Comparative evaluation of serum C-reactive protein (CRP) levels in the different histological subtypes of esophageal cancer (squamous cell carcinoma and adenocarcinoma of esophagus).

Elevated C-reactive protein (CRP) levels have been found in patients with several malignancies. The aim of the present study was to analyze the diagnostic and prognostic values of CRP levels measurement in esophageal cancer (EC) patients in relation to its different histological subtypes (squamous cell carcinoma-ESCC and adenocarcinoma-AC of esophagus) and compared them with classic tumor markers-carcinoembryonic antigen (CEA) and squamous cell cancer antigen (SCC-Ag). The diagnostic sensitivity, specificity, and the areas under receiver operating characteristic curves (AUC) for all the proteins tested were defined. Serum CRP levels were statistically higher in EC, ESCC, and AC patients compared to healthy subjects and significantly increased in EC and ESCC patients with the presence of lymph node and distant metastases. The percentage of elevated CRP results in all the analyzed subgroups (EC, ESCC, and AC) was higher than CEA and SCC-Ag, similarly as AUC for CRP in comparison to SCC-Ag. Serum CRP level was a significant predictor of EC and ESCC patients' survival in univariate analysis. In conclusion, these results indicate that CRP can be used as an adjunct in evaluating the tumor markers-CEA and SCC-Ag and may improve the clinical diagnosis and follow-up of EC patients, especially for ESCC subgroup.

Clinical significance of serum macrophage-colony stimulating factor (M-CSF) in esophageal cancer patients and its comparison with classical tumor markers.

BACKGROUND: Hematopoietic growth factors (HGFs), such as macrophage-colony stimulating factor (M-CSF) are produced aberrantly in many malignancies. Esophageal cancer (EC) is characterized by late diagnosis, rapid progression and poor survival. The purpose of the present study was to determine the clinical usefulness of M-CSF in the diagnosis of EC and its histological type - squamous cell cancer of the esophagus (ESCC). METHODS: The study included 80 patients with EC (54 with ESCC and 26 with adenocarcinoma of the esophagus) and 30 healthy subjects. The serum concentrations of M-CSF, carcinoembryonic antigen (CEA) and squamous cell cancer antigen (SCC-Ag) were determined using immunoenzyme assays. We defined the percentage of increased concentrations of proteins tested and the areas under the receiver-operating characteristics (ROC) curves. RESULTS: In EC and ESCC patients, serum concentrations of M-CSF, CEA and SCC-Ag were significantly higher compared with healthy subjects. Concentrations of M-CSF in both groups analyzed (EC and ESCC) showed a tendency for increases with depth of tumor invasion, the presence of lymph node and distant metastases. The combined use of M-CSF with SCC-Ag increased their percentage of increased concentrations, and this value was higher than for classical tumor markers in both groups analyzed. The area under ROC curve for M-CSF was larger than for CEA in EC patients. CONCLUSIONS: Our findings suggest the potential usefulness of serum M-CSF concentrations as a tumor marker for EC, especially in combination with SCC-Ag. However, the diagnostic value of this cytokine may be limited because of its non-specific nature.

Alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase activity in the sera of patients with esophageal cancer.

Various alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) exist in the human esophageal mucosa. In our last experiments we have shown that ADH and ALDH are present also in the esophageal cancer cells. Moreover, the activities of total ADH and class IV isoenzymes were significantly higher in cancer tissue than in healthy mucosa, which suggests that these changes may be reflected by enzyme activity in the serum. Therefore, we measured the activity of total alcohol dehydrogenase, and classes I-IV of this enzyme and aldehyde dehydrogenase in the sera of patients with this cancer. Serum samples were taken for routine biochemical investigation from 67 patients with esophageal cancer before treatment. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline (NDMA) as a substrate and ALDH activity by the fluorometric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I and II isoenzymes, we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III alcohol dehydrogenase was measured by the photometric method with formaldehyde and class IV with m-nitrobenzaldehyde as a substrate. A statistically significant increase of class IV alcohol dehydrogenase isoenzymes was found in the sera of cancer patients. The median activity of this class isoenzyme in the total cancer group increased by about 26.5% (7.42 mU/l) in comparison to the control level (5.46 mU/l). The total alcohol dehydrogenase activity was significantly higher (30%) among patients with cancer. The activities of other tested ADH isoenzymes and total ALDH were unchanged. The activity of the class I ADH isoenzyme was significantly higher in the sera of drinkers with esophageal cancer than non-drinking patients. The increased total activity of alcohol dehydrogenase and class IV isoenzyme in the sera of patients with esophageal cancer probably can be caused by release of this isoenzyme from cancer cells or might be stimulated by alcohol drinking.

