Everything you ever wanted to know about cancer stem cells in neuroendocrine neoplasms but were afraid to ask.

While the role of cancer stem cells (CSCs) in tumorigenesis, chemoresistance, metastasis, and relapse has been extensively studied in solid tumors, such as adenocarcinomas or sarcomas, the same cannot be said for neuroendocrine neoplasms (NENs). While lagging, CSCs have been described in numerous NENs, including gastrointestinal and pancreatic NENs (PanNENs), and they have been found to play critical roles in tumor initiation, progression, and treatment resistance. However, it seems that there is still skepticism regarding the role of CSCs in NENs, even in light of studies that support the CSC model in these tumors and the therapeutic benefits of targeting them. For example, in lung neuroendocrine carcinoids, a high percentage of CSCs have been found in atypical carcinoids, suggesting the presence of CSCs in these cancers. In PanNENs, CSCs marked by aldehyde dehydrogenases or CD90 have been identified, and targeting CSCs with inhibitors of molecular pathways has shown therapeutic potential. Overall, while evidence exists for the presence of CSCs in NENs, either the CSC field has neglected NENs or the NEN field has not fully embraced the CSC model. Both might apply and/or may be a consequence of the fact that NENs are a relatively rare and heterogeneous tumor entity, with confusing histology and nomenclature to match. Regardless, this review intends to summarize our current knowledge of CSCs in NENs and highlight the importance of understanding the role of CSCs in the biology of these rare tumors, with a special focus on developing targeted therapies to improve patients' outcomes.