Pancreatic neuroendocrine tumor cancer stem cells: potential novel therapeutic targets?

New therapeutic treatments are urgently needed for patients with pancreatic neuroendocrine tumors (PanNETs) that are insensitive or resistant to current therapeutic methods. The cancer stem cells (CSCs) in PanNETs may imply a promising and novel therapeutic approach to treat patients with advanced stage tumor and improve patient survival through targeting various molecular pathways. In this review, we define the process of identifying CSCs in PanNETs and address the potential therapeutic implications of targeting CSCs. The CSCs in PanNETs are marked by aldehyde dehydrogenases (ALDH) or CD90. We discuss the relevant molecular pathways in ALDH+ and CD90+ CSCs, including the Src, Notch, Hedgehog, Wnt/β-catenin, mammalian target of rapamycin (mTOR), epidermal growth factor receptor (EGFR) and signal transducers and activators of transcription 3 (STAT3) signaling pathways. The function of Src signaling has been identified in a NET cell line, which suggests it could become a new therapeutic target in PanNETs. With the exception of the STAT3 signaling pathway, signaling pathways involved in the tumorigenicity of CSCs in many other cancers play a role in the pathophysiology of PanNETs. These molecular pathways may be potential targets for the treatment of PanNETs despite a lack of studies relating them to PanNET CSCs and more studies are needed to clarify the role of these signaling pathways in PanNETs. Additionally, targeting of the cellular surface markers CD47 and CD73 decreased the tumor growth of ALDH+ CSCs in PanNETs cell lines. In conclusion, the study of PanNET CSCs could aid in the development of novel therapeutic targets for PanNETs, and this review details the molecular pathways that might become new targets.