Adeno-associated virus-mediated expression of apolipoprotein (a) kringles suppresses hepatocellular carcinoma growth in mice.
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.
Lee
Kyuhyun
K
Gene Therapy Laboratory, Biomolecular Engineering Division, MOGAM Biotechnology Research Institute, Yongin, Kyonggi-Do, Republic of Korea.
Yun
Sung-Tae
ST
Kim
Young-Gun
YG
Yoon
Yeup
Y
Jo
Eui-Cheol
EC
D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000628:therapy*; D049109:Cell Proliferation; D000229:Dependovirus; D015316:Genetic Therapy; D006801:Humans; D018082:Kringles; D008113:Liver Neoplasms / Q000473:pathology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic; D014407:Tumor Cells, Cultured
D001054:Apolipoproteins A