The activity of class I, II, III, and IV alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in esophageal cancer.

BACKGROUND/AIMS: Ethanol consumption is associated with an increased risk of esophageal cancer. The carcinogenic compound is acetaldehyde, the product of ethanol metabolism. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the main enzymes involved in ethanol metabolism, which leads to generation of acetaldehyde. In this study the activity of ADH isoenzymes and ALDH in esophageal cancer were compared with the activity in normal tissue. METHODS: For measurement of the activity of class I and II ADH isoenzymes and ALDH activity fluorimetric methods were employed. Total ADH activity and activity of class III and IV isoenzymes was measured by the photometric method. Samples were taken from 59 esophageal cancer patients (27 adenocarcinoma, 32 squamous cell cancer). RESULTS: The total activity of ADH and activity of class IV ADH were significantly higher in cancer cells than in healthy tissues. The other tested classes of ADH showed a tendency toward higher activity in cancer than in normal cells. Differences between the activity of enzymes of drinkers and non-drinkers in both cancer and healthy tissue were not significant. CONCLUSION: Increased ADH IV activity may be a factor intensifying carcinogenesis, because of the increased ability to form acetaldehyde from ethanol.

The diagnostic value of the measurement of matrix metalloproteinase 9 (MMP-9), squamous cell cancer antigen (SCC) and carcinoembryonic antigen (CEA) in the sera of esophageal cancer patients.

BACKGROUND: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases associated with tumor progression. It was proved that expression of MMP-9 in human esophageal cancer tissues correlated with stages of the disease. The aim of the present study was to determine potential clinical use of serum MMP-9 as a tumor marker of esophageal cancer. METHODS: The study included 89 patients with esophageal cancer and 30 healthy subjects (control group). We assayed serum levels of MMP-9 and classical tumor markers (SCC-Ag and CEA). We defined the prognostic value and diagnostic criteria for the measurands. RESULTS: Serum levels of MMP-9, CEA and SCC-Ag in esophageal cancer (EC) patients were statistically higher than in the control group. MMP-9 serum concentrations were associated with clinical stages of EC and tumor size. The diagnostic sensitivity of MMP-9 (70%) was higher than tumor markers and increased in combination with SCC-Ag (92%). The area under the ROC curve for MMP-9 (0.733) was lower than for SCC-Ag (0.811) and higher than for CEA (0.673). In Cox's univariate analysis serum MMP-9, SCC-Ag and CEA were not significant for prognosis of EC. CONCLUSION: The results suggest the usefulness of MMP-9 as a tumor marker in diagnosis, but not in prognosis of esophageal cancer.

Lymphatics-associated genes are downregulated at transcription level in non-small cell lung cancer.

