Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness.
Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness.
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DOI：
10.1172/jci153626
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发表时间：
2022-03-15
期刊：
影响因子：
--
通讯作者：
Kubota Y
中科院分区：
文献类型：
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作者：
Ando T;Tai-Nagara I;Sugiura Y;Kusumoto D;Okabayashi K;Kido Y;Sato K;Saya H;Navankasattusas S;Li DY;Suematsu M;Kitagawa Y;Seiradake E;Yamagishi S;Kubota Y
血管异常改变了癌细胞的代谢，促进了癌细胞的播散和转移。然而，促进癌症进展的异常血管的生物学特征以及它们是否可以被靶向治疗尚未得到充分研究。在这里，我们发现，轴突导向分子，纤连蛋白富含亮氨酸跨膜蛋白2（FLRT 2），在人类晚期结直肠癌的异常血管中优先表达，其表达与长期生存呈负相关。在小鼠中，内皮细胞特异性缺失Flrt 2选择性地修剪异常血管，导致称为“氧-葡萄糖解偶联”的独特代谢状态，其抑制肿瘤转移。此外，Flrt 2缺失导致成熟血管数量增加，导致免疫检查点阻断剂的抗肿瘤作用显著增加。从机制上讲，我们发现FLRT 2形成非典型的内皮细胞间粘连，通过嗜同性结合保护免受氧化应激。总之，我们的研究结果表明，存在肿瘤特异性内皮细胞间粘连，使异常的血管，以促进癌症的侵袭性。针对这种类型的粘附复合物可能是抑制癌症进展的安全有效的治疗选择。
Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans and that its expression correlates negatively with long-term survival. Endothelial cell–specific deletion of Flrt2 in mice selectively pruned abnormalized vessels, resulting in a unique metabolic state termed “oxygen-glucose uncoupling,” which suppressed tumor metastasis. Moreover, Flrt2 deletion caused an increase in the number of mature vessels, resulting in a significant increase in the antitumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms noncanonical interendothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrated the existence of tumor-specific interendothelial adhesions that enable abnormalized vessels to facilitate cancer aggressiveness. Targeting this type of adhesion complex could be a safe and effective therapeutic option to suppress cancer progression.