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-β family, and in context of Marfan syndrome excessive TGF-β activation has been observed. TGF-β activation is highly dependent on integrin binding, including integrin αvβ8 and αvβ6, which are upregulated upon TGF-β exposure. TGF-β 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-β plasma concentrations and tumor vascularity. Interestingly, fibrillin-1 has a higher affinity to TGF-β and, therefore, has a higher capacity to sequester TGF-β 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-β sequestering by microfibrils, leading to a locally higher active TGF-β concentration in the tumor microenvironment. From a therapeutic perspective, fibrillin-2 might serve as a potential target for future anti-cancer therapies.

中文翻译：

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原纤维蛋白2在肿瘤血管生成和结缔组织疾病中控制TGF-β活化的作用。

原纤维蛋白构成大的细胞外糖蛋白家族，其多聚形成微纤维，这是细胞外基质中的重要结构。长期以来，人们一直认为在出生后几乎不存在原纤维蛋白-2，但是现在很清楚，原纤维蛋白-2分子形成了微纤维的结构核心，并被原纤维蛋白-1的外层所掩盖。原纤维蛋白的突变会引起可遗传的结缔组织疾病，包括马凡氏综合征和先天性挛缩蛛网膜畸形。原纤维蛋白在转化生长因子-β家族成员的基质螯合中也起重要作用，在马凡氏综合征的背景下，已观察到过度的TGF-β活化。TGF-β的激活高度依赖于整联蛋白的结合，包括整联蛋白αvβ8和αvβ6，它们在TGF-β暴露后会上调。TGF-β也参与肿瘤的进展，转移，上皮到间充质转化和肿瘤血管生成。在几种高度血管化类型的癌症（例如肝细胞癌）中，发现TGF-β血浆浓度升高与肿瘤血管形成呈正相关。有趣的是，与原纤维蛋白-2相比，原纤维蛋白-1对TGF-β具有更高的亲和力，因此具有更高的螯合TGF-β的能力。先前报道的肿瘤内皮中原纤维蛋白-1的下调会影响微纤维中原纤维蛋白-1 /原纤维蛋白-2的比例，从而暴露出通常隐藏的原纤维蛋白-2。我们推测，通过影响微纤维的TGF-β螯合，在肿瘤内皮中暴露的原纤维蛋白2会直接刺激肿瘤血管生成，导致肿瘤微环境中局部较高的活性TGF-β浓度。从治疗的角度来看，原纤维蛋白2可能作为未来抗癌治疗的潜在靶标。