid tumors, as a significant number of false positive results were detected in healthy individuals and patients with non-malignant diseases.

Tumor M2-pyruvate kinase, a new metabolic marker for pancreatic cancer.

An isoenzyme of pyruvate kinase (Tu M2-PK) is overexpressed by tumor cells and can be measured in blood by a specific immunoenzymatic assay. Our objective was to investigate the diagnostic value of Tu M2-PK in comparison with that of CA 19-9 in pancreatic cancer. We studied 265 subjects: 60 with histologically confirmed pancreatic cancer, 43 with benign pancreatic diseases (acute and chronic pancreatitis), 5 with benign cystic neoplasms of the pancreas, 9 with neuroendocrine tumors, 77 with other abdominal malignancies, 47 with benign digestive diseases, and 24 healthy controls. Levels of plasma Tu M2-PK and serum CA 19-9 were determined by commercially available specific immunoassays. The diagnostic sensitivity and specificity of Tu M2-PK for pancreatic cancer were 85 and 41%, respectively, while those of CA 19-9 were 75 and 81%. The combination of the two tests significantly increased sensitivity (97%) but lowered specificity (38%). In discriminating between pancreatic cancer and acute or chronic pancreatitis, Tu M2-PK turned out to be less accurate than CA 19-9. In patients without pancreatic tumor, cholestasis appeared not to affect the values of Tu M2-PK, while CA 19-9 was found to be significantly higher. Tu M2-PK was also abnormally high in the majority of patients with other digestive malignancies or neuroendocrine tumors. The results demonstrate that Tu M2-PK has a satisfactory sensitivity but a poor specificity in the diagnosis of pancreatic cancer. Used together with CA 19-9, the sensitivity increases considerably.

Faecal tumour M2 pyruvate kinase: a new, sensitive screening tool for colorectal cancer.

Proliferating cells, especially tumour cells, express a special isoenzyme of pyruvate kinase, termed M2-PK, which can occur in a tetrameric form with a high affinity to its substrate, phosphoenolpyruvate (PEP), and in a dimeric form with a low PEP affinity. In tumour cells, the dimeric form is usually predominant and is therefore termed Tumour M2-PK. The levels of Tumour M2-PK within tumours and in EDTA-plasma correlate with staging and the ability of the tumour cells to metastasise. Since most colorectal tumours grow intraluminally, it appeared interesting to determine whether Tumour M2-PK is detectable in the faeces of tumour patients. Stool samples were tested by ELISA from controls without colorectal cancer and colorectal cancer patients. Whereas Tumour M2-PK levels were low in the control group (mean value±s.e.m.: 3.3±0.4, n=144), they were high in the case of colorectal cancer (56.1±15.3, n=60). At a cutoff value of 4 U ml−1, the sensitivity was 73%. TNM and Dukes' classification of the tumours revealed a strong correlation between faecal Tumour M2-PK levels and staging. The determination of Tumour M2-PK in faeces provides a new promising screening tool for colorectal tumours.

Tumor M2-pyruvate kinase: Is it a new useful marker for neuroendocrine tumors?

Tumor M2-pyruvate kinase: Is it a new useful marker for neuroendocrine tumors?

Tumor M2-pyruvate kinase in the follow-up of inoperable lung cancer patients: a pilot study

Tumor markers were used for disease monitoring in lung cancer patients. The goal of this pilot study was to determine the diagnostic efficiency of a new tumor metabolic marker, Tumor M2-pyruvate kinase (Tumor M2-PK) for the detection of tumor growth in inoperable lung cancer patients. Fifty-seven consecutive and primary inoperable lung cancer patients were included in this prospective study. Changes in plasma levels of Tumor M2-PK were compared to the clinical course of the disease. Clinical monitoring was evaluated according to the standard criteria of the WHO. Of the 57 patients, 19 were in remission, 18 showed signs of stable disease and there were 20 tumor progressions under therapy. In the further follow-up after treatment, tumor relapse occurred in 30 patients. Tumor M2-PK was measured in plasma before and after treatment as well as at time of relapse. During tumor remission Tumor M2-PK levels decreased significantly under treatment ( P=0.0004). As might be expected, pre- and post-treatment marker concentrations did not differ significantly in patients with stable disease. In progressive lung cancer patients a significant increase in Tumor M2-PK was detectable ( P=0.0094). Overall, a decrease of Tumor M2-PK was seen in 17 (89%) of all responders, while an increase could be detected in 16 (80%) of the patients experiencing tumor progression. After treatment tumor relapse occurred in 30 patients. Tumor M2-PK increased significantly ( P=0.0201) at time of relapse in 17 patients with non-small cell lung cancers and exceeded the cut-off in 11 of the 17 (65%). In conclusion, Tumor M2-PK proved useful as a diagnostic aid for therapy control in lung cancer patients. This marker can also be used to detect tumor relapse after treatment. Tumor M2-PK could be well suited to complete the present diagnostic panel for monitoring of inoperable lung cancer patients.

