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VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors

Oncogene volume 35, pages 4379–4387 (2016)Cite this article

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Abstract

We identify a limited subpopulation of epidermal cancer stem cells (ECS cells), in squamous cell carcinoma, that form rapidly growing, invasive and highly vascularized tumors, as compared with non-stem cancer cells. These ECS cells grow as non-attached spheroids, and display enhanced migration and invasion. We show that ECS cell-produced vascular endothelial growth factor (VEGF)-A is required for the maintenance of this phenotype, as knockdown of VEGF-A gene expression or treatment with VEGF-A-inactivating antibody reduces these responses. In addition, treatment with bevacizumab reduces tumor vascularity and growth. Surprisingly, the classical mechanism of VEGF-A action via interaction with VEGF receptors does not mediate these events, as these cells lack VEGFR1 and VEGFR2. Instead, VEGF-A acts via the neuropilin-1 (NRP-1) co-receptor. Knockdown of NRP-1 inhibits ECS cell spheroid formation, invasion and migration, and attenuates tumor formation. These studies suggest that VEGF-A acts via interaction with NRP-1 to trigger intracellular events leading to ECS cell survival and formation of aggressive, invasive and highly vascularized tumors.

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Acknowledgements

This work was supported by grants from the Maryland Stem Cell Research Foundation (RLE) and the National Institutes of Health (RLE - CA131074, CA184027) and a pilot grant from the Greenebaum Cancer Center (P30 CA134274).

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Authors and Affiliations

  1. Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MA, USA

    D Grun, G Adhikary & R L Eckert

  2. Departments of Dermatology, University of Maryland School of Medicine, Baltimore, MA, USA

    R L Eckert

  3. Departments of Reproductive Biology, University of Maryland School of Medicine, Baltimore, MA, USA

    R L Eckert

  4. Departments of Marlene and Stewart Greenebaum Cancer, University of Maryland School of Medicine, Baltimore, MA, USA

    R L Eckert

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Correspondence to R L Eckert.

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Grun, D., Adhikary, G. & Eckert, R. VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors. Oncogene 35, 4379–4387 (2016). https://doi.org/10.1038/onc.2015.507

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