CD31 Expression Determines Redox Status and Chemoresistance in Human Angiosarcomas

Purpose: Angiosarcomas (AS) are soft tissue sarcomas with endothelial differentiation and vasoformative capacity. Most AS show strong constitutive expression of the endothelial adhesion receptor CD31/PECAM-1 pointing to an important role of this molecule. However, the biological function of CD31 in AS is unknown. Experimental Design: The expression levels of CD31 in AS cells and its effects on cell viability, colony formation and chemoresistance was evaluated in human AS clinical samples and in cell lines through isolation of CD31^high and CD31^low cell subsets. The redox-regulatory CD31 function linked to YAP signaling was determined using a CD31 blocking antibody and siRNA approach and was further validated in CD31-knockout endothelial cells. Results: We found that most AS contain a small CD31^low cell population. CD31^low cells had lost part of their endothelial properties, were more tumorigenic and chemoresistant than CD31^high cells due to more efficient reactive oxygen species (ROS) detoxification. Active downregulation of CD31 resulted in loss of endothelial tube formation, nuclear accumulation of YAP, and YAP-dependent induction of antioxidative enzymes. Addition of pazopanib, a known enhancer of proteasomal YAP degradation re-sensitized CD31^low cells for doxorubicin resulting in growth suppression and induction of apoptosis. Conclusions: Human AS contain a small aggressive CD31^low population that have lost part of their endothelial differentiation programs and are more resistant against oxidative stress and DNA damage due to intensified YAP signaling. Our finding that the addition of YAP inhibitors can re-sensitize CD31^low cells towards doxorubicin may aid in the rational development of novel combination therapies to treat AS.

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