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The melanoma cell adhesion molecule, shed from endothelial and cancer cells, is a soluble growth factor that induces tumor angiogenesis and growth. However, the molecular mechanism accounting for its generation in a tumor context is still unclear. To investigate this mechanism, we performed in vitro experiments with endothelial/cancer cells, gene expression analyses on datasets from human colorectal tumor samples, and applied pharmacological methods in vitro/in vivo with mouse and human colorectal cancer cells. We found that soluble MCAM generation is governed by ADAM17 proteolytic activity and NOX1-regulating ADAM17 expression. The treatment of colorectal tumor-bearing mice with pharmacologic NOX1 inhibitors or tumor growth in NOX1-deficient mice reduced the blood concentration of soluble MCAM and abrogated the anti-tumor effects of anti-soluble MCAM antibodies while ADAM17 pharmacologic inhibitors reduced tumor growth and angiogenesis in vivo. Especially, the expression of MCAM, NOX1, and ADAM17 was more prominent in the angiogenic, colorectal cancer-consensus molecular subtype 4 where high MCAM expression correlated with angiogenic and lymphangiogenic markers. Finally, we demonstrated that soluble MCAM also acts as a lymphangiogenic factor in vitro. These results identify a role for NOX1/ADAM17 in soluble MCAM generation, with potential clinical therapeutic relevance to the aggressive, angiogenic CMS4 colorectal cancer subtype. [ABSTRACT FROM AUTHOR]