Cell-based protein delivery system for the inhibition of the growth of pancreatic cancer: NK4 gene-transduced oral mucosal epithelial cell sheet.
OBJECTIVE
Pancreatic resection for pancreatic cancer is the only curative modality, but the high incidence of local recurrence after surgery results in a very poor prognosis. This study aims to develop a new therapeutic tool that could inhibit the growth of remnant cancer cells, which is based on local delivery of NK4 (hepatocyte growth factor antagonist) secreted from an NK4 gene-transduced oral mucosal epithelial cell (OMEC) sheet (NK4-sheet), which is adhered to the resected surface.


METHODS
OMECs, harvested and cultured according to 3T3 feeder layer technique, were seeded on a collagen mesh-overlayered, biodegradable VICRYL mesh to produce an OMEC sheet. NK4 gene transduction was mediated by recombinant adenovirus (Ad-NK4). Applicability of OMECs for cell-based NK4 delivery was examined. An experimental model using nude mice was established to determine the effect of an NK4-sheet on both tumor growth and angiogenesis.


RESULTS
NK4 secreted from Ad-NK4-transduced OMECs suppressed MRC-5-induced invasion of pancreatic cancer cell lines. Heterotopically implanted gene-transduced OMECs remained for >/==" BORDER="0">10 days while gradually decreasing. NK4-sheets inhibited both angiogenesis and tumor growth in vivo.


CONCLUSIONS
Autologous OMEC was found to be suited to this purpose because of no secretion of hepatocyte growth factor, ease in harvesting from a patient, reasonably high proliferation potential, and no immune reaction. Although NK4-sheets under development exhibited a low level and short period of NK4 secretion, it is expected that this system may have a great potentiality of protein delivery system to target tissue at clinical situations when it is loaded with multilayered OMECs.
Manabe
Tatsuya
T
Divisions of Biomedical Engineering and Surgery and Oncology, Graduate School of Medicine, Kyushu University, Maidashi, Fukuoka, Japan.
Mizumoto
Kazuhiro
K
Nagai
Eishi
E
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Nukiwa
Toshihiro
T
Tanaka
Masao
M
Matsuda
Takehisa
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001672:Biocompatible Materials; D002448:Cell Adhesion; D002455:Cell Division; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008934:Mitogens; D008954:Models, Biological; D009061:Mouth Mucosa / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000628:therapy*; D011098:Polyglactin 910 / Q000737:chemistry; D011379:Prognosis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D001672:Biocompatible Materials; C066855:HGF protein, human; D008934:Mitogens; D011098:Polyglactin 910; D017228:Hepatocyte Growth Factor; D003094:Collagen