Gallbladder cancer treatment using adenovirus expressing the HGF/NK4 gene in a peritoneal implantation model.
Gallbladder cancer cells are stimulated by hepatocyte growth factor (HGF) in vitro and in vivo. We constructed an adenovirus vector, AdCMV.NK4, carrying the HGF antagonist HGF/NK4 (NK4) and evaluated whether or not this vector can suppress the peritoneal implantation of gallbladder cancer in a novel peritoneal injury mouse model. A human gallbladder cancer cell line (GB-d1) and human peritoneal mesothelial cells infected with the adenovirus vector produced a substantial level of NK4 protein. An invasion of GB-d1 cells was determined by a coculture with AdCMV.NK4-infected human mesothelial cells in vitro. Both the invasion and migration of GB-d1 cells were dramatically inhibited by this vector in a multiplicity of infection (MOI)-dependent manner. GB-d1 cells were intraperitoneally injected into the nude mice with peritoneal injury, followed by either AdCMV.NK4 or a control vector (AdCMV.LacZ). The incidence and the size of the metastatic tumor drastically decreased by AdCMV.NK4 (MOI 100: n=4, P<.0001). Real-time PCR analysis revealed a transient elevation of mouse HGF mRNA expression at the peritoneal injury sites. AdCMV.NK4 has been suggested to induce the inhibition of the implantation and growth of gallbladder cancer cells in vivo through its anti-HGF activity, and the use of NK4 gene transfer could be an effective modality for preventing peritoneal metastasis of gallbladder cancer.
Tanaka
Toshihiro
T
First Department of Surgery, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan.
Shimura
Hideo
H
Sasaki
Takamitsu
T
Narumi
Kou
K
Maemondo
Makoto
M
Nukiwa
Toshihiro
T
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Ikeda
Seiyo
S
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005706:Gallbladder Neoplasms / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D051379:Mice; D008934:Mitogens / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D018076:DNA, Complementary; C066855:HGF protein, human; D008934:Mitogens; D012333:RNA, Messenger; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor