The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma (CRC), or colorectal liver metastasis (CRM).
We identified a panel of genes consistently upregulated by tumor blood vessels of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and CRC blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in CRC. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting.
Cancer research. 2016 Feb 26 [Epub ahead of print]
Joseph W Wragg, Jonathan P Finnity, Jane A Anderson, Henry J Ferguson, Emilio Porfiri, Rupesh I Bhatt, Paul G Murray, Victoria L Heath, Roy Bicknell
Cancer Research UK Angiogenesis Group, Institute for Biomedical Research, University of Birmingham., Cancer Research UK Angiogenesis Group, Institute for Biomedical Research, University of Birmingham., Institute of Cancer and Genomic Sciences, University of Birmingham., Cancer Research UK Angiogenesis Group, Institute for Biomedical Research, University of Birmingham., Queen Elizabeth Medical Centre, Queen Elizabeth Hospital., Queen Elizabeth Medical Centre, Queen Elizabeth Hospital., Institute of Cancer and Genomic Sciences, University of Birmingham., Cancer Research UK Angiogenesis Group, Institute for Biomedical Research, University of Birmingham., Cancer Research UK Angiogenesis Group, Institute for Biomedical Research, The University of Birmingham