Adeno-associated virus-mediated expression of apolipoprotein (a) kringles suppresses hepatocellular carcinoma growth in mice
| Autor: | Sung-Tae Yun, Eui-Cheol Jo, Young-Gun Kim, Yeup Yoon, Kyuhyun Lee |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Pathology medicine.medical_specialty Carcinoma Hepatocellular Apolipoprotein B viruses Transgene Genetic enhancement Biology medicine.disease_cause Neovascularization Mice Kringles medicine Carcinoma Tumor Cells Cultured Animals Humans Adeno-associated virus Apolipoproteins A Cell Proliferation Mice Inbred BALB C Hepatology Neovascularization Pathologic Liver Neoplasms Genetic Therapy Dependovirus medicine.disease digestive system diseases Apoptosis Hepatocellular carcinoma biology.protein medicine.symptom |
| Zdroj: | Hepatology (Baltimore, Md.). 43(5) |
| ISSN: | 0270-9139 |
| Popis: | Hepatocellular carcinoma (HCC) constitutes more than 90% of all primary liver cancers. HCC is a hypervascular tumor that develops from dedifferentiation of small avascular HCC and is therefore a good target for anti-angiogenic gene therapy. Recent studies have identified apolipoprotein(a) [apo(a)] kringles LK68 and LK8 (LKs) as having a potential antiangiogenic and anti-tumor activity, and the current study evaluates the therapeutic potential of gene therapy with recombinant adeno-associated virus carrying genes encoding LKs (rAAV-LK) in the treatment of hypervascular HCC. We generated rAAV-LK to obtain persistent transgene expression in vivo, which is essential for anti-angiogenic therapy. The rAAV-produced LKs substantially inhibited proliferation and migration of human umbilical vein endothelial cells (HUVECs) in vitro, validating their anti-angiogenic potential. Intramuscular administration of rAAV-LK gave 60% to 84% suppression (P < .05) of tumor growth in mice bearing subcutaneously transplanted HCC derived from Huh-7 and Hep3B cells, respectively. Histological and immunohistochemical analyses of HCC tumor sections showed that a single administration of rAAV-LK gave rise to persistent expression of LKs that inhibited tumor angiogenesis and triggered tumor apoptosis, and, thus, significantly suppressed tumor growth. The administration of rAAV-LK provided a significant survival benefit (P < .05), and 3 of 10 rAAV-LK-treated mice were still alive without visible tumors and without clinical symptoms 188 days after treatment. In conclusion, rAAV-LK is a potential candidate for anti-angiogenic gene therapy in the treatment of HCC. |
| Databáze: | OpenAIRE |
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