Biomedical subjects

József Dudás

Publications and source records attributed to József Dudás.

6 recordsLinked to original sources

PubMed2006

Agrin, a novel basement membrane component in human and rat liver, accumulates in cirrhosis and hepatocellular carcinoma.

Agrin is a multifunctional heparan sulfate proteoglycan originally discovered in the neuromuscular junctions and later observed in numerous other localizations. The presence of agrin in the liver, either healthy or diseased, has formerly not been reported. We detected agrin in minor amounts in the basement membranes of blood vessels and bile ducts in the healthy liver. The proliferation of bile ductules and the formation of new septal blood vessels in liver cirrhosis, as well as neoangiogenesis in the hepatocellular carcinoma (HCC) result in a dramatic increase in the quantity of agrin. Vascular and peribiliary basement membranes were strongly immunopositive for agrin in 29/29 human liver specimens with cirrhosis and HCC. However, sinusoidal walls of regenerative nodules in the cirrhotic liver consistently remained negative. Given the selectivity of agrin for tumor microvessels, agrin immunohistochemistry may prove helpful in recognizing malignant transformation in cirrhotic livers. Similar immunohistochemical observations were made on the liver of rats exposed to a combined cirrhosis/HCC induction treatment. In both human and rats, agrin probably originates from activated myofibroblasts, vascular smooth muscle cells and biliary epithelial cells. Increased agrin expression in human specimens, in the liver of 4/4 treated rats, as well as in isolated rat liver mesenchymal cells was verified by quantitative RT-PCR. Considering that agrin binds various growth factors, and it directly interacts with cell membrane receptors such as alphav-integrins, we hypothesize a stimulatory role for agrin in neoangiogenic processes such as tumor vascularization, and a supportive role in bile ductule proliferation.

Agrin↗

PubMed2006

Repopulation of osteosarcoma cells after treatment with doxorubicin in the presence of extracellular matrix biopolymers.

PURPOSE: To elucidate the role of extracellular matrix (ECM) in repopulation capacity of osteosarcoma cells after doxorubicin treatment. METHODS: OSCORT cells established in our laboratory from a human osteosarcoma, were treated with doxorubicin in monolayer for 4 h, then cells were further incubated either in monolayer or in ECM-containing three-dimensional cell-culture (3-DCC), apoptosis induction and changes in cell number were measured. Alkaline comet assay was applied to estimate DNA damage, immunoblot technique and immunocytochemistry were used to investigate p53 protein synthesis, and the repopulating capacity in monolayer culture and in ECM-based 3-DCC, after doxorubicin treatment was measured. In addition to OSCORT culture five other human cell lines (HT-1080, PC-3, MDA-MB231, A-431 and ZR-75-1) were used to compare the antimigratory and antiproliferative effects of doxorubicin. RESULTS: The apoptotic index, the extent of DNA damage and the representation of p53 were much lower in the OSCORT cell cultures if the cells were exposed to ECM after treatment with doxorubicin. The doxorubicin-treated OSCORT cells transferred from the monolayer culture were not able to proliferate at all, at the same time, the cytoprotection provided by ECM prevailed upon transferring the cells into plastic dish, and resulted in potent repopulation capacity of the cells. CONCLUSIONS: Present data indicate that ECM contributes to failure in therapy of human osteosarcoma in clinical situation. Overall, the application of ECM-based 3-DCC could be suggested as an appropriate model system for the better understanding of antitumor drug action and hereby to set the stage for promising novel pharmacological approaches in cancer therapy.

Antibiotics, Antineoplastic↗

PubMed2005

Invasive growth and topoisomerase-switch induced by tumorous extracellular matrix in osteosarcoma cell culture.

Osteosarcoma cells are capable of extracellular matrix (ECM) synthesis. The ability of ECM to trigger the proliferation of a novel osteosarcoma cell line (OSCORT) was tested in this study in relation to a known tumor ECM, isolated from Engelbreth-Holm-Swarm (EHS) sarcoma (EHS-ECM). OSCORT was grown in monolayer, in EHS-ECM and in ECM deposited by the cells (OSCORT-ECM). Both EHS-ECM and OSCORT-ECM increased the proliferation and migration of OSCORT cells. Among the ECM biopolymers, heparan sulfate proteoglycan (HSPG) and fibronectin enhanced invasive growth, collagen type IV reduced it, while laminin had no effect. Among the ECM components HSPG and collagen IV increased both the synthesis and activation of collagenase type IV, and all the ECM components substantially increased beta1 integrin levels in the cells. The majority of ECM biopolymers decreased the level of topoisomerase I (except laminin) and elevated topoisomerase II (except fibronectin) in OSCORT. The switch in the ratio between the activities of topoisomerases I and II was mainly due to HSPG. The HSPG synthesized by OSCORT cells is described as agrin, which is a novel finding. The present study showed that HSPG (agrin) showed the most remarkable stimulatory action on the growth and migration of OSCORT cells. HSPG-induced topoisomerase II-induction deserves further experimentation, to discover its relevance to tumor progression.

