Max Planck Institute of Biochemistry, Martinsried, Germany.
Neoplasia. 2013 Aug;15(8):925-38. doi: 10.1593/neo.13762.
Fibronectin is ubiquitously expressed in the extracellular matrix, and experimental evidence has shown that it modulates blood vessel formation. The relative contribution of local and circulating fibronectin to blood vessel formation in vivo remains unknown despite evidence for unexpected roles of circulating fibronectin in various diseases. Using transgenic mouse models, we established that circulating fibronectin facilitates the growth of bone metastases by enhancing blood vessel formation and maturation. This effect is more relevant than that of fibronectin produced by endothelial cells and pericytes, which only exert a small additive effect on vessel maturation. Circulating fibronectin enhances its local production in tumors through a positive feedback loop and increases the amount of vascular endothelial growth factor (VEGF) retained in the matrix. Both fibronectin and VEGF then cooperate to stimulate blood vessel formation. Fibronectin content in the tumor correlates with the number of blood vessels and tumor growth in the mouse models. Consistent with these results, examination of three separate arrays from patients with breast and prostate cancers revealed that a high staining intensity for fibronectin in tumors is associated with increased mortality. These results establish that circulating fibronectin modulates blood vessel formation and tumor growth by modifying the amount of and the response to VEGF. Furthermore, determination of the fibronectin content can serve as a prognostic biomarker for breast and prostate cancers and possibly other cancers.
纤连蛋白广泛表达于细胞外基质中，有实验证据表明它可调节血管生成。尽管有证据表明循环纤连蛋白在各种疾病中具有意想不到的作用，但局部和循环纤连蛋白对体内血管生成的相对贡献仍不清楚。通过使用转基因小鼠模型，我们发现循环纤连蛋白通过促进血管生成和成熟而促进骨转移的生长。这种作用比内皮细胞和周细胞产生的纤连蛋白的作用更为重要，因为后者对血管成熟只有很小的附加作用。循环纤连蛋白通过正反馈回路增强其在肿瘤中的局部产生，并增加基质中保留的血管内皮生长因子（VEGF）的量。纤连蛋白和 VEGF 随后共同刺激血管生成。肿瘤中的纤连蛋白含量与小鼠模型中的血管数量和肿瘤生长相关。这些结果与以下结果一致：对来自乳腺癌和前列腺癌患者的三个独立阵列的检查表明，肿瘤中纤连蛋白染色强度高与死亡率增加相关。这些结果表明，循环纤连蛋白通过改变 VEGF 的量和反应来调节血管生成和肿瘤生长。此外，纤连蛋白含量的测定可以作为乳腺癌和前列腺癌以及可能其他癌症的预后生物标志物。
