In this study, we report that (i) MCAM, NOX1, and ADAM17 are associated in a protein complex in endothelial and cancer cells, and both ADAM17 and NOX1 regulate the shedding of membrane MCAM and the release of soluble MCAM, an angiogenic tumor growth factor; (ii) ADAM17 targeting reinforces the anti-tumor, anti-angiogenic, and anti-lymphangiogenic effects observed previously with NOX1 inhibition. The gene discussed is NOX1; the disease is cancer.