The present study aimed to verify a possibility of ongoing lymphangiogenesis in non-small cell lung cancer (NSCLC) via examination of mRNA levels of a number of lymphangiogenesis-associated genes in tumors. It was hypothesized that transcriptional activation of these genes would occur in tumors that stimulate new lymphatic vessel formation. The study was performed on 140 pairs of fresh-frozen surgical specimens of cancer and unaffected lung tissues derived from NSCLC stage I-IIIA patients. mRNA levels were evaluated with the reverse transcription-quantitative polymerase chain reaction method and expressed as fold change differences between the tumor and normal tissues. Possible associations between expression and patient clinicopathological characteristics and survival were analyzed. In the NSCLC tissue samples, vascular endothelial growth factor (VEGF) C, VEGFD, VEGFR3, VEGFR2, VEGFR1, lymphatic vessel endothelial hyaluronan receptor 1, integrin subunit α 9, FOX2, neuropilin 2, fibroblast growth factor 2 genes were significantly downregulated (P<0.001 for all) compared with matched normal lung tissues, whereas mRNA levels for VEGFA, spleen associated tyrosine kinase, podoplanin, and prospero homeobox 1 genes were similar in both tissues. Neither lymph node status, nor disease pathological stage influenced expression, whereas more profound suppression of gene activities appeared to occur in squamous cell carcinomas compared with adenocarcinomas. The VEGFR1 mRNA expression level was significantly connected with patient survival in the univariate analysis, and was an independent prognostic factor for overall survival in the multivariate Cox's proportional hazards model (HR 2.103; 95% confidence interval: 1.005-4.401; P=0.049). The results support a hypothesis of absence of new lymphatic vessel formation inside growing NSCLC tumor mass, however do not exclude a possibility of lymphangiogenesis in narrow marginal tumor parts.

Identification of the vasodilatory endothelial cannabinoid receptor in the human pulmonary artery.

BACKGROUND: The endocannabinoid anandamide is implicated in the pathogenesis of hypotension in haemorrhagic, endotoxic, and cardiogenic shock. It has been demonstrated in animal, but not in human, vessels that the vasodilatory effects of anandamide and abnormal cannabidiol are partially mediated by an as yet unidentified endothelial cannabinoid receptor. Our study was performed to examine the influence of abnormal cannabidiol on the human pulmonary artery. METHODS: Isolated human pulmonary arteries were obtained from patients without clinical evidence of pulmonary hypertension during resection of lung carcinoma. Vasodilatory effects of abnormal cannabidiol were examined on endothelium-intact vessels preconstricted with serotonin or potassium chloride. RESULTS: Anandamide and abnormal cannabidiol relaxed serotonin-preconstricted vessels concentration-dependently. The effect of abnormal cannabidiol was reduced by endothelium denudation, pertussis toxin and two antagonists of the novel endothelial receptor, cannabidiol and O-1918, but not by the nitric oxide synthase inhibitor L-NAME given together with the cyclooxygenase inhibitor indomethacin. It was also diminished by blockade of calcium-activated potassium channels by the nonselective blocker tetraethylammonium or by combination of selective blockers of small (apamin) and intermediate and large (charybdotoxin) conductance calcium-activated potassium channels. The potency of abnormal cannabidiol to relax vessels was lower in potassium chloride than in serotonin-preconstriced preparations. CONCLUSIONS: Abnormal cannabidiol relaxes human pulmonary arteries in an endothelium-independent and endothelium-dependent manner. The latter component is probably mediated via the putative endothelial cannabinoid receptor, activation of which may release endothelium-derived hyperpolarizing factor, which in turn acts via calcium-activated potassium channels. Abnormal cannabidiol is behaviourally inactive; it may have a therapeutic implication in vascular diseases, especially in the treatment of pulmonary hypertension.

Serum soluble Fas ligand (sFasL) in patients with primary squamous cell carcinoma of the esophagus.

Esophageal carcinomas have been shown to express Fas ligand (FasL) and down-regulate Fas to escape from host immune surveillance. Circulating soluble FasL (sFasL) has been suggested to provide protection from Fas-mediated apoptosis. The aim of this study was to assess serum sFasL levels in esophageal cancer. The pretreatment levels of sFasL in the serum of 100 patients with esophageal squamous cell cancer and 41 healthy volunteers were determined by ELISA. Probability of survival was calculated according to the method of Kaplan-Meier. The prognostic influence of high and low level of sFasL was analyzed with the log-rank test. The mean serum level of sFasL in patients with esophageal cancer was significantly higher than that in healthy donors (1.567+/-1.786 vs 0.261+/-0.435, p<0.0001). The levels of serum sFasL were significantly higher in advanced stages (II vs IV p<0.034; III vs IV p<0.041; except II vs III p=0.281), patients with lymph node (N0 vs N1 p<0.0389) or distant (M0 vs. M1 p<0.0388) metastases and significantly lower in patients with well differentiated tumors (G1 vs G2 p<0.0272). The serum levels of soluble FasL were not related to gender, age, tumor size, T-stage, tobacco smoking and history of chronic alcohol intake. The survival difference between pretreatment high and low level of sFasL in surgery and chemio- and/or radiotherapy group was not statistically significant (p=0.525; p=0.840). Our results indicate that elevated serum sFasL levels might be associated with a disease progression in patients with esophageal squamous cell carcinoma.

