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Cell Rep. 2019 Jul 23;28(4):949-965.e7. doi: 10.1016/j.celrep.2019.06.036.

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

Author information

1
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
2
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore. Electronic address: sayanc@imcb.a-star.edu.sg.
3
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
4
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
5
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore 636921, Singapore; Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, Singapore 169856, Singapore; Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK. Electronic address: wangxiaomeng@ntu.edu.sg.

Abstract

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.

KEYWORDS:

Agrin; ECM stiffness; VEGFR2; angiogenesis; cell adhesion; endothelial-NOS; focal adhesion kinase (FAK); integrins; tumor angiogenesis

PMID:
31340156
DOI:
10.1016/j.celrep.2019.06.036
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