Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination.
Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination.
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DOI：
10.1084/jem.20120662
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发表时间：
2013-03-11
期刊：
影响因子：
--
通讯作者：
Pietras K
中科院分区：
文献类型：
--
作者：
Anderberg C;Cunha SI;Zhai Z;Cortez E;Pardali E;Johnson JR;Franco M;Páez-Ribes M;Cordiner R;Fuxe J;Johansson BR;Goumans MJ;Casanovas O;ten Dijke P;Arthur HM;Pietras K
内皮糖蛋白的遗传缺陷通过削弱内皮细胞屏障而导致转移能力增加。治疗诱导的耐药性仍然是癌症患者实现持久反应和治愈的重大障碍。我们研究了基因受损的血管生成的长期后果，通过工程多个肿瘤模型剥夺内皮糖蛋白，一个共同受体的TGF-β在内皮细胞积极参与血管生成。来自内皮糖蛋白缺陷小鼠的肿瘤适应于减弱的血管生成反应，并且对内皮糖蛋白信号传导减弱的不应性伴随着转移能力的增加。在多种小鼠癌症模型中的机制研究表明，内皮糖蛋白的缺乏导致肿瘤血管系统显示出内皮向间充质转化的标志，这是癌症生物学中以前未知的重要性的过程，但我们显示与血管系统避免肿瘤细胞内和外渗的能力降低有关。然而，剥夺内皮糖蛋白的肿瘤表现出对抗VEGF（血管内皮生长因子）剂的抗性的延迟发生，说明了组合靶向多种血管生成途径用于治疗癌症的治疗效用。
Genetic deficiency for endoglin leads to increased metastatic capability by weakening the endothelial cell barrier. Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.
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DOI：
10.1084/jem.20091846
发表时间：
2010-03-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Helfrich I;Scheffrahn I;Bartling S;Weis J;von Felbert V;Middleton M;Kato M;Ergün S;Augustin HG;Schadendorf D
通讯作者：
Schadendorf D
影响因子：
--
作者：
Duwel, Annette;Eleno, Nelida;Lopez-Novoa, Jose M.
通讯作者：
Lopez-Novoa, Jose M.
影响因子：
20.3
作者：
Franco, Marcela;Roswall, Pernilla;Pietras, Kristian
通讯作者：
Pietras, Kristian
影响因子：
2.7
作者：
Arthur, HM;Ure, J;Diamond, AG
通讯作者：
Diamond, AG
影响因子：
20.1
作者：
Egorova AD;Khedoe PP;Goumans MJ;Yoder BK;Nauli SM;ten Dijke P;Poelmann RE;Hierck BP
通讯作者：
Hierck BP