MCAM and LAMA4 Are Highly Enriched in Tumor Blood Vessels of Renal Cell Carcinoma and Predict Patient Outcome

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 8; pp. 2314 - 2326
• Main Authors: Wragg, Joseph W, Finnity, Jonathan P, Anderson, Jane A, Ferguson, Henry J M, Porfiri, Emilio, Bhatt, Rupesh I, Murray, Paul G, Heath, Victoria L, Bicknell, Roy
• Format: Journal Article
• Language: English
• Published: United States 15-04-2016
• Subjects: Animals; Carcinoma, Renal Cell - blood supply; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - therapy; CD146 Antigen - metabolism; Human Umbilical Vein Endothelial Cells; Humans; Kidney Neoplasms - blood supply; Kidney Neoplasms - metabolism; Kidney Neoplasms - therapy; Laminin - metabolism; Mice; Neoplasm Metastasis; Treatment Outcome; Vascular Endothelial Growth Factor A - pharmacology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-15-1364

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, or colorectal liver metastasis. 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 colorectal carcinoma blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in colorectal carcinoma. 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 Res; 76(8); 2314-26. ©2016 AACR.