Manabe Tatsuya, Mizumoto Kazuhiro, Nagai Eishi, Matsumoto Kunio, Nakamura Toshikazu, Nukiwa Toshihiro, Tanaka Masao, Matsuda Takehisa
Divisions of Biomedical Engineering and Surgery and Oncology, Graduate School of Medicine, Kyushu University, Maidashi, Fukuoka, Japan.
Clin Cancer Res. 2003 Aug 1;9(8):3158-66.
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.
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.
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.
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.
胰腺癌的胰腺切除术是唯一的治愈方式，但术后局部复发的高发生率导致预后极差。本研究旨在开发一种新的治疗工具，该工具可抑制残留癌细胞的生长，其基于从转导了NK4基因的口腔黏膜上皮细胞（OMEC）片（NK4片）分泌的NK4（肝细胞生长因子拮抗剂）的局部递送，该NK4片粘附于切除表面。
按照3T3饲养层技术收获并培养的OMEC接种于覆盖有胶原蛋白网的可生物降解的聚丙交酯乙交酯网片上，以制备OMEC片。NK4基因转导由重组腺病毒（Ad-NK4）介导。检测了OMEC用于基于细胞的NK4递送的适用性。建立了使用裸鼠的实验模型，以确定NK4片对肿瘤生长和血管生成的影响。
Ad-NK4转导的OMEC分泌的NK4抑制了MRC-5诱导的胰腺癌细胞系的侵袭。异位植入的基因转导的OMEC在逐渐减少的同时可保留>/==" BORDER="0">10天。NK4片在体内抑制血管生成和肿瘤生长。
发现自体OMEC适合此目的，因为其不分泌肝细胞生长因子、易于从患者获取、具有相当高的增殖潜力且无免疫反应。尽管正在开发的NK4片显示出较低水平且较短时间的NK4分泌，但当加载多层OMEC时，预计该系统在临床情况下可能具有向靶组织递送蛋白质的巨大潜力。