[Posttranslational p53 phosphorylation in non small cell lung cancer cells after radio/chemotherapy]. / Potranslacyjna fosforylacja bialka p53 w komórkach niedrobnokomórkowego raka pluca po radio-i chemioterapii

INTRODUCTION: p53 protein is a critical regulator of cell cycle and apoptosis. Many stimuli change its expression and modify its functions. The aim of our work was to determine stability and chosen posttranslational modification of p53 protein during the treatment of lung cancer. MATERIAL AND METHODS: We investigated levels of poly-ADP-ribose- a marker of cellular DNA damage, DNA ploidy, Ki-67 expression, wild type and mutated p53 protein expression and intensity of phosphorylation of chosen p53 serine sites: C-terminal Ser392, and N-terminal Ser15, and Ser20 in fiberoptic bronchoscopy biopsy samples taken from patients suffering from recurrent squamous cell lung cancer before and after radio/chemotherapy. Analysis was based on results obtained from 23 patients after surgery in I-IIIA clinical stage of the disease. RESULTS: Therapy lowered the number of G2/M cells, but increased S fraction cell population in about 50%. Therapy increased p53 expression and p53 phosphorylation at Ser392 and Ser20, and these changes correlated with poly-ADP-ribose levels and Ki-67 expression. CONCLUSIONS: Our results indicate that apart from changes in p53 quantity, p53 posttranslational phosphorylation play a role in regulation of neoplastic cells proliferation in response to drugs.

The epidemiology of asbestos-related diseases.

Asbestos has been recognised as a potential health hazard since the 1940s. Of the two major species of asbestos; white asbestos (chrysotile) and blue asbestos (crocidolite), both of which are hazardous. The workers at extraction facilities are at the greatest risk of exposure to asbestos and, therefore, the development of asbestos-related diseases, commonly mesothelioma. However, other individuals at a high risk of exposure include asbestos-cement workers, insulation workers and ship-yard workers. Environmental exposure to asbestos can occur as a result of living in areas either characterised by natural outcrops of asbestos or asbestos-related materials, or those close to asbestos-producing or -using plants. Unfortunately, man-made fibre alternatives to asbestos, such as rock and slag-wool and glass wool, have also been shown to have a detrimental effect on human health. A characteristic of mesothelioma is that there is a long latency period (20-30 years) before the signs and symptoms of the disease become apparent. In addition, diagnosis of the disease can be difficult. The use of biological markers, such as tissue polypeptide antigen, may play a useful role in the early detection of the disease in individuals at risk.

The alcohol dehydrogenase isoenzyme (ADH IV) as a candidate tumour marker of esophageal cancer.

OBJECTIVE: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are present in esophageal cancer cells. Moreover the total activity of ADH as well as the activity of class IV ADH isoenzyme is significantly higher in cancer tissue than in healthy mucosa. The activity of these enzymes in cancer cells is reflected in the sera and could thus be helpful for diagnostics of esophageal cancer. The aim of this study was to investigate a potential significance of ADH isoenzymes and ALDH as tumour markers of esophageal cancer. We defined diagnostic sensitivity, specificity, predictive value for positive and negative results, and receiver-operating characteristics (ROC) curve for tested enzymes. METHODS: Serum samples were taken for routine biochemical investigation from 180 patients with esophageal cancer before treatment. Total ADH activity was measured by a photometric method with p-nitrosodimethylaniline as a substrate and ALDH activity by a fluorometric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I and II isoenzymes we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III alcohol dehydrogenase was measured by a photometric method with formaldehyde and class IV with m-nitrobenzaldehyde as a substrate. RESULTS: There was a significant increase in the activity of class IV of ADH isoenzyme (7.65 mU/l vs 5.88 mU/l) and total ADH activity (1198 mU/l vs 848 mU/l) in the sera of esophageal cancer patients compared to the control. The diagnostic sensitivity for ADH IV was 72%, the specificity 76%, the positive and negative predictive values were 80% and 72% respectively. The area under the ROC curve for ADH IV was 0.65. CONCLUSION: The results suggest a potential significance of ADH IV as a marker of esophageal cancer.

