HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer.
HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer.
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DOI：
10.1158/1078-0432.ccr-08-3252
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发表时间：
2009-06-01
期刊：
影响因子：
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通讯作者：
Siegfried JM
中科院分区：
文献类型：
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作者：
Knowles LM;Stabile LP;Egloff AM;Rothstein ME;Thomas SM;Gubish CT;Lerner EC;Seethala RR;Suzuki S;Quesnelle KM;Morgan S;Ferris RL;Grandis JR;Siegfried JM
我们检测了肝细胞生长因子(HGF)和c-Met在人头颈部鳞状细胞癌(HNSCC)细胞和原代组织中的表达和信号转导，并检测了c-Met酪氨酸激酶抑制剂(TKI)对HGF诱导的生物信号转导的阻断能力。用免疫印迹、酶联免疫吸附试验和免疫组织化学方法检测细胞的表达和信号转导。生物终点包括伤口愈合、细胞增殖和侵袭。在体外和在裸鼠体内建立的异种移植瘤中，测试了c-Met TKI阻断HGF诱导的信号和生物学效应的能力。C-Met在HNSCC细胞中表达并具有一定的功能。HGF由HNSCC肿瘤成纤维细胞分泌，但不由HNSCC细胞分泌。C-Met的激活促进了AKT和丝裂原活化蛋白激酶的磷酸化，以及炎性细胞因子IL-8的释放。HGF还能促进细胞生长和创面愈合。C-Met TKIs阻断HGF诱导的信号转导、白介素8的释放和伤口愈合。HGF中和抗体可完全阻断肿瘤来源的成纤维细胞对HNSCC细胞侵袭能力的增强。PF-2341066是一种c-Met TKI，在体内对HNSCC肿瘤的生长有50%的抑制作用，肿瘤内细胞增殖减少，细胞凋亡增加。HNSCC组织中HGF和c-Met蛋白的表达均高于正常粘膜。这些结果表明，HGF在HNSCC细胞中主要作为旁分泌因子，HGF/c-Met途径在HNSCC中经常上调并发挥作用，临床上相关的c-Met TKI在体内显示出抗肿瘤活性。阻断HGF/c-Met通路可能对HNSCC的治疗有临床意义。
We determined hepatocyte growth factor (HGF) and c-Met expression and signaling in human head and neck squamous cell carcinoma (HNSCC) cells and primary tissues and tested the ability of c-Met tyrosine kinase inhibitors (TKI) to block HGF-induced biological signaling. Expression and signaling were determined using immunoblotting, ELISA, and immunohistochemistry. Biological end points included wound healing, cell proliferation, and invasion. c-Met TKIs were tested for their ability to block HGF-induced signaling and biological effects in vitro and in xenografts established in nude mice. c-Met was expressed and functional in HNSCC cells. HGF was secreted by HNSCC tumor-derived fibroblasts, but not by HNSCC cells. Activation of c-Met promoted phosphorylation of AKT and mitogen-activated protein kinase as well as release of the inflammatory cytokine interleukin-8. Cell growth and wound healing were also stimulated by HGF. c-Met TKIs blocked HGF-induced signaling, interleukin-8 release, and wound healing. Enhanced invasion of HNSCC cells induced by the presence of tumor-derived fibroblasts was completely blocked with a HGF-neutralizing antibody. PF-2341066, a c-Met TKI, caused a 50% inhibition of HNSCC tumor growth in vivo with decreased proliferation and increased apoptosis within the tumors. In HNSCC tumor tissues, both HGF and c-Met protein were increased compared with expression in normal mucosa. These results show that HGF acts mainly as a paracrine factor in HNSCC cells, the HGF/c-Met pathway is frequently up-regulated and functional in HNSCC, and a clinically relevant c-Met TKI shows antitumor activity in vivo. Blocking the HGF/c-Met pathway may be clinically useful for the treatment of HNSCC.