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首页> 外文期刊>Biochimica et biophysica acta. Reviews on cancer >Role of fibrillin-2 in the control of TGF-beta activation in tumor angiogenesis and connective tissue disorders
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Role of fibrillin-2 in the control of TGF-beta activation in tumor angiogenesis and connective tissue disorders

机译:Fibrillin-2在肿瘤血管生成和结缔组织疾病中对TGF-β激活的控制的作用

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Fibrillins constitute a family of large extracellular glycoproteins which multimerize to form microfibrils, an important structure in the extracellular matrix. It has long been assumed that fibrillin-2 was barely present during postnatal life, but it is now clear that fibrillin-2 molecules form the structural core of microfibrils, and are masked by an outer layer of fibrillin-1. Mutations in fibrillins give rise to heritable connective tissue disorders, including Marfan syndrome and congenital contractural arachnodactyly. Fibrillins also play an important role in matrix sequestering of members of the transforming growth factor-beta family, and in context of Marfan syndrome excessive TGF-beta activation has been observed. TGF-beta activation is highly dependent on integrin binding, including integrin alpha v beta 8 and alpha v beta 6, which are upregulated upon TGF-beta exposure. TGF-beta is also involved in tumor progression, metastasis, epithelial-to-mesenchymal transition and tumor angiogenesis. In several highly vascularized types of cancer such as hepatocellular carcinoma, a positive correlation was found between increased TGF-beta plasma concentrations and tumor vascularity. Interestingly, fibrillin-1 has a higher affinity to TGF-beta and, therefore, has a higher capacity to sequester TGF-beta compared to fibrillin-2. The previously reported downregulation of fibrillin-1 in tumor endothelium affects the fibrillin-1/fibrillin-2 ratio in the microfibrils, exposing the normally hidden fibrillin-2. We postulate that fibrillin-2 exposure in the tumor endothelium directly stimulates tumor angiogenesis by influencing TGF-beta sequestering by microfibrils, leading to a locally higher active TGF-beta concentration in the tumor microenvironment. From a therapeutic perspective, fibrillin-2 might serve as a potential target for future anti-cancer therapies.
机译:Fiblillins构成了一种大型细胞外糖蛋白的家族,其多化以形成微纤维,是细胞外基质中的重要结构。已经假定了纤维蛋白-2在后期生命中几乎没有存在,但现在清楚地清楚的是,Fiblillin-2分子形成微纤维的结构核,并被纤维蛋白-1的外层掩盖。 Fiblillins中的突变产生遗传性结缔组织疾病,包括Marfan综合征和先天性收缩术。 Fiblillins还在转化生长因子-β0系列成员的基质螯合中发挥着重要作用,并且在Marfan综合征的背景下已经观察到过量的TGF-β激活。 TGF-β激活高度依赖于整联蛋白结合,包括整合蛋白αVβ8和αVβ6,其在TGF-β暴露时上调。 TGF-β还参与肿瘤进展,转移,上皮对间充质转换和肿瘤血管生成。在几种高度血管化类型的癌症如肝细胞癌中,在增加的TGF-β血浆浓度和肿瘤血管之间发现阳性相关性。有趣的是,Fibrillin-1对TGF-β具有更高的亲和力,因此与Fibrillin-2相比具有更高的诱导TGF-β的能力。先前报道的肿瘤内皮中Fibrillin-1的下调影响微纤维中的原纤蛋白-1 /纤维蛋白-2比,暴露通常隐藏的纤维蛋白-2。我们假设肿瘤内皮中的纤维蛋白-2暴露在肿瘤内皮中直接刺激肿瘤血管生成,通过影响微纤维螯合螯合,导致肿瘤微环境中的局部活性TGF-β浓度。从治疗角度来看,Fiblillin-2可以作为未来抗癌疗法的潜在目标。

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