The Urokinase Receptor Promotes Cancer Metastasis Independently of Urokinase-Type Plasminogen Activator in Mice
The Urokinase Receptor Promotes Cancer Metastasis Independently of Urokinase-Type Plasminogen Activator in Mice
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DOI：
10.2353/ajpath.2009.081053
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发表时间：
2009-07-01
影响因子：
6
通讯作者：
Gonias, Steven L.
中科院分区：
文献类型：
--
作者：
Jo, Minji;Takimoto, Shinako;Gonias, Steven L.
尿激酶受体（uPAR）促进人类恶性肿瘤的转移，然而，其作用机制仍不完全清楚。已建立的模型集中于uPAR结合尿激酶型纤溶酶原激活剂（uPA）并促进肿瘤细胞微环境中的蛋白酶活化的能力;然而，uPAR还通过uPA依赖性和非依赖性机制在体外调节细胞信号传导和迁移。uPAR作为细胞信号受体在体内的意义尚不清楚。在这项研究中，我们在人胚肾（HEK-293）细胞中表达了人或小鼠uPAR。我们选择HEK-293细胞，因为与大多数癌细胞不同，它们不内源性表达uPA或uPAR。小鼠和人uPAR均增加细胞在玻连蛋白上的粘附和迁移。Rac 1被激活并负责细胞迁移的增加。不表达uPAR的HEK-293细胞在严重的联合免疫缺陷小鼠中形成明显的肿瘤;然而，转移是非常罕见的。异种移植物含有丰富的小鼠uPA，通过浸润小鼠细胞产生，但没有人uPA。小鼠uPA仅与小鼠uPAR结合，而不与人uPAR结合，因此不能与异种移植物中表达人uPAR的HEK-293细胞相互作用。然而，小鼠和人uPAR均显著增加HEK-293细胞转移到肺中。人uPAR的活性表明uPAR可能独立于uPA促进癌症转移。候选机制包括其对粘附、迁移和Rac 1激活的影响。(Am J Pathol 2009，175：190-200; DOI：10.2353/ajpath.2009.081053）
The urokinase receptor (uPAR) promotes metastasis of human malignancies; however, its mechanism of action remains incompletely understood. Established models focus on the ability of uPAR to bind urokinase-type plasminogen activator (uPA) and promote protease activation in the tumor cell microenvironment; however, uPAR also regulates cell signaling and migration by both uPA-dependent and -independent mechanisms in vitro. The significance of uPAR as a cell-signaling receptor in vivo remains unclear. in this study, we expressed either human or mouse uPAR in human embryonic kidney (HEK-293) cells. We selected HEK-293 cells because, unlike most cancer cells, they do not express uPA or uPAR endogenously. Both mouse and human uPAR increased cell adhesion and migration on vitronectin. Rac1 was activated and responsible for the increase in cell migration. HEK-293 cells that did not express uPAR formed palpable tumors in severe combined immunodeficient mice; however, metastases were exceedingly rare. The xenografts contained abundant mouse uPA, produced by infiltrating mouse cells, but no human uPA. Mouse uPA bound only to mouse uPAR and not human uPAR and, thus, could not interact with human uPAR-expressing HEK-293 cells in xenografts. Nevertheless, both mouse and human uPAR significantly increased HEK-293 cell metastasis into the lungs. The activity of human uPAR suggests that uPAR may promote cancer metastasis independent of uPA. Candidate mechanisms include its effects on adhesion, migration, and Rac1 activation. (Am J Pathol 2009, 175:190-200; DOI: 10.2353/ajpath.2009.081053)