Adolescent↗

PubMed2004

[Proteoglycans in the liver].

Proteoglycans are macromolecules formed by a protein core to which sugar chains are covalently attached. They are present on the cell surface and in the ECM of living things. In normal liver syndecan-1 is the dominant transmembrane proteoglycan, trace amounts of ECM proteoglycans are in the stromal components. The amounts of proteoglycans we studied increase in liver cirrhosis. In liver cancer abnormal localization of syndecan-1 and stroma rich in agrin was characteristic. The core proteins as well as the sugar chains of proteoglycans interact with and modulate the effect of regulatory factors. This implies that structural alterations of proteoglycans contribute to the development of malignant phenotype. Heparan sulfate chains of liver cancer are undersulfated with decreased or altered biological activity. Their binding capacity for transcription factor decreases, and they do not inhibit topoisomerase I enzyme. Truncated form of syndecan-1 lacking the extracellular domain of the molecule induces differentiation of hepatoma cell line and inhibits the shedding of syndecan-1. This phenomenon calls attention to the importance of syndecan-1 shedding in the regulation of cell behavior.

Animals↗

PubMed2002

Proteoglycans and tumor progression: Janus-faced molecules with contradictory functions in cancer.

Understanding the details of the molecular mechanism of tumor dissemination revealed that several proteoglycan species are involved in the process but their role can be described as Janus-faced. One level of proteoglycan alterations is at the expression of their genes coding for the core protein. Characteristically, in progressing tumors two patterns emerged: loss or neoexpression of surface proteoglycans (PG) depending on the initial expression pattern of the cell type of origin. The situation is similarly complex concerning the changes of glycosaminoglycan (GAG) of the PG during tumor progression. This is due to the fact that the majority of PGs involved is hybrid molecule meaning that their core protein can be glycanated both with chondroitin and heparan sulfate. However, such an alteration in glycanation of PG may fundamentally change the function of the molecule, especially the one operating at the cell surface. Among the extracellular PGs, decorin emerged as inhibitor of progression while perlecan as a promoter of the process. Analysis of the available data indicate that during metastatization tumor cells must express at least one cell surface HSPG species from the syndecan-glypican-CD44v3 group. Furthermore, the HS-chain of these proteoglycan(s) carry important molecular signatures (suphution or epimerization patterns). Experimental data suggest that tumor cell surface heparan sulfate (PG) may provide a target for specific anti-metastatic interventions.

Animals↗

PubMedDate not supplied

Antiproliferative and antimigratory effects of doxorubicin in human osteosarcoma cells exposed to extracellular matrix.

Osteosarcoma cells are involved in the remodeling of the extracellular matrix (ECM) that affects their growth, invasive and metastatic activities. The tumour ECM provided effective protection against chemotherapy agents in several previously studied malignancies. The current study examined the effects of doxorubicin on cells that were migrated into a 3-dimensional extracellular matrix gel (ECM-gel) in comparison with its effects on cells remaining in the monolayer compartment. A human osteosarcoma cell line (OSCORT) was treated with doxorubicin in monolayer culture for 4 or 24 hours, and then overlaid by ECM-gel for 24 hours. Tumour cells remaining in the monolayer were separated from the cells migrated into ECM-gel, and both of them were characterized. OSCORT cells migrated into ECM-gel showed elevated levels and activity of topoisomerase II, increased protein expression of beta1 integrin and matrix metalloproteinase-9 activity. Doxorubicin treatment for 4 hours resulted in increased cytotoxicity in the monolayer compartment relative to the cells migrated into ECM-gel, whereas 24-hour treatment at a low concentration (0.01 microg/ml) showed an antimigratory effect. Different antiproliferative and antimigratory effects of doxorubicin treatment schedules warrant short-term, high-dose treatment for targeting the tumour growth, and long-term, low-dose treatment for targeting the invasion of osteosarcoma.

Antibiotics, Antineoplastic↗