Comparative Analysis of Metastasis Variants Derived from Human Prostate Carcinoma Cells Roles in Intravasation of VEGF-Mediated Angiogenesis and uPA-Mediated Invasion
Comparative Analysis of Metastasis Variants Derived from Human Prostate Carcinoma Cells Roles in Intravasation of VEGF-Mediated Angiogenesis and uPA-Mediated Invasion
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DOI：
10.2353/ajpath.2009.090384
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发表时间：
2009-10-01
影响因子：
6
通讯作者：
Quigley, James P.
中科院分区：
文献类型：
--
作者：
Conn, Erin M.;Botkjaer, Kenneth A.;Quigley, James P.
为了分析肿瘤细胞内渗的过程，我们使用人肿瘤-鸡胚自发转移模型从人PC-3前列腺癌细胞细颗粒中筛选体内高（PC-hi/diss）和低（PC-lo/diss）播散变体。这些变异体在鸡胚和小鼠自发转移模型中的浸润和播散能力显著不同。伴随着增强的内渗，PC-hi/diss在禽类和小鼠模型中表现出增加的血管生成潜力。PC-hi/diss血管生成和血管内渗依赖于血管内皮生长因子（VEGF）分泌的增加，因为用功能阻断性抗VEGF抗体治疗发展中的肿瘤同时抑制了这两个过程，而不影响原发性肿瘤生长。PC-hi/diss细胞也更具迁移性和侵袭性，提示由于基质降解活性，逃避原发性肿瘤的能力增强。与这一建议相一致，PC-hi/diss细胞产生更多的丝氨酸蛋白酶尿激酶型纤溶酶原激活剂（uPA）相比，PC-lo/diss. uPA在PC-hi/diss传播的功能作用，证实了抑制侵袭，血管生成，并与特定的功能阻断抗体，防止uPA激活和阻断uPA活性的内渗。这些过程对抑肽酶（一种丝氨酸蛋白酶（包括uPA产生的纤溶酶）的强效抑制剂）同样敏感。因此，我们对PC-3内渗变体的比较指出uPA-纤溶酶系统在PC-hi/diss内渗中的关键作用，可能是通过（1）促进肿瘤细胞基质侵袭和（2）促进VEGF依赖性血管生成血管的发育。(Am J Pathol 2009，175：1638-1652; DOI：10.2353/ajpath.2009.090384）
To analyze the process of tumor cell intravasation, we used the human tumor-chick embryo spontaneous metastasis model to select in vivo high (PC-hi/diss) and low (PC-lo/diss) disseminating variants from the human PC-3 prostate carcinoma cell fine. These variants dramatically differed in their intravasation and dissemination capacities in both chick embryo and mouse spontaneous metastasis models. Concomitant with enhanced intravasation, PC-hi/diss exhibited increased angiogenic potential in avian and murine models. PC-hi/diss angiogenesis and intravasation were dependent on increased secretion of vascular endothelial growth factor (VEGF), since treating developing tumors with a function-blocking anti-VEGF antibody simultaneously inhibited both processes without affecting primary tumor growth. PC-hi/diss cells were also more migratory and invasive, suggestive of heightened ability to escape from primary tumors due to matrix-degrading activity. Consistent with this suggestion, PC-hi/diss cells produced more of the serine protease urokinase-type plasminogen activator (uPA) as compared with PC-lo/diss. The functional role of uPA in PC-hi/diss dissemination was confirmed by inhibition of invasion, angiogenesis, and intravasation with specific function-blocking antibodies that prevented uPA activation and blocked uPA activity. These processes were similarly sensitive to aprotinin, a potent inhibitor of serine proteases, including uPA-generated plasmin. Thus, our comparison of the PC-3 intravasation variants points to key roles for the uPA-plasmin system in PC-hi/diss intravasation, possibly via (1) promoting tumor cell matrix invasion and (2) facilitating development of VEGF-dependent angiogenic blood vessels. (Am J Pathol 2009, 175:1638-1652; DOI: 10.2353/ajpath.2009.090384)