Biomedical subjects

László Kopper

Publications and source records attributed to László Kopper.

At least 19 recordsLinked to original sources

PubMed2007

[Molecular pathology and targeted therapy of clear cell renal cancer].

The golden standard of care for advanced renal cell cancer (RCC) was until now the cytokine therapy with relatively low response rates. Advances of molecular genetics in RCC revealed several molecular targets such as VHL and angiogenic genotype or EGFR in the clear cell variant. Among the novel targeted agents, multiple tyrosine kinase inhibitors were proved to be clinically effective against advanced clear cell renal cancer, changing the standard of care. It is a further question how molecular diagnostics can improve these results by the detection of these targets or gene defects in individual tumors.

Adenocarcinoma, Clear Cell↗

PubMed2006

Proteasome inhibitors sensitize colon carcinoma cells to TRAIL-induced apoptosis via enhanced release of Smac/DIABLO from the mitochondria.

The synergistic interaction between proteasome inhibitors and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising approach to induce cell death in tumor cells. However, the molecular and biochemical mechanisms of this synergism have been proven to be cell type specific. We therefore focused our investigation on TRAIL-resistant colon carcinoma cells in this study. DNA fragmentation, mitochondrial membrane depolarization and increased caspase-3-like enzyme activity was exclusively induced only by combined treatment with proteasome inhibitors (epoxomicin, MG132, bortezomib/PS-341) and TRAIL. The expression level of anti-apoptotic proteins (XIAP, survivin, Bcl-2, Bcl-XL), regulated by NF-kappaB transcription factor, was not effected by any of these treatments. TRAIL alone induced only partial activation of caspase-3 (p20), while the combination of TRAIL and proteasome inhibition led to the full proteolytic activation of caspase-3 (p17). Only the combination treatment induced marked membrane depolarization and the release of cytochrome c, HtrA2/Omi and Smac/DIABLO. Apoptosis-inducing factor (AIF) was not released in any of these conditions. These results are consistent with a model where the full activation of caspase-3 by caspase-8 is dependent on the release of Smac/DIABLO in response to the combined treatment. This molecular mechanism, independent of the inhibition NF-kappaB activity, may provide rationale for the combination treatment of colon carcinomas with proteasome inhibitors and recombinant TRAIL or agonistic antibody of TRAIL receptors.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

[Tumor stem cells--a possible scenario].

More and more evidence support that tumors arise from somatic stem cells or from cells, either progenitors or differentiated ones, with the properties of stemness. It is a question whether all tumor cells have the capacity for self renewal and unlimited growth or only a fraction of them, i.e. the tumor stem cells. The concept is challenging, since the existence of tumor stem cells has an important practical consequence: only stem cells should be removed or stopped in order to control the tumor, while the other cells have temporary proliferative capacity.

Animals↗

PubMed2006

Genomics of renal cell cancer-- does it provide breakthrough?

It is a strong hope that the more we characterize the pathways in an individual tumor, the better we will be able to evaluate the response to a specific therapy. Different array technologies could be powerful tools to achieve this goal, i.e. selecting patients on the basis of the genomic and/or proteomic profiles who would really benefit from the target-designed therapy. Genomic analysis of RCC accumulated ample of data which now can be exploited in clinical management of a previously almost uncontrollable disease. Beside the previously identified genetic abnormalities (VHL, MET, EGFR), CAIX seems to be a novel molecular marker of RCC. Array studies also outlined a small set of tumor markers, vimentin, galectin-3, CD74 and parvalbumin, which can define the individual histologic subtypes of RCC. We are at the beginning to take advantage of the genomic results. Some new approaches will interfere with the progression of RCC (anti-VEGF, anti-VEGFR or anti-EGFR therapies). Further novel molecular targets are available, such as HIF, HSP90 or the IFN-regulated genes, which can be used to the fine-tuning of RCC therapy.

Biomarkers, Tumor↗

PubMed2005

Genomics of prostate cancer: is there anything to "translate"?

