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紧密连接Claudins的血管异质性引导了嗜器官转移

原文发布日期：2024-09-17

英文摘要：

摘要翻译：

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文章：

紧密连接Claudins的血管异质性引导了嗜器官转移

Vascular heterogeneity of tight junction Claudins guides organotropic metastasis

原文发布日期：2024-09-17

英文摘要：

Carcinomas are associated with metastasis to specific organs while sparing others. Breast cancer presents with lung metastasis but rarely kidney metastasis. Using this difference as an example, we queried the mechanism(s) behind the proclivity for organ-specific metastasis. We used spontaneous and implant models of metastatic mammary carcinoma coupled with inflammatory tissue fibrosis, single-cell sequencing analyses and functional studies to unravel the causal determinants of organ-specific metastasis. Here we show that lung metastasis is facilitated by angiopoietin 2 (Ang2)-mediated suppression of lung-specific endothelial tight junction protein Claudin 5, which is augmented by the inflammatory fibrotic microenvironment and prevented by anti-Ang2 blocking antibodies, while kidney metastasis is prevented by non-Ang2-responsive Claudins 2 and 10. Suppression of Claudins 2 and 10 was sufficient to induce the emergence of kidney metastasis. This study illustrates the influence of organ-specific vascular heterogeneity in determining organotropic metastasis, independent of cancer cell-intrinsic mechanisms.

摘要翻译：

癌变与特定器官的转移有关，而对其他器官转移则较少。乳腺癌常伴有肺部转移，但肾部转移罕见。通过这种差异为例，我们探讨了组织特异性转移倾向的原因机制。我们利用自发性及移植模型的乳腺癌以及炎症组织化纤维化、单细胞测序分析和功能研究等方法，揭示了组织特异性转移的发生因果关系。在此研究中，我们发现肺部转移受Angiopoietin 2（Ang2）介导的抑制血管内皮紧连接蛋白Claudin5的作用增强，并由炎症组织化的微环境进一步促进，而通过对抗Ang2结合的抗体则可阻止。肾部转移受到非Ang2应答的Claudins 2和10的抑制作用，并且通过抑制Claudins 2和10也可诱导肾部转移的发生。本研究说明了由于器官特异性血管异质性，而导致组织特异转移的现象，这种影响与癌细胞自身机制无关。