TISSUE FACTOR PROMOTES MELANOMA METASTASIS BY A PATHWAY INDEPENDENT OF BLOOD-COAGULATION
TISSUE FACTOR PROMOTES MELANOMA METASTASIS BY A PATHWAY INDEPENDENT OF BLOOD-COAGULATION
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DOI：
10.1073/pnas.92.18.8205
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发表时间：
1995-08-29
影响因子：
11.1
通讯作者：
GAREN, A
中科院分区：
文献类型：
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作者：
BROMBERG, ME;KONIGSBERG, WH;GAREN, A
几项研究已经建立了血液凝固和慢跑之间的联系，更具体地说，组织因子（TF）（一种参与启动血液凝固的跨膜蛋白）和肿瘤转移之间存在联系。在此报告的研究中，使用人类黑色素瘤转移的小鼠模型进行了两项实验，（i）第一个实验旨在测试人类黑色素瘤细胞中不同的 TF 表达水平对其转移潜力的影响。通过逆转录病毒介导的转染 非转移亲代系，通过将肿瘤细胞注射到严重联合免疫缺陷（SCID）小鼠的尾静脉中，然后检查肺部和其他组织的肿瘤发展情况，比较两组转染系的转移潜力。在注射高 TF 细胞系的小鼠中有 86% 检测到转移性肿瘤，在注射低 TF 细胞系的小鼠中有 5% 检测到转移性肿瘤，这表明高 TF 水平促进 SCID 小鼠模型中人类黑色素瘤的转移。这种 TF 对转移的作用发生在静脉注射的黑色素瘤细胞中，但不会发生在皮下注射的黑色素瘤细胞形成的原发性肿瘤中，这表明 TF 在转移的晚期阶段起作用，即肿瘤细胞从原发部位逃逸并进入血液后，（ii）第二个实验旨在分析TF促进黑色素瘤转移的机制。该程序涉及测试跨膜 TF 分子的细胞外或细胞质结构域中的突变对转移的影响。细胞外突变引入了两个氨基酸取代，抑制了 TF 启动凝血级联；细胞质突变删除了大部分细胞质结构域，但不损害TF的凝血功能。通过逆转录病毒介导将相应的TF cDNA转染到非转移性亲代黑色素瘤细胞系中，产生了表达高水平的两种突变TF分子中的任何一种的几种人类黑色素瘤细胞系，并在SCID小鼠模型中测试了每个转染细胞系的转移潜力， 大多数注射表达细胞外 TF 突变体的黑色素瘤系的小鼠中发生转移，但在大多数注射表达细胞质 TF 突变体的黑色素瘤系的小鼠中未检测到转移。细胞外 TF 突变体的结果表明 TF 在 SCID 小鼠模型中的转移作用不涉及凝血级联产物。细胞质 TF 突变体的结果表明 TF 的细胞质结构域对于转移效应很重要，表明 TF 可以转导促进转移的黑色素瘤细胞信号。
Several studies have established a link between blood coagulation and canter, and more specifically between tissue factor (TF), a transmembrane protein involved in initiating blood coagulation, and tumor metastasis. In the study reported here, a murine model of human melanoma metastasis was used for two experiments, (i) The first experiment was designed to test the effect of varying the level of TF expression in human melanoma cells on their metastatic potential, Two matched sets of cloned human melanoma lines, one expressing a high level and the other a low level of the normal human TF molecule, were generated by retroviral-mediated transfections of a nonmetastatic parental line, The metastatic potential of the two sets of transfected lines was compared by injecting the tumor cells into the tail vein of severe combined immunodeficiency (SCID) mice and later examining the lungs and other tissues for tumor development. Metastatic tumors were detected in 86% of the mice injected with the high-TF lines and in 5% of the mice injected with the low-TF lines, indicating that a high TF level promotes metastasis of human melanoma in the SCID mouse model, This TF effect on metastasis occurs with i.v.-injected melanoma cells but does not occur with primary tumors formed from s.c.-injected melanoma cells, suggesting that TF acts at a late stage of metastasis, after tumor cells have escaped from the primary site and entered the blood, (ii) The second experiment was designed to analyze the mechanism by which TF promotes melanoma metastasis. The procedure involved testing the effect on metastasis of mutations in either the extracellular or cytoplasmic domains of the transmembrane TF molecule, The extracellular mutations introduced two amino acid substitutions that inhibited initiation by TF of the blood-coagulation cascade; the cytoplasmic mutation deleted most of the cytoplasmic domain without impairing the coagulation function of TF, Several human melanoma lines expressing high levels of either of the two mutant TF molecules were generated by retroviral-mediated transfection of the corresponding TF cDNA into the nonmetastatic parental melanoma line, and the metastatic potential of each transfected line was tested in the SCID mouse model, Metastases occurred in most mice injected with the melanoma lines expressing the extracellular TF mutant but were not detected in most mice injected with the melanoma lines expressing the cytoplasmic TF mutant, Results with the extracellular TF mutant indicate that the metastatic effect of TF in the SCID mouse model does not involve products of the coagulation cascade. Results with the cytoplasmic TF mutant indicate that the cytoplasmic domain of TF is important for the metastatic effect, suggesting that the TF could transduce a melanoma cell signal that promotes metastasis.