This review provides an up-dated collection of data concerning the genetic and epigenetic changes during development, growth and progression of prostate cancer. Hereditary and susceptibility factors have a long list, similarly to the expression of single genes connected to various cell functions. It was a hope that covering a large set of genes, array technologies would clarify very rapidly the role of genetics in malignant diseases, offering targets for molecular diagnostics and therapy. The power of high-throughput techniques for the detection and global analysis of gene expression is unquestionable, interesting, astonishing as well as puzzling data have already been obtained. However, the standardization of the procedures is still missing and the reproducibility is rather low in many instances. Moreover, the different array methods can select different gene expression profiles, which makes the decision rather difficult. Another important question is, coming again from the array technologies, how far the genotype (the gene profiles or fingerprints) can reflect the actual phenotype in a highly complex and readily changing disease as cancer. Proteomics will provide a closer look to this seemingly unanswerable problem. We are at the beginning of the exploration of the behavior of cancer cells in order to apply a more effective therapy based on a more reliable set of diagnostic and prognostic informations.

DNA, Neoplasm↗

PubMed2005

[Epidermal growth factor receptor (EGFR): therapeutic target in the treatment of lung adenocarcinoma].

Revolution in biotechnology made possible to identify those gene errors, which via their encoded proteins (mostly kinase enzymes) are key players in tumor development, growth and progression, and could be considered as molecular targets in tumor diagnosis and therapy. Activity of EGFR (epidermal growth factor receptor), an outstanding representative of the regulatory cell surface receptors, can be inhibited by drugs proved for clinical use. In the past year many groups observed that those lung adenocarcinoma cells, which contain activating mutation in the tyrosine kinase domain of EGFR show remarkable sensitivity to anti-EGFR compounds. The basis of the effective therapy is the identification of the mutations. The clinical advantage of EGFR is an example from the coming age of tumor chemotherapy, when the presence of molecular targets will guide the therapeutic choice.

Adenocarcinoma↗

PubMed2005

Alpha-fetoprotein expression is a potential prognostic marker in hepatocellular carcinoma.

AIM: To characterize the alpha-fetoprotein (AFP) positive and negative hepatocellular carcinoma (HCC) samples. METHODS: Thirty-seven paraffin-embedded human HCC samples were analyzed by immunohistochemistry for the following antigens: AFP, beta-catenin, p53, CD44, MSH-2, MLH-1, and HNF-4. The tumors were divided into two groups based on the AFP expression. The immunophenotypic data and important clinical parameters were studied between the two groups. RESULTS: Twenty-one of the thirty-seven examined HCCs were AFP positive. Seven with nuclear p53 staining were AFP positive, while seven tumors with nuclear beta-catenin staining were AFP negative. CD44 staining and high histological tumor grade were more frequent among the AFP-positive HCCs. The other immunophenotypical and clinical parameters did not show statistically significant difference in their distribution between the AFP positive and negative samples. CONCLUSION: AFP expression in HCC correlates with unfavorable prognostic factors, while nuclear beta-catenin positivity is more common among the AFP-negative liver tumors. This observation supports the microarray data on in vivo human tumors.

Biomarkers, Tumor↗

PubMed2005

Development of the vasculature in "pushing-type" liver metastases of an experimental colorectal cancer.

A mechanism for stroma formation (development of vasculature and supportive connective tissue) is suggested in an experimental "pushing-type" colorectal carcinoma liver metastasis model. The key element is the appearance of smooth muscle actin (SMA)-positive cells and the sinusoidal lakes at the border of the metastases. These lakes are the consequence of the disappearance ('stepping back' of hepatocytes from the border zone, resulting in the fusion of partially capillarized sinusoids. The growing tumor incorporates SMA-expressing cells and sinusoidal lakes. SMA-positive cells produce collagenous matrix, whereas the lakes become the central vessels within the connective tissue columns. Formation of these columns within the tumor is a consequence of the compression atrophy of the base of the incorporated liver tissue, leading to partial separation of the innermost part of the invagination containing functional vessel(s) from the surrounding liver.

Actins↗

PubMed2005

Genomics of pancreatic cancer: does it make any improvement in diagnosis, prognosis and therapy?

Pancreatic cancer (PanC) is an extremely lifethreatening neoplasm due to its late discovery, rapid progression and resistance to chemo- and radiotherapy. In the past years a significant research attention turned to this cancer. Extensive genomic analysis of PanC revealed numerous alterations, however, none of them emerged yet as a key regulator of tumor progression. Our increasing knowledge on the molecular targets in various cancer types started to change their management. Examples of success of the molecular therapies (in CML, GIST, NSCLC) may initiate more activity in pancreatic cancer as well.

Genomics↗

PubMed2005

Genomics of lung cancer may change diagnosis, prognosis and therapy.

Despite significant improvements in tumor management in general, the prognosis of lung cancer patients remains dismal. It is a hope that our increasing knowledge in molecular aspects of tumor development, growth and progression will open new targets for therapeutic interventions. In this review we discuss some of the more recent results of this field. This includes the susceptibility factors, an association between genetic changes in EGFR pathway and tyrosine kinase inhibitors, the role of gene hypermethylation and genetic profiling, as well as different molecular aspects of tumor progression. Available data all support that lung cancer is a group of diseases with not only distinct histological but with similarly different genetic characters. Accordingly, the diagnosis, prognosis and therapy must accommodate this heterogeneity.

Genomics↗

PubMed2005

Smad signal and TGFbeta induced apoptosis in human lymphoma cells.

Transforming growth factor beta1 (TGF beta1) has antiproliferative and/or apoptotic effect on lymphoid cells. In certain lymphomas exogenous TGF beta1 is able to induce apoptosis, however many lymphoid malignancies are resistant to the endogenous TGF beta1 production. We studied the expression and the activity of TGF beta1 signalling components in B cell lymphoma cell lines (e.g. HT 58 cells) and in isolated human peripheral mononuclear cells (PBMCs) from healthy individual's and B-CLL patient's blood. We found that all signal transducer Smads (Smad2,-3; Smad4) and at least one of the inhibitory Smads (Smad6,-7) were expressed in non-treated lymphoma cells, but the inhibitory Smads did not in normal/control PBMCs. However, after TGF beta1 treatment Smad6 disappeared, while the expression of Smad7 increased in HT 58 cells. The activity of Smad signals was proved by phosphorylation of Smad2, nuclear translocation of Smad2/3, and the increased expression of Smad-dependent gene, TIEG in TGF beta1 treated lymphoma cells. These results showed that Smad signaling is available in certain different human lymphoma cells, however ISmads expression could inhibit the signal transmission. This findings indicates that the lost sensitivity of lymphoma cells toward a physiological regulatory factor could be reversed.

Apoptosis↗

PubMed2005

[Soluble syndecan-1 levels in different plasma cell dyscrasias].

INTRODUCTION: Syndecans are a family of cell surface proteoglycans. In the bone marrow of multiple myeloma patients syndecan-1 is expressed only on the surface of malignant plasma cells. The aim of the study was to determine the soluble syndecan-1 levels in different plasma cell dyscrasias. METHODS: The serum concentration of soluble syndecan-1 was measured using human syndecan-1 enzyme-linked immunosorbent assay kit. RESULTS: Patients with multiple myeloma showed a significantly higher median serum syndecan-1 level than patients with plasmocytoma or monoclonal gammopathy of undetermined significance. Statistically significant differences were also observed among Salmon-Durie subgroups of 50 patients suffering from multiple myeloma. In addition to these findings a statistical correlation with other independent prognostic factors such as serum beta2-microglobulin level, monoclonal immunoglobulin concentration, and bone marrow plasma cell count could also be noted. A significant decrease in median serum syndecan level was observed in patients who responded to chemotherapy, whereas no change in the median syndecan-1 level could be observed in nonresponders. CONCLUSION: These findings confirm the observation that high serum soluble syndecan-1 level is associated with a more advanced disease stage and is a strong independent indicator of poor prognosis. A diminished serum syndecan-1 reading as a result of chemotherapy may be a good indicator of favorable response to antitumor treatment.

