Transduction of soluble Flt-1 gene to peritoneal mesothelial cells can effectively suppress peritoneal metastasis of gastric cancer.
The prognosis of gastric cancer with peritoneal metastasis has not improved. Despite many promising studies, gene therapy has limited clinical application because of the lack of suitable vector systems to enable selective gene transduction to tumor cells. The aim of this study was to clarify whether gene therapy targeted to peritoneal mesothelial cells (PMCs) can inhibit peritoneal dissemination of gastric cancer. In vitro experiments showed that adenovirus expressing LacZ infected human omental tissue-derived PMCs more efficiently than human gastric cancer cell lines MKN1 and MKN45. When adenovirus expressing LacZ was injected into the peritoneal cavity of nude mice, the expression was detected in the peritoneum for at least 4 weeks. Furthermore, when adenovirus expressing soluble Flt-1 (Ad-sFLT-1) was i.p. administered in vivo, a high level of sFlt-1 protein could be detected in peritoneal lavage for 8 weeks. When MKN45 cells were i.p. inoculated 3 days after adenoviral vector injection, Ad-sFLT-1 markedly reduced the number of metastatic nodules larger than 1 mm in diameter on the peritoneal surface, and significantly prolonged the survival of nude mice without any significant side effects. Thus, peritoneal dissemination was significantly suppressed by a single i.p. injection of Ad-sFlt-1. Anti-angiogenic gene therapy targeted to PMCs could be a novel and practical strategy against peritoneal dissemination of gastric cancer, because it does not require tumor-specific gene transfer.
Sako
Akihiro
A
Department of Surgical Oncology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. sakou-dis@h.u-tokyo.ac.jp
Kitayama
Joji
J
Koyama
Hiroyuki
H
Ueno
Hikaru
H
Uchida
Hiroaki
H
Hamada
Hirofumi
H
Nagawa
Hirokazu
H
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018995:Myosin Heavy Chains; D024501:Nonmuscle Myosin Type IIB; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000517:prevention & control* / Q000556:secondary; D010537:Peritoneum / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D040281:Vascular Endothelial Growth Factor Receptor-1; D023041:Xenograft Model Antitumor Assays
D016326:Extracellular Matrix Proteins; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains