Passen Chiara Van, Krug Julia, Weiß Luisa, Abdou Mariam Mohamed, Tripal Philipp, Schmid Benjamin, Krüger René, Lyu Yanmin, Zohud Bisan Abdalfatah, Petter Katja, Geppert Carol, Merkel Susanne, Bärthlein Barbara, Busenhart Philipp, Scharl Michael, Naschberger Elisabeth, Stürzl Michael
Division of Molecular and Experimental Surgery, Uniklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Department of Dermatology, Venerology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Int J Cancer. 2025 Oct 1;157(7):1481-1495. doi: 10.1002/ijc.35504. Epub 2025 Jun 9.
Integrin β6 is associated with poor prognosis in colorectal cancer (CRC) patients, with metastasis being a crucial determinant. Capillary endothelial cells (EC) in the liver and lung are the primary sites of contact for circulating tumour cells during metastasis. Here, we analysed the role of integrin β6 in tumour cells for their interaction with EC. Integrin β6 functions as a heterodimer with integrin αv. Interestingly, we found that liver and lung EC strongly express fibronectin, a high-affinity ligand of αvβ6. Expression of ITGB6 in CRC tumour cells closely correlated with their adhesion to EC. This interaction was greatly reduced by silencing ITGB6 in the tumour cells and was integrin β6 dependent under both static and flow conditions. Binding assays with fibronectin-coated surfaces, competing RGD peptides, and integrin β6-neutralizing antibodies confirmed the crucial role of β6-fibronectin binding in the interaction between tumour cells and EC. Since metastatic tumours exhibit increased proteolytic activity, we examined integrin β6 stability under these conditions. Remarkably, β6 remained resistant to trypsin and the matrix metalloprotease 12, underscoring its role in maintaining tumour cell adhesion in proteolytic microenvironments. Furthermore, ITGB6 expression was significantly elevated in liver metastases compared to corresponding primary tumours from the same patients, suggesting an enrichment of β6-expressing cells in metastatic sites. These results suggest that tumour cell integrin β6 binding to EC-derived fibronectin may serve as a critical first step in metastasis formation. Targeting this interaction could provide a promising therapeutic strategy to repress CRC metastasis.
整合素β6与结直肠癌（CRC）患者的不良预后相关，转移是一个关键决定因素。肝脏和肺中的毛细血管内皮细胞（EC）是转移过程中循环肿瘤细胞的主要接触部位。在此，我们分析了整合素β6在肿瘤细胞与EC相互作用中的作用。整合素β6与整合素αv形成异二聚体发挥作用。有趣的是，我们发现肝脏和肺的EC强烈表达纤连蛋白，它是αvβ6的高亲和力配体。CRC肿瘤细胞中ITGB6的表达与其对EC的粘附密切相关。通过在肿瘤细胞中沉默ITGB6，这种相互作用大大降低，并且在静态和流动条件下均依赖于整合素β6。用纤连蛋白包被的表面、竞争性RGD肽和整合素β6中和抗体进行的结合试验证实了β6-纤连蛋白结合在肿瘤细胞与EC相互作用中的关键作用。由于转移性肿瘤表现出增强的蛋白水解活性，我们在这些条件下检测了整合素β6的稳定性。值得注意的是，β6对胰蛋白酶和基质金属蛋白酶12具有抗性，这突出了其在蛋白水解微环境中维持肿瘤细胞粘附的作用。此外，与同一患者的相应原发性肿瘤相比，肝转移灶中ITGB6的表达显著升高，表明转移部位中表达β6的细胞富集。这些结果表明，肿瘤细胞整合素β6与EC衍生的纤连蛋白结合可能是转移形成的关键第一步。靶向这种相互作用可能为抑制CRC转移提供一种有前景的治疗策略。