Adult↗

PubMed2005

[Mevastatin induced apoptosis in U266 human myeloma cell line].

Statins have been used successfully in the treatment of hypercholesteremia. Moreover, in vitro studies have shown that statins can trigger apoptosis in a variety of tumor cell lines. In the present study we analysed the effect of mevastatin -- a novel inhibitor of HMG-COA reductase, the rate-limiting enzyme of the mevalonate pathway -- on U266 human myeloma cells. Apoptosis induced by mevastatin was associated with increased caspase activity and depolarisation of mitochondrial membrane. Expression of BCL-2 mRNA and protein was down-regulated, with no change in BAX or BCLxL protein production. The mitochondrial program was supported by caspase-8 and cleaved BID activity. None of the antibodies neutralising death-ligand/death-receptor pathway -- TRAIL-R2Fc, anti-TNF-a, anti FASL (NOK-1) -- influenced the mevastatin-induced apoptosis. Mevastatin also stimulated shedding of syndecan-1 from the surface of myeloma cells.

Antineoplastic Agents↗

PubMed2005

Immunohistochemical analysis of cytokeratin 7 expression in resting and proliferating biliary structures of rat liver.

Cytokeratins are the largest subfamily of intermediate filament proteins and include more than 20 different gene products, which are expressed in an epithelial tissue-specific manner. We studied by immunohistochemistry and confocal microscopy the distribution of cytokeratin subtypes in the biliary system of adult rat liver. A cytokeratin (CK)19+/7- cholangiocyte population was observed in the smaller branches of the biliary tree including the canals of Hering. They proliferated after 2-acetaminofluorene (AAF) administration, although later the typical oval cells expressed CK7. This observation suggests that cholangiocytes with this cytokeratin phenotype may harbor adult hepatic stem cells. The CK19+/7- cholangiocytes were not present in the rat liver at birth, but developed postnatally. Similar cell populations were not observed in human livers. In conclusion, we propose that the CK19+/7- phenotype may be characteristic for adult hepatic stem cells in rat liver and that these cells are generated de novo after birth.

2-Acetylaminofluorene↗

PubMed2005

Aberrant somatic hypermutation and expression of activation-induced cytidine deaminase mRNA in mediastinal large B-cell lymphoma.

To determine the possible role of aberrant somatic hypermutation (ASHM) and activation-induced cytidine deaminase (AID) expression in the pathogenesis of mediastinal large B-cell lymphoma (MBL), the mutational status of genes affected by ASHM, including c-MYC, PAX-5 and RhoH, was analysed, and the expression level of AID mRNA in tumour specimens from six patients with MBL was determined. Mutations in one or more genes and high expression of AID mRNA were detected in all the six cases of MBL. These results suggest that ASHM and AID expression may have a role in the pathogenesis of MBL.

Cytidine Deaminase↗

PubMed2004

Tumor stem cells.

Stem cells possess two basic characteristics: they are able to renew themselves and to develop into different cell types. The link between normal stem cells and tumor cells could be examined in three aspects: what are the differences and similarities in the control of self-renewal capacity between stem cells and tumor cells; whether tumor cells arise from stem cells; do tumorous stem cells exist? Since tumor cells also exhibit self-renewal capacity, it seems plausible that their regulation is similar to that of the stem cells. The infinite self-renewal ability (immortalization) is assured by several, so far only partly known, mechanisms. One of these is telomerase activity, another important regulatory step for survival is the inhibition of apoptosis. Other signal transduction pathways in stem cell regulation may also play certain roles in carcinogenesis: e.g. Notch, Sonic hedgehog (SHH), and Wnt signals. Existence of tumor stem cells was suggested since it is simpler to retain the self-renewal capacity than to reactivate the immortality program in an already differentiated cell. Moreover, stem cells live much longer than the differentiated ones, and so they are exposed for a long period of time to impairments, collecting gene errors leading to the breakdown of the regulation. However, it is still an open question whether all cells in the tumor possess the capacity that produces this tissue or not, that is: are there tumor stem cells or there are not. If tumor stem cells exist, they would be the main target for therapy: only these must be killed since the other tumor cells possess limited proliferative capacity, therefore limited life span. The only problem is that during tumor progression stem-like cells can develop continuously and the identification but mainly the prevention of their formation is still a great challenge.

