The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies.
The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies.
复制标题
DOI：
10.1083/jcb.152.4.777
复制
发表时间：
2001-02-19
期刊：
影响因子：
--
通讯作者：
Noël A
中科院分区：
文献类型：
--
作者：
Bajou K;Masson V;Gerard RD;Schmitt PM;Albert V;Praus M;Lund LR;Frandsen TL;Brunner N;Dano K;Fusenig NE;Weidle U;Carmeliet G;Loskutoff D;Collen D;Carmeliet P;Foidart JM;Noël A
纤溶酶原(PLG)/纤溶酶原激活物(PA)系统可能通过调节细胞外基质降解和肿瘤细胞迁移在肿瘤进展中起关键作用。因此，目前正在开发尿激酶型纤溶酶原激活剂(UPA)/纤溶酶拮抗剂来抑制肿瘤生长和血管生成。然而，矛盾的是，高水平的PA抑制物-1(PAI-1)预示着癌症患者预后不良。我们先前已经证明PAI-1促进肿瘤血管生成，但其机制尚未解决。我们预计PAI-1通过其与VN和整合素的相互作用促进内皮细胞迁移。然而，利用PAI-1突变体的腺病毒基因转移，我们观察到PAI-1促进肿瘤血管生成，不是通过与VN相互作用，而是通过抑制蛋白分解活性，这表明过度的纤溶酶蛋白分解阻止了肿瘤血管的组装。UPA、组织型纤溶酶原激活剂(TPA)、uPA受体或VN的单独缺乏以及uPA和tPA的联合缺乏不会损害肿瘤的血管生成，而PLG的缺乏则会减少肿瘤的血管生成。总体而言，这些数据表明，尽管纤溶酶蛋白分解是必要的，但在肿瘤血管生成过程中必须严格控制，可能是为了使血管稳定和成熟。这些数据提供了对PAI-1促进肿瘤进展的临床悖论的洞察力，并证明了不受控制地使用uPA/纤溶酶拮抗剂作为肿瘤血管生成抑制剂。
The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase-type PA (uPA)/plasmin antagonists are currently being developed for suppression of tumor growth and angiogenesis. Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but by an unresolved mechanism. We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rather by inhibiting proteolytic activity, suggesting that excessive plasmin proteolysis prevents assembly of tumor vessels. Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it. Overall, these data indicate that plasmin proteolysis, even though essential, must be tightly controlled during tumor angiogenesis, probably to allow vessel stabilization and maturation. These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors.
登录
查看更多内容
蛋白水解活性的增加是表达中间 t-癌基因的内皮细胞形态发生行为异常的原因
影响因子：
64.5
作者：
MONTESANO, R;PEPPER, MS;ORCI, L
通讯作者：
ORCI, L
影响因子：
7.5
作者：
Chapman, HA
通讯作者：
Chapman, HA
影响因子：
8
作者：
Bugge, TH;Lund, LR;Degen, JL
通讯作者：
Degen, JL
影响因子：
15.9
作者：
CARMELIET, P;STASSEN, JM;COLLEN, D
通讯作者：
COLLEN, D
影响因子：
10.5
作者：
BUGGE, TH;FLICK, MJ;DEGEN, JL
通讯作者：
DEGEN, JL