Abstract
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.
Highlights
Colorectal cancer is the third most common cancer globally, making up about 10% of all malignant diagnoses [1]
Curative treatment heavily relies upon the achievement of a histologically clear resection margin at surgery [3, 4] and 80% of colorectal cancer (CRC) resections do achieve this, 50% will relapse to metastatic disease, due to the presence of micro-metastases present at the time of resection [2, 5]
The analysis identified GRIN2D to be positively expressed on the vessels of 40% of colorectal cancers, but only 10% of healthy colon samples
Summary
Colorectal cancer is the third most common cancer globally, making up about 10% of all malignant diagnoses [1]. There are over 1.4 million new cases annually, 65% of which are found in developed countries, with 695,000 deaths from the disease. More advanced disease, making up 50% of cases in the UK, has a poorer prognosis, and often requires the addition of adjuvant therapies such as chemotherapy [1]. The five-year survival rate in developed countries is around 65%, this drops to below 10% with metastatic disease [2]. Curative treatment heavily relies upon the achievement of a histologically clear resection margin at surgery [3, 4] and 80% of CRC resections do achieve this, 50% will relapse to metastatic disease, due to the presence of micro-metastases present at the time of resection [2, 5]. Improvements in treatment and prevention of metastatic disease, are of vital importance to achieve better outcomes in CRC
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