Maciej Szmitkowski

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.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the cancer diseases

Epidemiological data have identified chronic alcohol consumption as a significant risk factor for cancer in humans. The exact mechanism of ethanol-associated carcinogenesis has remained unknown. The metabolism of ethanol leads to generation of acetaldehyde (AA), which is highly toxic and carcinogenic. The amount of acetaldehyde to which cells or tissues are exposed after alcohol ingestion may be of great importance and may, among others, affects carcinogenesis. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH). The enzyme responsible for oxidation of acetaldehyde is aldehyde dehydrogenase (ALDH). Both formation and degradation of acetaldehyde depends on the activity of these enzymes. The total alcohol dehydrogenase activity is significantly higher in cancer tissues than in this healthy organs (e.g. liver, stomach, esophagus, colorectum). Moreover the activity of ADH is much higher than the activity of ALDH. This suggests that cancer cells have a greater capability for ethanol oxidation but less ability to remove acetaldehyde than normal tissues. In addition significant differences of ADH isoenzymes activities between cancer tissues and healthy organs may be a factor intensifying carcinogenesis by the increased ability to acetaldehyde formation from ethanol and disorders in metabolism of some biologically important substances (e.g. retinoic acid). The changes in activity of particular ADH isoenzymes in the sera of patients with different cancers, seem to be caused by release of these isoenzymes from cancer cells, and may be useful for diagnostics of this cancer. The particular isoenzymes of ADH present in the serum may indicate the cancer localization.

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.

Comparison between clinical significance of serum proinflammatory proteins (IL-6 and CRP) and classic tumor markers (CEA and CA 19-9) in gastric cancer

Gastric cancer (GC) is a second most common cause of cancer-related death and represents an inflammation-driven malignancy. It has been suggested that interleukin 6 (IL-6) and C-reactive protein (CRP) play a potential role in the growth and progression of GC. The aim of the present study was to compare clinical significance of IL-6 and CRP with classic tumor markers—carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) in GC patients. The study included 92 patients with GC and 70 healthy subjects. The serum concentrations of IL-6, CEA and CA 19-9 were determined using immunoenzyme assays, whereas CRP using immunoturbidimetric method. We defined the diagnostic criteria and prognostic value for proteins tested. In GC patients, the serum concentrations of all the proteins tested were significantly higher than in healthy subjects. The IL-6, CEA and CA 19-9 levels correlated with nodal metastases, while CRP with tumor stage, gastric wall invasion, presence of nodal and distant metastases. Diagnostic sensitivity of IL-6 was higher (85%) than those of other markers (CRP 66%, CA 19-9 34%, CEA 22%) and increased in combined use with CRP or CEA (88%). The area under ROC curve for IL-6 was larger than those of CRP and classic tumor markers (CEA and CA 19-9). None of the proteins tested was independent prognostic factor for the survival of GC patients. Our findings indicate better usefulness of serum proinflammatory proteins—IL-6 and CRP than classic tumor markers—CEA and CA 19-9 in the diagnosis of GC.

The importance of interleukin 18, glutathione peroxidase, and selenium concentration changes in acute pancreatitis

Cytokinemia and oxidative stress are important factors responsible for an inadequate immune response in the early course of acute pancreatitis (AP). The aim of the study was to evaluate the profiles of interleukin 18 (IL-18), glutathione peroxidase (GPx), and selenium concentrations in serum with respect to AP severity and to study the relationships between these parameters and recognized prognostic indicators of AP severity. Prospective clinical analyses were performed on 61 patients with mild and severe forms of AP and for 15 healthy volunteers. In both forms of AP severity, the IL-18 concentration in the serum was significantly higher than in healthy controls. In the severe form of AP, the IL-18 concentration was the highest and exceeded significantly the values recorded on the 1st, 2nd, 3rd, 5th, and 10th days of mild AP. A significantly lower GPx concentration in the serum was recorded in severe AP compared to the mild form and in the control group. There was a significantly lower selenium concentration in the severe form of AP. Significant correlations between GPx and selenium, between IL-18 and GPx, and between IL-18 and selenium were recorded. The ROC analysis shows a high prognostic accuracy of IL-18 and GPx concentrations in the determination of AP severity. IL-18 is released early in the course of AP and may be a key immunomodulator of the inflammatory response in the severe form of this disease. Low GPx and selenium concentrations in severe AP reflect the lower antioxidative ability in this form of AP. IL-18 and GPx may represent new indicators of AP severity.

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 plasma concentration of VEGF, HE4 and CA125 as a new biomarkers panel in different stages and sub-types of epithelial ovarian tumors

BackgroundVEGF may play a role in the pathogenesis of cancer disease, for example in cell growth, proliferation and angiogenesis. In this study, we investigated plasma levels of this cytokine in comparison to plasma levels of a new biomarker - HE4 and the established tumor marker CA125 in ovarian cancer patients (100) as compared to control groups: patients with a benign ovarian tumor (80) and healthy subjects (50).MethodsPlasma levels of VEGF were determined by ELISA, HE4 and CA125 by CMIA method.ResultsThe results showed that levels of VEGF, CA125 and HE4 were significantly higher in ovarian cancer (OC) patients as compared to the both control groups. VEGF has demonstrated as high as comparative markers values of the diagnostic sensitivity (SE), specificity (SP), the predictive values of positive and negative test results (PV-PR, PV-NR), and the area under the ROC curve (AUC) in early stages of cancer tested groups. The combined use of parameters studied resulted in the increase in the diagnostic criteria values and the AUC.ConclusionsThese findings suggest the usefulness of VEGF in the early diagnostics of ovarian cancer, especially in combination with CA125 and HE4, as a new biomarkers panel. Additionally, VEGF is the most useful tool in the diagnostics of locally advanced ovarian cancer without metastases. Investigated cytokine presented similar to HE4 usefulness in differentiation of OC according to its histopathlogical sub-type, and could be used especially in the diagnostics of endometrioid epithelial OC.

High-sensitivity C-reactive protein in the exhaled breath condensate and serum in stable and unstable asthma.

BACKGROUND Asthma is a chronic airway inflammatory disease. Measurement of serum high- sensitivity C-reactive protein (hs-CRP) levels has suggested the involvement of low-grade systemic inflammation in several disorders, such as cardiovascular disease and diabetes mellitus. In recent years, there have been some reports concerning hs-CRP assessment as a useful tool for detecting systemic inflammation in asthma. The study was undertaken to evaluate hs-CRP levels in the exhaled breath condensate (EBC) of asthmatics with different degrees of asthma severity and their relationship to hs-CRP levels in serum, clinical characteristics, and the intensification of airway inflammation. METHODS The study group was 62 patients with allergic asthma (20 with steroid-naïve mild asthma, 19 with ICS-treated, stable mild-to-moderate asthma, 23 with ICS-treated unstable, severe asthma) and 15 healthy volunteers. RESULTS In the three groups of asthmatics hs-CRP concentrations in EBC and serum were significantly higher than in healthy volunteers. hs-CRP levels both in EBC and serum were significantly higher in patients with unstable asthma than in the two groups with stable disease. hs-CRP concentrations in EBC strongly correlated with those measured in serum. There was a significant correlation between hs-CRP levels both in EBC and serum and exhaled nitric oxide (F(ENO)) in the three groups of asthmatics or serum ECP in the group of patients with steroid-naïve mild asthma and unstable, severe asthma. CONCLUSION The levels of hs-CRP in EBC are correlated with those measured in serum and may provide another useful diagnostic tool for detecting and monitoring low-grade inflammation in patients with asthma.

Hematopoietic cytokines as tumor markers

Abstract Stem cell factor (SCF), interleukin 3 (IL-3), granulocyte-macrophage-colony stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF) and macrophage-colony stimulating factor (M-CSF) are members of a group of glycoproteins called hematopoietic cytokines (HCs). These cytokines regulate the growth and differentiation of hematopoietic progenitor cells and functionally activate mature neutrophils or macrophages. The effect of HCs is not limited to bone marrow cells. Some studies have shown that HCs can also stimulate the proliferation of non-hematopoietic cells. The receptors for HCs have been detected in cancer cell lines, and stimulation of HCs receptors induced proliferation of tumor cells. Moreover, some investigations have shown HC mRNA expression in these cell lines and recent studies have demonstrated that HCs can stimulate tumor progression. Several cells of malignant tumors have been observed to secrete large amounts of HCs and increased concentrations of HCs have been found in the sera of cancer patients. There are a number of situations in which the measurement of HCs may provide clinically useful information, particularly regarding prognosis and response to treatment. In this paper we discuss the results of studies that have examined the potential use of HCs as tumor markers.

Hypogelsolinemia, a disorder of the extracellular actin scavenger system, in patients with multiple sclerosis

BackgroundExtracellular gelsolin (GSN) and GC-globulin/Vitamin D-binding protein (DBP) appear to play an important role in clearing the actin from extracellular fluids and in modulating cellular responses to anionic bioactive lipids. In this study we hypothesized that cellular actin release and/or increase in bioactive lipids associated with multiple sclerosis (MS) development will translate into alteration of the actin scavenger system protein concentrations in blood and cerebrospinal fluid (CSF) of patients with MS.MethodsWe measured GSN and DBP concentrations in blood and CSF obtained from patients diagnosed with MS (n = 56) in comparison to a control group (n = 20) that includes patients diagnosed with conditions such as idiopathic cephalgia (n = 11), idiopathic (Bells) facial nerve palsy (n = 7) and ischialgia due to discopathy (n = 2). GSN and DBP levels were measured by Western blot and ELISA, respectively.ResultsWe found that the GSN concentration in the blood of the MS group (115 ± 78 μg/ml) was significantly lower (p < 0.001) compared to the control group (244 ± 96 μg/ml). In contrast, there was no statistically significant difference between blood DBP concentrations in patients with MS (310 ± 68 μg/ml) and the control group (314 ± 82 μg/ml). GSN and DBP concentrations in CSF also did not significantly differ between those two groups.ConclusionsThe decrease of GSN concentration in blood and CSF of MS subjects suggests that this protein may be involved in chronic inflammation associated with neurodegeneration. Additionally, the results presented here suggest the possible utility of GSN evaluation for diagnostic purposes. Reversing plasma GSN deficiency might represent a new strategy in MS treatment.