Glutamate dependent NMDA receptor 2D is a novel angiogenic tumour endothelial marker in colorectal cancer
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Henry J.M. Ferguson1,2,*, Joseph W. Wragg1,*, Stephen Ward2, Victoria L. Heath1, Tariq Ismail2, Roy Bicknell1
1Molecular Angiogenesis Group, Institute for Biomedical Research, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
2Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Edgbaston, Birmingham, B15 2TH, UK
*These authors have contributed equally to this work
Henry J.M. Ferguson, e-mail: [email protected]
Keywords: colorectal cancer, GRIN2D, tumour endothelial marker, vaccination, active immunotherapy
Received: November 11, 2015 Accepted: January 31, 2016 Published: March 01, 2016
Current vascular-targeted therapies in colorectal cancer (CRC) have shown limited benefit. The lack of novel, specific treatment in CRC has been hampered by a dearth of specific endothelial markers. Microarray comparison of endothelial gene expression in patient-matched CRC and normal colon identified a panel of putative colorectal tumour endothelial markers. Of these the glutamate dependent NMDA receptor GRIN2D emerged as the most interesting target. GRIN2D expression was shown to be specific to colorectal cancer vessels by RTqPCR and IHC analysis. Its expression was additionally shown be predictive of improved survival in CRC. Targeted knockdown studies in vitro demonstrated a role for GRIN2D in endothelial function and angiogenesis. This effect was also shown in vivo as vaccination against the extracellular region of GRIN2D resulted in reduced vascularisation in the subcutaneous sponge angiogenesis assay. The utility of immunologically targeting GRIN2D in CRC was demonstrated by the vaccination approach inhibiting murine CRC tumour growth and vascularisation. GRIN2D represents a promising target for the future treatment of CRC.
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