Hepatic gene expression of NK4, an HGF-antagonist/angiogenesis inhibitor, suppresses liver metastasis and invasive growth of colon cancer in mice
Hepatic gene expression of NK4, an HGF-antagonist/angiogenesis inhibitor, suppresses liver metastasis and invasive growth of colon cancer in mice
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DOI：
10.1038/sj.cgt.7700705
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发表时间：
2004-06
影响因子：
6.4
通讯作者：
J. Wen;Kunio Matsumoto;N. Taniura;D. Tomioka;Toshikazu Nakamura
中科院分区：
文献类型：
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作者：
J. Wen;Kunio Matsumoto;N. Taniura;D. Tomioka;Toshikazu Nakamura
肝细胞生长因子（HGF）通过增强侵袭和转移参与癌细胞的恶性行为。我们之前发现 NK4（HGF 的四环片段）既可作为 HGF 拮抗剂，又可作为血管生成抑制剂。我们现在已经开展研究，以确定基于流体动力学的 NK4 基因递送和表达是否会抑制小鼠结肠癌细胞的肝转移和侵袭性生长。当通过基于流体动力学的基因传递将 NK4 的裸质粒引入小鼠体内时，NK4 在肝脏中主要呈高水平表达。 MC-38小鼠结肠癌细胞脾内接种后，细胞在肝脏中形成大量转移结节，并表现出侵袭性生长行为。另一方面，当小鼠被给予 NK4 质粒时，NK4 的肝基因表达抑制了肝转移和随后与微血管密度降低相关的生长。同样，NK4基因表达抑制癌细胞的肝内侵袭，这种抗侵袭作用与原位抑制c-Met受体酪氨酸磷酸化有关。此外，NK4基因表达延长了这些小鼠的存活时间。考虑到大多数结肠癌死亡是由于肝转移所致，可以考虑使用 NK4 肝基因表达治疗转移性结肠癌的潜在治疗用途。
Hepatocyte growth factor (HGF) is involved in malignant behavior of cancer cells by enhancing invasion and metastasis. We earlier found that NK4, a four-kringle fragment of HGF, functions as both an HGF antagonist and an angiogenesis inhibitor. We have now carried out studies to determine if hydrodynamics-based delivery and expression of the NK4 gene would inhibit liver metastasis and invasive growth of colon carcinoma cells in mice. When the naked plasmid for NK4 was introduced into mice by hydrodynamics-based gene delivery, a high level of expression of NK4 was predominant in the liver. After intrasplenic inoculation of MC-38 murine colon carcinoma cells, the cells formed numerous metastatic nodules in the liver and showed invasive growth behavior. On the other hand, when mice were given the NK4 plasmid, hepatic gene expression of NK4 inhibited the liver metastasis and subsequent growth associated with a decrease in microvessel density. Likewise, intrahepatic invasion of cancer cells was inhibited by NK4 gene expression, and this anti-invasive effect was associated with in situ inhibition of c-Met receptor tyrosine phosphorylation. Moreover, NK4 gene expression prolonged survival of these mice. Taken together with the knowledge that the majority of deaths from colon cancer are due to liver metastasis, the potential therapeutic use of hepatic gene expression of NK4 for metastatic colon cancer treatment can be given consideration.