Cancer Therapy and Research Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
Mol Carcinog. 2019 Dec;58(12):2316-2326. doi: 10.1002/mc.23120. Epub 2019 Sep 25.
Primary tumor can induce the formation of premetastatic niche. The hyperpermeability of the vessels in the premetastatic niche is the first step in the development of metastasis. However, the cellular and molecular mechanisms of vascular hyperpermeability remain to be elucidated. In this study, 4T1 breast cells were injected into the breasts of mice to establish a tumor model. Our results showed that primary tumors induced hyperpermeability of the vessels in the premetastatic lung. Subsequent studies showed that the level of vascular endothelial growth factor (VEGF) was elevated in the tumor-bearing mice serum and the levels of tight junction (TJ) proteins occludin and ZO-1 were decreased in the premetastatic lung. In vitro studies demonstrated that VEGF increased the permeability of dextran and decreased the levels of occludin and ZO-1 in human umbilical vein endothelial cells. Moreover, the hyperpermeability of vessels and the degradation of occludin was blocked by bevacizumab. Overexpression of occludin alleviated the VEGF-induced hyperpermeability. Further investigations revealed that VEGF-induced occludin phosphorylation at Ser-490 and ubiquitination. Finally, we showed that VEGF accelerated the process of occludin degradation through the ubiquitin-proteasome system. In conclusion, primary tumor-secrete VEGF induce the occludin phosphorylation/ubiquitination and downregulation, resulting in the disruption of TJs and hyperpermeability of vessels in premetastatic lung. The occludin phosphorylation/ubiquitination pathway may be the mechanism of VEGF-induced vascular hyperpermeability in the lung premetastatic niche.
原发肿瘤可诱导前转移龛的形成。前转移龛血管的高通透性是转移发展的第一步。然而，血管通透性增加的细胞和分子机制仍有待阐明。在这项研究中，将 4T1 乳腺细胞注射到小鼠的乳腺中建立肿瘤模型。我们的结果表明，原发肿瘤诱导了前转移肺血管的高通透性。随后的研究表明，荷瘤小鼠血清中血管内皮生长因子（VEGF）水平升高，前转移肺中的紧密连接（TJ）蛋白occludin 和 ZO-1 水平降低。体外研究表明，VEGF 增加了葡聚糖的通透性，并降低了人脐静脉内皮细胞中 occludin 和 ZO-1 的水平。此外，bevacizumab 阻断了血管的高通透性和 occludin 的降解。occludin 的过表达减轻了 VEGF 诱导的高通透性。进一步的研究表明，VEGF 诱导 occludin 在 Ser-490 位点磷酸化和泛素化。最后，我们表明 VEGF 通过泛素-蛋白酶体系统加速了 occludin 的降解过程。总之，原发肿瘤分泌的 VEGF 诱导 occludin 的磷酸化/泛素化和下调，导致前转移肺中 TJ 的破坏和血管的高通透性。occludin 的磷酸化/泛素化途径可能是 VEGF 诱导肺前转移龛血管高通透性的机制。
