Amarzguioui Mohammed, Peng Qian, Wiiger Merete T, Vasovic Vlada, Babaie Eshrat, Holen Torgeir, Nesland Jahn M, Prydz Hans
The Biotechnology Centre of Oslo, Norway.
Clin Cancer Res. 2006 Jul 1;12(13):4055-61. doi: 10.1158/1078-0432.CCR-05-2482.
The coagulation trigger tissue factor has been implicated in tumor growth, angiogenesis, and metastasis. In this study, we explore the effects of ex vivo and in vivo delivery of short interfering RNA (siRNA) targeting tissue factor on B16 melanoma colonization of the lung in a murine model for metastasis. The purposes of this work are to establish a noncytotoxic in vivo model for investigation of tissue factor function and provide preclinical assessment of the therapeutic potential of tissue factor siRNA for prevention of metastasis.
C57BL/6 mice were evaluated for pulmonary metastases following tail vein injection of B16 cells transfected with either active or inactive siRNA. Mice receiving cells transfected with active siRNA had significantly lower numbers of pulmonary tumors compared with mice injected with control cells (transfected with inactive siRNA). The average time point at which the mice started to exhibit tumor-associated stress was also increased significantly from 22 days for the control group to 27 days for the experimental group (P = 0.01). In a therapeutically more relevant model, where the siRNA was delivered i.p. and the cells (untransfected) by tail vein injection, an inhibitory effect on metastasis was observed when the siRNA treatment was initiated either before or at the time of cell injection.
The results suggest that tissue factor has a crucial function in promoting lung tumor metastasis of blood-borne tumor cells in the early stages of the tumor take process and further suggest that treatment with tissue factor siRNA may become a viable clinical strategy for prevention of tumor metastasis.
凝血触发因子组织因子与肿瘤生长、血管生成和转移有关。在本研究中，我们在小鼠转移模型中探究了靶向组织因子的短发夹RNA（shRNA）离体和体内递送对B16黑色素瘤肺定植的影响。本研究的目的是建立一种用于研究组织因子功能的无细胞毒性体内模型，并对组织因子shRNA预防转移的治疗潜力进行临床前评估。
对经活性或非活性shRNA转染的B16细胞尾静脉注射后的C57BL/6小鼠进行肺转移评估。与注射对照细胞（经非活性shRNA转染）的小鼠相比，接受活性shRNA转染细胞的小鼠肺肿瘤数量显著减少。小鼠开始出现肿瘤相关应激的平均时间点也从对照组的22天显著增加到实验组的27天（P = 0.01）。在一个更具治疗相关性的模型中，通过腹腔注射递送shRNA并通过尾静脉注射细胞（未转染），当在细胞注射前或注射时开始进行shRNA治疗时，观察到对转移有抑制作用。
结果表明组织因子在肿瘤植入过程早期促进血行肿瘤细胞的肺肿瘤转移中起关键作用，并进一步表明用组织因子shRNA治疗可能成为预防肿瘤转移的可行临床策略。
