Gene transduction of NK4, HGF antagonist, inhibits in vitro invasion and in vivo growth of human pancreatic cancer.
In this study, we investigated the therapeutic effects of adenovirally-mediated transfer of the sequence of NK4, an antagonist for hepatocyte growth factor (HGF), against human pancreatic carcinoma. HGF has been implicated to play an important role in invasion and metastasis of various human cancers through tumor-stromal interactions. Although NK4 has been shown to block the metastatic behavior of cancer cells, problems with cellular delivery of NK4 must be addressed before it can be used for clinical trials. The effects of NK4 gene transduction mediated by recombinant adenovirus (Ad-NK4) were evaluated in a human pancreatic cancer cell line (SUIT-2) by in vitro scattering assays, invasion assays, and subcutaneous transplantation in nude mice. NK4 transduction markedly inhibited scattering and invasion of SUIT-2 cells stimulated by HGF without affecting cell proliferation in vitro. Furthermore, Ad-NK4 significantly inhibited the growth of tumors transplanted to nude mice. The tumor reduction induced by Ad-NK4 was associated with a decreased number of blood vessels surrounding the tumors. These findings suggest that Ad-NK4 gene therapy may be a unique and promising strategy for the treatment of pancreatic cancer.
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Naoki
N
Maehara
Eishi
E
Nagai
Kazuhiro
K
Mizumoto
Norihiro
N
Sato
Kunio
K
Matsumoto
Toshikazu
T
Nakamura
Ko
K
Narumi
Toshihiro
T
Nukiwa
Masao
M
Tanaka
D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000502:physiology*; D000818:Animals; D002277:Carcinoma / Q000098:blood supply / Q000473:pathology* / Q000628:therapy; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008934:Mitogens; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012983:Soft Tissue Neoplasms / Q000473:pathology / Q000628:therapy; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; C066855:HGF protein, human; D008934:Mitogens; D011993:Recombinant Fusion Proteins; D017228:Hepatocyte Growth Factor