Targeting dimethylarginine dimethylaminohydrolase 1 to suppress vasculogenic mimicry in breast cancer: Current evidence and future directions

Nitric oxide (NO) plays a critical pathophysiological role in cancer by modulating several processes such as angiogenesis, tumor growth, and metastatic potential. However, the role of NO in vasculogenic mimicry, an alternative neovascularization process involving the formation of vessel-like networks directly by the tumor cells themselves and predicting high metastatic burden and poor survival, is less clear. The pathophysiological and clinical significance of vasculogenic mimicry have been particularly well studied in triple-negative breast cancer (TNBC), a type of breast cancer characterized by aggressive behavior, high relapse rate, poor prognosis, and lack of effective targeted treatments. Recent studies have reported that isoform 1 of the enzyme dimethylarginine dimethylaminohydrolase (DDAH1), responsible for the metabolism of the endogenous NO synthase inhibitors, the methylated arginines asymmetric NG,NG-dimethyl-l-arginine and NG-monomethyl-l-arginine, is essential for TNBC cells to undertake vasculogenic mimicry. Furthermore, treatment with small-molecule arginine analogs with inhibitory activity toward DDAH1 has been shown to significantly reduce vasculogenic mimicry by TNBC cells. This chapter describes the current knowledge regarding the pathophysiological and clinical significance of vasculogenic mimicry, the biology of DDAH1 and methylated arginines, and the role of DDAH1 as a promising “druggable” target to suppress vasculogenic mimicry in cancer, with a focus on TNBC.