Nectin cell adhesion molecule 4 regulates angiogenesis through Src signaling and serves as a novel therapeutic target in angiosarcoma

Abstract

Angiosarcoma is a rare, life-threatening soft tissue sarcoma with malignant endothelial cells that is mainly found in the skin. Multidisciplinary approaches are used to treat patients with unresectable metastasized lesions; considering the cellular origin of angiosarcoma, anti-angiogenic therapy has also been used recently. However, these treatments have limited efficacy, and the survival rate remains low. Thus, more effective treatments need to be developed. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in malignant tumors and promotes tumor progression. Thus, NECTIN4 is expected to be a novel therapeutic target for cancer. However, the significance of NECTIN4 in angiosarcoma remains unknown. Using immunohistochemistry, we investigated NECTIN4 expression in 74 tissue samples from angiosarcoma patients, finding variable NECTIN4 expression. In addition, we investigated NECTIN4 expression and function in human angiosarcoma cell lines. NECTIN4 expression was higher in angiosarcoma cells than normal endothelial cells, and angiosarcoma cells were sensitive to monomethyl auristatin E, the cytotoxic part of a NECTIN4-targetting antibody–drug conjugate. NECTIN4 knockdown inhibited the proliferation and angiogenesis of angiosarcoma cells, and Src kinase signaling was shown to be involved in NECTIN4 function, at least in part. NECTIN4-targeted therapy has the potential to be a novel treatment strategy for angiosarcoma.