Tumor M2 pyruvate kinase – determination in breast cancer patients receiving trastuzumab therapy

This study was designed to investigate the value of tumor M2 pyruvate kinase (tumor M2-PK) determination as an early marker for response to trastuzumab therapy in patients with metastasized breast cancer. Plasma samples of 20 trastuzumab patients were collected immediately after standard hematological investigations. The tumor M2-PK level was quantified using an enzyme linked immunosorbent assay (ScheBo ® Biotech) and CA 15-3 was measured automatically using the Bayer Immuno 1™ immunoanalyzer and the corresponding assay. Each assay was performed in duplicate. The values were analyzed for correlation to the clinical course of each patient. Median observation time was 13 months with a range from 4 to 22 months. In 17/20 (85%) patients, tumor M2-PK determination was a marker for the clinical course of their disease. In this ‘tumor M2-PK sensitive’ group, 49 known clinical events (remission or progression according to UICC criteria) were recorded. The variation in tumor M2-PK level paralleled 63% of the clinical events (31/49). Our data suggest that tumor M2-PK determination in the plasma of patients with metastasized breast cancer could be a helpful tool for monitoring therapeutic success.

Tumor M2 Pyruvate Kinase in Plasma of Patients with Urological Tumors

The M2 isoenzyme of pyruvate kinase (M2-PK) is specifically expressed in tumor cells (TU M2-PK) and may therefore provide a tumor marker for malignancies. We have investigated the plasma concentrations of TU M2-PK in patients with renal cell carcinoma (RCC), transitional cell carcinoma of the bladder (BCA), prostate cancer (PCA) and benign prostatic hyperplasia (BPH). TU M2-PK was quantified with a commercially available enzyme-linked immunosorbent assay (ELISA) kit. Using this ELISA kit, plasma samples of 57 healthy individuals were compared to 63 patients with RCC, 36 patients with BCA, 58 patients with PCA and 28 patients with BPH. Patients with carcinomas were subdivided into those patients with nonmetastatic and those with metastatic disease. Only patients with RCC (nonmetastatic and metastatic) showed significantly increased concentrations of TU M2-PK compared to normal individuals. In metastatic RCC, TU M2-PK levels were highest and were also significantly enhanced compared to nonmetastatic RCC. The sensitivity for nonmetastatic RCC was 27.5% and for metastatic RCC 66.7% at the 95% reference value of the control group. In BCA, PCA and BPH, no significant differences could be detected. Our results indicate that TU M2-PK concentrations in plasma may be a potential biomarker of advanced RCC.

Free fibula flap: Is it the flap of choice for most oromandibular defects?

This study was designed to investigate the value of tumor M2 pyruvate kinase (tumor M2-PK) determination as an early marker for response to trastuzumab therapy in patients with metastasized breast cancer.Plasma samples of 20 trastuzumab patients were collected immediately after standard hematological investigations. The tumor M2-PK level was quantified using an enzyme linked immunosorbent assay (ScheBo® Biotech) and CA 15-3 was measured automatically using the Bayer Immuno 1™ immunoanalyzer and the corresponding assay. Each assay was performed in duplicate. The values were analyzed for correlation to the clinical course of each patient.Median observation time was 13 months with a range from 4 to 22 months. In 17/20 (85%) patients, tumor M2-PK determination was a marker for the clinical course of their disease. In this ‘tumor M2-PK sensitive’ group, 49 known clinical events (remission or progression according to UICC criteria) were recorded. The variation in tumor M2-PK level paralleled 63% of the clinical events (31/49).Our data suggest that tumor M2-PK determination in the plasma of patients with metastasized breast cancer could be a helpful tool for monitoring therapeutic success.