Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice.
NK4, a 4-kringle fragment of hepatocyte growth factor (HGF), is an HGF antagonist that also acts as an angiogenesis inhibitor. NK4 strongly inhibits the infiltration, metastasis, and tumor growth of pancreatic cancer. The aim of our study was to evaluate the antitumor effect of adenovirus-mediated NK4 gene transfer to the liver on hepatic metastasis of pancreatic cancer in vivo. We constructed recombinant adenoviral NK4 (Ad-NK4), which encodes a secreted form of human NK4. Intrasplenic injection of Ad-NK4 induced high and relatively maintained expression of NK4 protein in the liver and suppressed the number and growth of metastatic foci in the liver in a nude mouse model. Microscopically, central necrosis was found even in small metastatic foci in Ad-NK4 treated mice. Immunohistochemical analysis of metastatic tumors showed a remarkable decrease in microvessel density and an increase in the number of apoptotic tumor cells after treatment with Ad-NK4. These results indicate that intraportal injection of Ad-NK4 may be a useful therapeutic modality for the clinical control of hepatic metastasis in pancreatic cancer.
Murakami
Mitsuhiko
M
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nagai
Eishi
E
Mizumoto
Kazuhiro
K
Saimura
Michiyo
M
Ohuchida
Kenoki
K
Inadome
Naoki
N
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Maemondo
Makoto
M
Nukiwa
Toshihiro
T
Tanaka
Masao
M
D000230:Adenocarcinoma / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007274:Injections, Intraperitoneal; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008934:Mitogens / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013154:Spleen / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C066855:HGF protein, human; D008934:Mitogens; D017228:Hepatocyte Growth Factor