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.

Lymphatic vessel invasion detected by the endothelial lymphatic marker D2-40 (podoplanin) is predictive of regional lymph node status and an independent prognostic factor in patients with resected esophageal cancer.

The discovery of markers to lymphatic endothelial cells and the development of novel antibodies to these markers have brought increasing attention to the lymphatics and progress in the understanding of lymphangiogenesis and cancer metastasis. In this study, we investigate the presence of lymphatic vessel invasion (LVI) detected by D2-40 immunohistochemical staining in resected esophageal cancer and correlated with clinicopathologic data and patient survival. Sixty nine patients, who had a primary resection of esophageal cancer, were analyzed by univariate and multivariate logistic regression, and univariate and multivariate survival analysis. The total rate of LVI was 72% (50/69). Positive LVI was significantly correlated with lymph node metastasis (p < 0.001), tumor size (p < 0.001), histological grading (p = 0.017), tumor depth (p = 0.001), and stage (p < 0.001). Multivariate logistic analysis identified LVI (p = 0.036) as a predictor of regional lymph node metastasis. On univariate survival analysis, patients with LVI had a significantly shorter disease-free survival, cancer-specific survival and overall survival. Multivariate analysis proved that LVI diagnosed by D2-40 is an independent prognostic factor of both disease-free survival (p = 0.04) and overall survival (p = 0.032) in resected esophageal cancer. These results show that LVI assessment identifies patients at high risk for regional lymph node metastasis and that LVI is an independent prognostic factor in patients with esophageal cancer.

Serum vascular endothelial growth factors C and D in patients with oesophageal cancer.

OBJECTIVE: Lymph node metastasis is a characteristic of malignant cancers and is observed more frequently in oesophageal cancer than in other digestive tract cancers, making it one of the most important prognostic factors. Vascular endothelial growth factors C (VEGF-C) and D (VEGF-D) are important lymphangiogenic factors in human cancers and lymphangiogenesis is associated with lymph node metastasis. The aim of the study was to determine the correlation between pre-treatment serum levels of VEGF-C (sVEGF-C) and VEGF-D (sVEGF-D) and clinicopathologic features in patients with oesophageal cancer. METHODS: Serum VEGF-C and sVEGF-D were measured by enzyme-linked immunoadsorbent assay (ELISA) on 149 patients with oesophageal cancer, 29 patients with benign oesophageal diseases and 30 healthy controls. RESULTS: Serum VEGF-C and sVEGF-D levels were significantly higher in patients with oesophageal carcinoma than in the control group (p<0.001 and p=0.001, respectively) or in the benign oesophageal diseases group (p=0.04 and p=0.03, respectively). Subgroup analysis showed that lymph node metastasis (p=0.001), stage (p=0.001), tumour depth (p=0.006), resectability (p=0.002), tumour size (p=0.01), distant metastases (p=0.01) and histological grading (p=0.04) were correlated with an elevated level of sVEGF-C. Elevated levels of sVEGF-D were associated with tumour depth (p=0.002), stage (p=0.01) and lymph node metastasis (p=0.02). Among the patients (n=83) who underwent potentially curative surgery, the overall survival time (p=0.008) was shorter for patients with a high level (>8667 pg ml(-1)) of sVEGF-C than for those with a low level (<8667 pg ml(-1)), when the cut-off value was determined on the basis of the median value in oesophageal cancer patients. On univariate regression analysis, tumour size, tumour depth, stage, lymph node metastases, distant metastases, resectability and sVEGF-C were found to be significant prognostic factors. CONCLUSIONS: These results suggest that pre-treatment levels of sVEGF-C and sVEGF-D reflect lymph node metastases and advanced stage of oesophageal cancer. Serum VEGF-C may be useful in predicting poor outcome for patients undergoing a potentially curative oesophagectomy.

