Inhibition of invasiqn and metastasis of pancreatobiliary cancers by HGF/NK4 gene.

胰胆管癌是高度恶性的，由于癌细胞广泛侵袭和转移到周围组织或器官，其预后较差。我们之前发现肝细胞生长因子（HGF）通过其受体c-met原癌基因刺激肿瘤的侵袭和转移。为了控制这些癌症的侵袭和转移，我们制造了一种拮抗剂HGF/NK4，并研究了它对侵袭和肿瘤生长的抑制作用。我们在本研究中检测了HGF/NK4基因转移到细胞中是否会抑制其侵袭和转移。将携带HGF/NK4基因的质粒转染到胆囊癌细胞系GB-d1中，不能抑制亲本GB-dl的侵袭性。携带HGF/NK4基因的腺病毒载体AdCMV。纯化了NK4并用于小鼠模型的治疗。腺病毒载体感染的GB-d1细胞和间皮细胞产生大量的NK4蛋白。病毒极大地抑制了GB-d1细胞的侵袭和迁移。在裸鼠GB-d1细胞腹膜转移模型中，腹腔注射该病毒后，转移瘤的大小减小。由此可见，携带HGF/NK4基因的腺病毒载体可能通过诱导HGF/NK4蛋白，有效控制胆道肿瘤的传播或转移。

Pancreatobiliary cancers are highly malignant and its prognosis is poor due to extensive invasion and metastasis of the cancer cells to surrounding tissues or organs. We previously revealed that hepatocyte growth factor (HGF) stimulates cancer invasion and metastasis via its receptor c-met protooncogene. To control invasion and metastasis of these cancers, we created an antagonist, HGF/NK4, and its inhibitory effect on invasion and cancer growth. We examined in this study whether HGF/NK4 gene transfer into the cells results in suppression of the invasion and metastasis or not. Transfection of a plasmid carrying HGF/NK4 gene into a gallbladder cancer cell line, GB-d1, could not suppress invasive nature of the parental GB-dl. An adenovirus vector carrying HGF/NK4 gene, AdCMV. NK4, was purified and used for therapy in a murine model. GB-d1 cells and mesothelial cells infected with the adenovirus vector produced substantial level of NK4 protein. And the invasion and migration of GB-d1 cells was extremely inhibited by the virus. In nude mouse model for peritoneal metastasis of GB-d1 cells, the size of the metastasis tumor was decreased after injection of the virus into peritoneal cavity. We concluded that the adenovirus vector carrying HGF/NK4 gene might be effective to control biliary cancer dissemination or metastasis by induction of HGF/NK4 protein.