Magdalena Groblewska

The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer

Esophageal cancer (EC) is one of the most aggressive malignant tumors of the gastrointestinal tract. There are two distinct histological types of EC: esophageal squamous cell carcinoma and adenocarcinoma of the esophagus. Etiologic factors and the patterns of incidence of both subtypes are different. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in esophageal carcinogenesis. Gellatinases MMP-2 and MMP-9 are able to degrade collagen IV from basement membranes and extracellular matrix which is related to tumor progression, including invasion, metastasis, growth and angiogenesis. It has been shown that increased expression of MMPs plays a crucial role in the development of several human malignancies, including esophageal cancer. The activity of MMPs is regulated by their endogenous natural inhibitors (TIMPs). Among these, the roles of TIMP-1 and TIMP-2 in EC development, tumor progression and formation of metastases have been most extensively characterized and best recognized.

Serum levels of granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) in pancreatic cancer patients.

Abstract Background: Pancreatic cancer is an aggressive malignancy of the gastrointestinal tract and one of the most lethal human cancers. It has been shown that endogenous cytokines, produced aberrantly in many malignancies, including pancreatic cancer, may act as autocrine growth factors or as indicators of the immune response to tumors. Granulocyte-colony stimulating factor (G-CSF) and macrophage-colony stimulating factor (M-CSF) are hematopoietic growth factors (HGFs), i.e., cytokines that induce proliferation of hematopoietic and cancer cells. Methods: Serum levels of G-CSF, M-CSF, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) were determined using immunoenzymatic assays in 62 patients with pancreatic cancer before and 30 days after surgery, and in 65 healthy controls. Results: Cancer patients had significantly higher levels of all parameters measured compared to healthy subjects, especially in non-resectable tumors. Higher values of diagnostic parameters [specificity, sensitivity and area under receiver operating characteristic (ROC) curve] were observed for M-CSF than G-CSF, and for combined use of M-CSF with CA 19-9. Based on Cox analysis, elevated preoperative serum M-CSF was a significant prognostic factor for patient survival, although not independent of tumor stage. Conclusions: Our findings suggest the usefulness of M-CSF as a tumor marker for pancreatic cancer, especially in combination with CA 19-9. Clin Chem Lab Med 2007;45:30–4.

Interleukin 6 and C-reactive protein in esophageal cancer.

Esophageal cancer (EC) is one of the most aggressive malignant tumors of the gastrointestinal tract. It is well known that cancer initiation and tumor development are closely linked with inflammation. C-reactive protein (CRP) and interleukin-6 (IL-6) are acute-phase proteins involved in cancer development. It was suggested that CRP and IL-6 play potential roles in the growth and progression of malignant tumors, including EC. The aim of the study was to describe the significance of IL-6 and CRP in the development of esophageal cancer and to assess the potential role of their serum levels as prognostic indicators of EC patients survival.

The role of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the pathophysiology of neurodegeneration: a literature study.

Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) are involved in cell signaling processes and the release of extracellular matrix (ECM) and non-ECM molecules. Nonregulated MMP activity and an imbalance between metalloproteinases and their inhibitors might contribute to various disorders, including neurodegenerative diseases such as Alzheimers disease (AD), which is the most common cause of dementia. There is a complex relationship between MMPs and TIMPs with AD. It has been shown that MMPs and TIMPs are localized in neuritic senile plaques and neurofibrillary tangles in the postmortem brains of patients with AD. Some MMPs have also been shown to induce tau aggregation and the formation of neurofibrillary tangles in vitro. Moreover, MMPs contribute to AD pathogenesis via the disruption of the blood-brain barrier and promotion of neurodegeneration. However, MMPs can degrade both soluble and fibrillar forms of amyloid-β (Aβ). It has also been shown that Aβ enhances the expression of MMPs in neuroglial cultures and induces the release of TIMP-1 by brain cells. Inhibition of Aβ-induced MMP activity resulted in an improvement of performance tests in mice. Moreover, simultaneous examination of MMP-9, MMP-2, and TIMP-1 in the CSF contributed to the ability to differentiate between AD and other types of dementia. Thus, the aim of this literature study was to describe the role of MMPs and TIMPs in neurodegeneration, as well as their potential usefulness as CSF or plasma biomarkers in the diagnosis of AD as well as other neurodegenerative disorders and vascular dementia.

Serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinases 2 (TIMP-2) in colorectal cancer patients.

The objective of the study was the assessment of serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in patients with colorectal cancer (CRC). The study included 72 CRC patients and 68 healthy subjects. The serum levels of MMP-2 and TIMP-2 were measured using enzyme-linked immunosorbent assay (ELISA) method, whereas tissue expression of MMP-2 and TIMP-2 in cancer cells, interstitial inflammatory cells, and adjacent normal colorectal mucosa were examined by immunohistochemical staining of tumor samples. The serum levels of MMP-2 and TIMP-2 in cancer patients were significantly lower than those in control group, but the percentage of positive immunoreactivity of these proteins were higher in malignant and inflammatory cells as compared to normal tissue. There was a significant correlation between MMP-2 immunoreactivity in inflammatory cells and the presence of distant metastases and between TIMP-2 expression in inflammatory cells and tumor size, nodal involvement, and distant metastases. Area under receiver operating characteristic (ROC) curve (AUC) for serum MMP-2 was higher than for serum TIMP-2. Moreover, positive tissue expression of MMP-2 was a significant prognostic factor for CRC patients’ survival. Our findings suggest that MMP-2 and TIMP-2 might play a role in the process of colorectal cancer invasion and metastasis, but the significance of their interactions with tumor stroma and interstitial inflammatory infiltration in colorectal neoplasia require further elucidation.

Pre-treatment serum and plasma levels of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) in gastric cancer patients

Abstract Background: The invasion and metastases of gastric cancer (GC) depends on the activities of matrix metalloproteinases and tissue inhibitors of metalloproteinases. It was suggested that the concentration of plasma matrix metalloproteinase-9 (MMP-9) is better than the concentration of serum MMP-9 for prediction of evolution of GC. The aim of the present study was to compare the clinical usefulness of plasma and serum tissue inhibitor of metalloproteinases-1 (TIMP-1) in the diagnosis and prognosis of GC. Methods:Plasma and serum concentrations of TIMP-1, MMP-9 and carcinoembryonic antigen (CEA) were assayed in 73 patients with GC and 61 healthy controls. The diagnostic criteria and prognostic value for the measurands were defined. Results: Plasma and serum TIMP-1, MMP-9 and CEA were significantly higher in GC patients compared with healthy controls. The area under the ROC curve (AUC) (0.961), diagnostic sensitivity (89%) and accuracy (91%) of plasma TIMP-1 were higher than those for MMP-9 and CEA. An increased pre-treatment concentration of plasma TIMP-1 was a significant independent prognostic factor for the survival of patients with GC. Conclusions: These findings suggest that the plasma TIMP-1 is a better biomarker than the serum TIMP-1 and might be useful for the diagnosis of GC and prognosis of patient survival. Clin Chem Lab Med 2009;47:1133–9.

Evaluation of Visinin-Like Protein 1 Concentrations in the Cerebrospinal Fluid of Patients with Mild Cognitive Impairment as a Dynamic Biomarker of Alzheimer's Disease

BACKGROUND The correlations between pathology of neurodegenerative diseases, especially Alzheimers disease (AD), and concentrations of neuronal calcium sensor proteins, such as visinin-like protein 1 (VILIP-1), in cerebrospinal fluid (CSF) have been discussed in the literature but its utility as biomarker of AD in comparison with mild cognitive impairment (MCI) has not been studied yet. OBJECTIVE Therefore, the aim of our study was to assess the clinical utility of the measurement of CSF concentrations of VILIP-1 in patients with AD, MCI subjects, and non-demented controls. The clinical and neuropsychological diagnoses were supported by CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aβ1-42 and/or Aβ42/40 ratio and increased concentrations of Tau and pTau181 proteins. METHODS The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of biomarkers tested were determined by using the ELISA method. RESULTS Concentrations of VILIP-1 in CSF were significantly higher in AD patients compared to the MCI subjects and elderly individuals without cognitive impairment. Increased concentrations of VILIP-1 correlated significantly with reduced Aβ42/40 ratio and higher pTau181 in AD group. CONCLUSION Our findings suggest that VILIP-1 may play a role in the AD pathophysiology and is a good candidate for dynamic biomarker of AD, although this issue requires further investigation.