Animals↗

PubMed2004

Apoptosis and P53, Bcl-2 and Bax gene expression in parathyroid glands of patients with hyperparathyroidism.

Altogether 107 patients were operated on at the Department of Transplantation and Surgery of Semmelweis University in the past four years, for clinical symptoms of hyperparathyroidism. Clinical and laboratory data of the patients supported the diagnosis of primary or secondary hyperparathyroidism. Chronically impaired renal function was found in 52 cases. The removed parathyroid glands showed hyperplasia in 54, adenoma in 50 and carcinoma in 3 cases. The majority of parathyroid lesions in primary hyperparathyroidism were adenomas (41 cases) and in secondary hyperparathyroidism were hyperplasias (43 cases). The ratio of oxyphil to chief cells as well as occasional mitotic and apoptotic figures were determined. The oxyphil component was present in both hyperplastic and tumorous lesions. Apoptosis and mitosis were rarely seen in hyperplasias and adenomas (under 2%), whereas in carcinomas 3% of the tumor cells were apoptotic and 4% showed mitosis. Cytoplasmic p53 positivity could be observed in 3 of the adenomas and in 2 of the hyperplasias. The carcinomas, four adenomas and 3 hyperplasias showed nuclear p53 positivity. Bcl-2 and Bax were detected in the cytoplasm of the tumor cells in the majority of adenomas and in the cells of hyperplasias. Oxyphil cells were more frequently positive than chief cells or clear cells. Colocalization of Bcl-2 and Bax was found randomly in all types of lesions. The very low incidence of carcinoma, the low mitotic and apoptotic ratio in adenomas and hyperplasias suggest a potent antiproliferative defense mechanism in the parathyroid cell population. This may also be reflected in the cytoplasmic colocalization of various gene products which regulate cell death and cell proliferation. No significant differences in the p53, Bcl-2 and Bax spectrum were found between the primary and secondary (i.e. renal failure) parathyroid alterations.

Adenocarcinoma↗

PubMed2004

2-acetylaminofluorene dose-dependent differentiation of rat oval cells into hepatocytes: confocal and electron microscopic studies.

The 2-acetylaminofluorene (AAF)/partial hepatectomy (PH) model is one of the most extensively studied experimental systems for oval cell proliferation and differentiation. We have previously described the oval cells as forming ductular structures surrounded by basement membrane, representing extensions of the canals of Hering. Herein we analyze the differentiation of oval cells into hepatocytes after varying degrees of liver damage induced by AAF. At a low dose of AAF, most oval cells synchronously differentiate into small hepatocytes by 6 days after the PH, resulting in complete restoration of the liver structure in 10 days. Higher doses of AAF delay the differentiation process and the new hepatocytes form foci, in contrast to what is observed at the low dose. Qualitatively, the differentiation process seems to be identical at the cellular level under both conditions. The transition from the expanding oval cell population into hepatocytes was correlated with the upregulation of hepatocyte nuclear factor 4 and the disappearance of the basement membrane. Also, the differentiation of oval cells into hepatocytes coincided with the loss of alpha-fetoprotein and OV-6 staining, and the replacement of the biliary cell-specific alpha6 integrin and connexin 43 with the hepatocyte-specific alpha1 integrin and connexin 32. In addition, bile canaliculi form between the new hepatocytes. In conclusion, these results indicate the rate of oval cell differentiation into hepatocytes is context dependent and suggest that, under favorable conditions, oval cells can complete this process much faster than previously appreciated.

2-Acetylaminofluorene↗