Gastroenteropancreatic neuroendocrine tumor cancer stem cells: do they exist?

Neuroendocrine tumors (NETs) comprise a broad range of neoplasms that share biological and embryological origin. A deeper knowledge in the underlying molecular biology that results in the development and spread of NETs has allowed the use of novel-targeted therapies against angiogenesis and intracellular pathways, key checkpoints that govern growth, and proliferation of these tumors. Unfortunately, the possibility of cure is still far for patients with advanced stages. Cancer stem cells (CSCs) are present in most solid tumors. Nevertheless, there is limited evidence for the presence of CSCs in NETs. In this review, we will discuss the embryonic origin and possible existence of a gastroenteropancreatic neuroendocrine cancer stem cell. Here, we summarize the body of evidence supporting the presence of active embryological pathways like Notch, Wnt-β-catenin, Hedgehog, or transforming growth factor-β in NETs. New therapeutic approaches in the field of CSCs seem to have a clear role in the treatment of medulloblastomas and basal cell carcinomas, but their future value in other solid tumor types including NETs remains unclear.