Elevated levels of serum metalloproteinase 9 in patients with esophageal squamous cell carcinoma.

INTRODUCTION: Matrix metalloproteinase 9 (MMP-9) is a proteolytic enzyme which is associated with tumor progression including invasion, migration, angiogenesis, and metastasis due to its ability to degrade type IV collagen. OBJECTIVES: The aim of the study was to assess clinical significance of MMP-9 measurement in the diagnostic evaluation of patients with esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: The study included 63 patients with ESCC and 30 healthy subjects. We assayed serum MMP-9 levels and squamous cell carcinoma antigen (SCC-Ag), a tumor marker. We defined diagnostic criteria for both markers. RESULTS: In ESCC patients serum levels of MMP-9 and SCC-Ag were found to be statistically higher compared with healthy subjects. Serum concentrations of MMP-9 and SCC-Ag tended to increase in patients with advanced cancer. The percentage of elevated MMP-9 concentrations (75%) was higher than that of SCC-Ag (68%) and increased for the combined use of both markers (97%). CONCLUSIONS: The results suggest the potential usefulness of MMP-9 in establishing the diagnosis of ESCC, especially when analyzed in combination with SCC-Ag.

Immunoexpression of P16INK4a, Rb and TP53 proteins in bronchiolar columnar cell dysplasia (BCCD) in lungs resected due to primary non-small cell lung cancer.

Lung cancer is the leading cause of death worldwide. High mortality comes out mainly of the fact that majority of the cases are diagnosed in advanced stadium. An expanded diagnostics of precancerous conditions would certainly contribute to lowering the mortality rate. Many of the molecular changes accompanying the multistep cancer development could be observed using the immunohistochemistry method. In this paper we describe the morphology and cell cycle proteins immunoexpression of the novel probable preinvasive lesion - bronchiolar columnar cell dysplasia (BCCD). Thirty cases of BCCD selected out of 193 patients population, treated for primary non-small cell lung cancer were investigated. Loss of P16INK4a protein was observed in 70% of all cases and was statistically significant in patients with adenocarcinoma. Two cases show abnormal cytoplasmic localization of this protein. TP53 protein accumulates in 26.7% of all BCCD. Rb protein was active in 48.3% of the BCCD cases. In two cases we observed differentiation of the cells composing BCCD into multilayer epithelium of the squamous type, which occurs with formation of desmosomes. We suppose that BCCD may be preneoplastic lesion leading to adenocarcinoma as well as to peripheral squamous cell lung cancer.

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.

Ligands at beta2-, beta3-, and the low-affinity state of beta1-adrenoceptors block the alpha1-adrenoceptor-mediated constriction in human pulmonary and rat mesenteric arteries.

We examined whether the beta2-adrenoceptor agonists fenoterol and salbutamol, the beta3-adrenoceptor agonists CL 316243 and ZD 2079, and the agonists of the low-affinity state of beta-adrenoceptors, cyanopindolol and CGP 12177 block alpha1-adrenoceptors in that concentration range in which they relax the human pulmonary and rat mesenteric arteries preconstricted with phenylephrine 10 microM and 1 microM, respectively. For quantification of vasodilatation pEC25 values and for the antagonism toward alpha1-adrenoceptors, pA2 values were determined. We found that in the rat mesenteric artery, (1) the pEC25 values of the beta-adrenoceptor ligands resemble their respective pA2 values (difference < or = 0.9 log units), and (2) the order of potencies is the same for both parameters, ie, cyanopindolol approximately fenoterol > CGP 12177 > salbutamol > ZD 2079 > CL 316243. In the human pulmonary artery, (1) the pEC25 values are slightly lower (by 0.6-1.3 log units) than their respective pA2 values, and (2) the rank order of potencies is the same for both parameters. In conclusion, the present study suggests that ligands of beta2-adrenoceptors and of non-beta1-non-beta2-adrenoceptors relax rat and human vessels preconstricted with phenylephrine or norepinephrine mainly through their alpha1-adrenolytic effects. Hence, for the investigation of the role of beta-adrenoceptors in vessels, the constrictor agent should be chosen with great caution.