Concentrations of Matrix Metalloproteinases and their Tissue Inhibitors in the Cerebrospinal Fluid of Patients with Alzheimer's Disease

BACKGROUND A growing body of evidence shows the involvement of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in neurodegeneration processes, but reports of their concentrations in the cerebrospinal fluid (CSF) are inconsistent. OBJECTIVE Therefore, the aim of our study was to evaluate the CSF concentrations of MMP-2, MMP-3, MMP-9, and their inhibitors (TIMP-1 and TIMP-2) in carefully selected groups of patients with Alzheimers disease (AD), mild cognitive impairment (MCI), and non-demented controls, whose clinical and neuropsychological diagnoses were confirmed by the corresponding CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aβ1-42 and/or Aβ42/40 ratio, and increased concentrations of Tau and pTau181 proteins. METHODS The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of MMPs and TIMPs were determined with ELISAs. RESULTS CSF concentrations of MMP-9 were significantly lower, and the concentrations of MMP-3 significantly higher in AD patients compared to the controls. Neither MMP-2 nor TIMPs showed significant changes among the groups investigated. CONCLUSION Altered concentrations of two out of three MMPs investigated in this study suggest that this family of biomolecules may play a role in the AD pathophysiology. Further studies are needed to establish their potential diagnostic utility.

Expression of matrix metalloproteinase-9 in the neoplastic and interstitial inflammatory infiltrate cells in the different histopathological types of esophageal cancer.

Metalloproteinase-9 (MMP-9) is the proteolytic enzyme degrading type IV collagen, and plays important role in the invasiveness and metastatic potential of tumor cells. The aim of the current study was to compare the association between the intensity of MMP-9 expression in neoplastic cells and in the interstitial inflammatory infiltrate cells in esophageal cancer with clinicopathological features of esophageal cancer (EC) and in different histopatological types of EC, e.g. adenocarcinoma and esophageal squamous cell carcinoma. The study included 32 EC patients, 17 cases of squamous cell carcinoma and 15 cases of adenocarcinoma, verified histopatologically. The presence of MMP-9 in cancer tissue was investigated by immunohistochemistry on formalin-fixed, wax-embedded sections of esophageal cancers. The light microscopy was used to evaluate the expression of metalloproteinase-9 in cancer cells and in inflammatory infiltrate in the neoplastic interstitium in semi-quantitative scale. The expression of MMP-9 in cancer cells was positive in 81% of cases whereas in inflammatory cells - in 75% and increased with tumor stage, depth of tumor invasion (T factor) and lymph node metastases (N factor). In squamous cell cancer the MMP-9 expression in cancer cells and in inflammatory infiltrate was higher than those in adenocarcinoma. Mean value of MMP-9 expression in inflammatory cells was higher in early stages of EC, whereas mean expression of this enzyme in cancer cells increased with tumor stage. In conclusion, this is the first study comparing the expression of metalloproteinase-9 in cancer and inflamatory infiltrate cells in different histopatological types of esophageal cancer. We proved the synthesis of MMP-9 by cancer cells as well as by inflammatory cells and its correlation with tumor stage, tumor size, depth of tumor invasion and lymph node metastases. The results suggest the role of MMP-9 in esophageal tumorigenesis, although this issue requires further investigations.

Serum matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases 2 in esophageal cancer patients

The positive expression of MMP-2 and TIMP-2 were found in esophageal cancer (EC) tissue and correlated with cancer stage and clinico-pathological features of tumor and patients’ survival. However, little is known about serum levels of those proteins in EC patients. The aim of the present study was to investigate the diagnostic significance of MMP-2 and TIMP-2 serum levels in EC patients in relation to clinico-pathological features of cancer. The study included 53 EC patients and 92 healthy controls. The serum levels of MMP-2, TIMP-2 and classical tumor markers CEA (carcinoembryonic antigen) and SCC (squamous cell carcinoma antigen) were assayed. The prognostic values and diagnostic criteria for the biomarkers tested were defined. Serum levels of MMP-2, TIMP-2 in EC patients were significantly lower, whereas CEA and SCC significantly higher than in control group. The diagnostic sensitivity of TIMP-2 (57%) was higher than those for other biomarkers tested and increased in combination with SCC (70%). Area under ROC curve for TIMP-2 (0.8698) was larger than for other proteins. In Cox’s univariate analysis only SCC serum levels were significant prognostic factors for EC patients’ survival. The results suggest the limited value of serum analyses of MMP-2 for tumor staging and prognosis in EC and the better usefulness of TIMP-2 than MMP-2 as a tumor marker in the diagnosis of EC, especially in combined use with SCC.