Milsom Chloe C, Yu Joanne L, Mackman Nigel, Micallef Johann, Anderson G Mark, Guha Abhijit, Rak Janusz W
Henderson Research Centre, McMaster University, Hamilton, Ontario, Canada.
Cancer Res. 2008 Dec 15;68(24):10068-76. doi: 10.1158/0008-5472.CAN-08-2067.
ErbB oncogenes drive the progression of several human cancers. Our study shows that in human carcinoma (A431) and glioma (U373) cells, the oncogenic forms of epidermal growth factor receptor (EGFR; including EGFRvIII) trigger the up-regulation of tissue factor (TF), the transmembrane protein responsible for initiating blood coagulation and signaling through interaction with coagulation factor VIIa. We show that A431 cancer cells in culture exhibit a uniform TF expression profile; however, these same cells in vivo exhibit a heterogeneous TF expression and show signs of E-cadherin inactivation, which is coupled with multilineage (epithelial and mesenchymal) differentiation. Blockade of E-cadherin in vitro, leads to the acquisition of spindle morphology and de novo expression of vimentin, features consistent with epithelial-to-mesenchymal transition. These changes were associated with an increase in EGFR-dependent TF expression, and with enhanced stimulation of vascular endothelial growth factor production, particularly following cancer cell treatment with coagulation factor VIIa. In vivo, cells undergoing epithelial-to-mesenchymal transition exhibited an increased metastatic potential. Furthermore, injections of the TF-blocking antibody (CNTO 859) delayed the initiation of A431 tumors in immunodeficient mice, and reduced tumor growth, vascularization, and vascular endothelial growth factor expression. Collectively, our data suggest that TF is regulated by both oncogenic and differentiation pathways, and that it functions in tumor initiation, tumor growth, angiogenesis, and metastasis. Thus, TF could serve as a therapeutic target in EGFR-dependent malignancies.
ErbB癌基因推动多种人类癌症的进展。我们的研究表明，在人类癌细胞系（A431）和神经胶质瘤细胞系（U373）中，表皮生长因子受体（EGFR）的致癌形式（包括EGFRvIII）会引发组织因子（TF）的上调，TF是一种跨膜蛋白，负责启动血液凝固并通过与凝血因子VIIa相互作用进行信号传导。我们发现，培养的A431癌细胞呈现出一致的TF表达谱；然而，这些相同的细胞在体内表现出异质性的TF表达，并显示出E-钙黏蛋白失活的迹象，这与多谱系（上皮和间充质）分化相关。体外阻断E-钙黏蛋白会导致细胞获得纺锤体形态并从头表达波形蛋白，这些特征与上皮-间充质转化一致。这些变化与EGFR依赖性TF表达的增加以及血管内皮生长因子产生的增强刺激有关，尤其是在癌细胞用凝血因子VIIa处理后。在体内，经历上皮-间充质转化的细胞表现出更高的转移潜能。此外，注射TF阻断抗体（CNTO 859）可延迟免疫缺陷小鼠中A431肿瘤的起始，并减少肿瘤生长、血管生成和血管内皮生长因子的表达。总体而言，我们的数据表明TF受致癌途径和分化途径的调控，并且在肿瘤起始、肿瘤生长、血管生成和转移中发挥作用。因此，TF可作为EGFR依赖性恶性肿瘤的治疗靶点。
