Andrea Reszegi, Zsolt Horváth, Hajnalka Fehér, Katalin Karászi, Victoria Postniková, Eszter Regős, Ilona Kovalszky, Kornélia Baghy
1st Department of Pathology and Experimental Cancer Research, Semmelweis University Budapest, Hungary.
Introduction: Hepatocellular carcinoma (HCC) and colorectal (CRC) cancer represents the third and the second most common cause of cancer death worldwide. A key constituent of the hepatic microenvironment is the small leucine-rich proteoglycan decorin known to interfere with cellular events of tumorigenesis mainly by blocking various receptor tyrosine kinases and inducing p21WAF1/CIP1.
Aims: We designed a model system, in which we examined the role of decorin both in the process of primary hepatocarcinogenesis and liver metastasis.
Methods: Tissue microarrays were assembled from human HCC and CRC cases and immunostained for decorin. For in vivo transfection, pLIVE vector coding human decorin cDNA and its control vector were targeted to the liver. For monitoring vector operation, a control vector coding for serum alkaline phosphatase was also applied. Vectors were ingested by hydrodynamic gene delivery. Hepatocarcinogenesis was induced by thioacetamide administration. Liver metastasis of colon carcinoma was modelled by inoculating murine colon 38 cell line into the spleen. Receptor tyrosine kinase activity was analyzed by Proteome Profiler pRTK assay.
Results: In hepatocellular carcinoma, decorin expression is reduced or completely blocked as seen in human samples. In vivo transfection of the liver by decorin expressing vector was performed. Exogenous decorin expressed by hepatocytes was able to effectively inhibit tumorigenesis evoked by thioacetamide. In liver metastases of colon carcinoma, decorin amount is significantly lower than that of primary tumor or normal colon reflecting on its possible antitumor action. In our mouse experiments, excessive decorin level significantly reduced colonization colon tumor cells into the liver. Artificial decorin expression decreased the levels of several RTKs in both models.
Conclusion: Decorin gene delivery is able to effectively inhibit the primary and metastatic tumor formation in the liver. Our results support the idea of decorin utilization as an anti-cancer agent in the battle of liver malignancies.
Doctoral School: Doctoral School of Pathological Sciences
Program: Experimental Oncology
Supervisor: Kornelia Baghy Ph.D
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