A Role of Agrin in Maintaining the Stability of Vascular Endothelial Growth Factor Receptor-2 during Tumor Angiogenesis

• Published in: Cell reports (Cambridge) 2019-07, Vol.28 (4), p.949-965.e7
• Main Authors: Njah, Kizito, Chakraborty, Sayan, Qiu, Beiying, Arumugam, Surender, Raju, Anandhkumar, Pobbati, Ajaybabu V., Lakshmanan, Manikandan, Tergaonkar, Vinay, Thibault, Guillaume, Wang, Xiaomeng, Hong, Wanjin
• Format: Article
• Language: English
• Subjects: Agrin; angiogenesis; cell adhesion; ECM stiffness; endothelial-NOS; focal adhesion kinase (FAK); integrins; tumor angiogenesis; VEGFR2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.06.036

Endothelial cell (EC) recruitment is central to the vascularization of tumors. Although several proteoglycans have been implicated in cancer and angiogenesis, their roles in EC recruitment and vascularization during tumorigenesis remain poorly understood. Here, we reveal that Agrin, which is secreted in liver cancer, promotes angiogenesis by recruiting ECs within tumors and metastatic lesions and facilitates adhesion of cancer cells to ECs. In ECs, Agrin-induced angiogenesis and adherence to cancer cells are mediated by Integrin-β1, Lrp4-MuSK pathways involving focal adhesion kinase. Mechanistically, we uncover that Agrin regulates VEGFR2 levels that sustain the angiogenic property of ECs and adherence to cancer cells. Agrin attributes an ECM stiffness-based stabilization of VEGFR2 by enhancing interactions with Integrin-β1-Lrp4 and additionally stimulates endothelial nitric-oxide synthase (e-NOS) signaling. Therefore, we propose that cross-talk between Agrin-expressing cancer and ECs favor angiogenesis by sustaining the VEGFR2 pathway. [Display omitted] •Extracellular matrix protein Agrin recruits ECs within tumors•Agrin promotes in vitro and in vivo tumor angiogenesis•Agrin and ECM stiffness stabilize VEGFR2 by Lrp4-Integrin β1-FAK axis•Targeting Agrin inhibits tumor angiogenesis by impairing VEGFR2 levels Njah et. al. show that the extracellular matrix protein Agrin recruits blood vessels within tumors. Agrin promotes adherence of endothelial cells (ECs) to tumor cells and enhances tumor angiogenesis. Mechanistically, matrix stiffness and Agrin stabilize VEGFR2 by enhancing interactions with Lrp4-Integrin-β1-FAK. Targeting Agrin may inhibit tumor angiogenesis by reducing VEGFR2 levels.