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

  • Oncogene. 2016 Aug 18;35(33):4379-87. doi: 10.1038/onc.2015.507.
D Grun  1 ,  G Adhikary  1 ,  R L Eckert  1  2  3  4
Affiliations
  • 1. Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MA, USA.
  • 2. Departments of Dermatology, University of Maryland School of Medicine, Baltimore, MA, USA.
  • 3. Departments of Reproductive Biology, University of Maryland School of Medicine, Baltimore, MA, USA.
  • 4. Departments of Marlene and Stewart Greenebaum Cancer, University of Maryland School of Medicine, Baltimore, MA, USA.
PMID: 26804163 DOI: 10.1038/onc.2015.507
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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