New strategy against pancteato-biliary carcinoma using NK4, a four-kringle antagonist of hepatocyte growth factor

由于其高度侵略性的行为，即，由于胰腺癌具有侵袭性、扩散性和转移性，因此胰腺癌患者的结局是病态的。更好地了解和干预胰腺癌的恶性行为可能会为治疗提供新的方向。我们在此报道了肝细胞生长因子（HGF）诱导人胰腺癌细胞的高运动性和侵袭性，以及一种新发现的HGF拮抗剂NK 4阻断这些特性。（AsPC-1、BxPC-3、H-48 N、KP-1 N、KP-2、KP-3、MIA PaCa-2和SUIT-2细胞），c-Met/HGF受体以不同水平表达。尽管仅在SUIT-2和KP-3细胞中观察到HGF的弱促有丝分裂活性，但HGF强烈刺激这些胰腺癌细胞的迁移和侵袭，除了BxPC-3和MIA PaCa-2细胞。与此相反，迁移和侵袭由HGF诱导的KP-1 N，KP-3，SUIT-2细胞的有力抑制NK 4。SUIT-2细胞的侵袭性也受到共培养的胰腺成纤维细胞和胰腺癌切除后获得的腹水的影响而有效地刺激，然而，在这种条件下癌细胞的侵袭性实际上被NK 4消除。结论胰腺癌术后患者腹水中含有高水平的HGF，携带NK 4的腺病毒（Ad-NK 4）对裸鼠移植瘤的生长有明显的抑制作用。Ad-NK 4诱导的肿瘤缩小与肿瘤周围血管减少有关，提示HGF可能参与胰腺癌的侵袭、播散和转移，尤其是通过肿瘤-间质相互作用和胰腺癌切除后的侵袭、播散和转移。NK 4是一种有效的HGF拮抗剂，可能具有抗肿瘤侵袭/转移的潜力。

Because of the highly aggressive behaviour, i.e., invasive, disseminative, and metastatic properties, the outcome for patients with pancreatic cancer is morbid. A better understanding and interference with the malignant behavior of pancreatic cancer may provide new directions for treatment. We report here the induction of highly motile and invasive properties in human pancreatic cancer cells by hepatocyte growth factor (HGF) and blockage of these properties by NK4, a newly identified antagonist for HGF.In all of 8 human pancreatic cancer cell lines we used (AsPC-1, BxPC-3, H-48N, KP-1N, KP-2, KP-3, MIA PaCa-2 and SUIT-2 cells), the c-Met/HGF receptor was expressed at varying levels. Although weak mitogenic activity of HGF was seen only in SUIT-2 and KP-3 cells, HGF strongly stimulated migration and invasion of these pancreatic cancer cells, except for BxPC-3 and MIA PaCa-2 cells. In contrast, migration and invasion potently induced by HGF in KP-1N, KP-3, and SUIT-2 cells were inhibited by NK4. The invasion of SUIT-2 cells was also potently stimulated with the influence of co-cultured pancreatic fibroblasts and by ascitic fluid obtained after pancreatic cancer resection, however, invasiveness of the cancer cells in such conditions was practically abolished by NK4. Consistently, the ascitic fluid in patients who had undergone pancreatic cancer surgery contained high levels of HGF.Furthermore, Adenovirus harboring NK4 (Ad-NK4) significantly inhibited the growth of transplanted tumors in nude mice. The tumor reduction induced by Ad-NK4 was associated with a decreased number of blood vessels surrounding the tumors.These findings mean that HGF is probably involved in invasion, dissemination, and metastasis of pancreatic cancer, particularly through tumour-stromal interaction and after resection of the pancreatic cancer. NK4, an effective antagonist of HGF, may prove to have the potential for anti-invasion/metastasis.