By Anna C. Greene, PhD, NETRF Chief Scientific Officer
A new open-access review article in Virchows Archiv, “Novel concepts of cell-of-origin in neuroendocrine neoplasms,” by Ilaria Marinoni, Simona Avanthay, and Nicolas Alcala, asks a deceptively simple question: what normal cell does a neuroendocrine neoplasm start from?
Neuroendocrine neoplasms, or NENs, are an umbrella term that includes both neuroendocrine tumors (NETs), which are often slow-growing and well-differentiated, and neuroendocrine carcinomas (NECs), which are typically faster-growing and poorly differentiated.
While it’s tempting to assume the starting cell is always a neuroendocrine cell, the review explains why that is not always true. In some cancers, cells that are not originally neuroendocrine can acquire neuroendocrine features over time, sometimes under treatment pressure. Some tumors also contain both neuroendocrine and non-neuroendocrine components. This plasticity, meaning a cell’s ability to change identity and behavior, helps explain why “neuroendocrine” can sometimes describe what a tumor becomes rather than where it started.
What the review suggests, by organ
Pancreas
Many pancreatic NETs appear to begin in the pancreas’s hormone-making cells, the cells that normally make insulin, glucagon, and other hormones, rather than in “starter” stem cells. The review also explains that pancreatic tumors may carry clues about which hormone-making cell they most resemble, and that this may relate to how they behave.
For the fastest-growing pancreatic neuroendocrine cancers, called pancreatic NECs, the story may be different. The review discusses evidence that some pancreatic NECs may start from non-hormone pancreatic cells and later take on neuroendocrine features, which could help explain why they act differently from many pancreatic NETs.
Lung
Lung neuroendocrine tumors may not all start the same way. The review summarizes evidence that different lung subtypes may begin in different areas of the lung and may come from different kinds of lung cells, which could help explain why some behave more slowly while others are more aggressive.
The review also notes that lung NECs, including small cell lung cancer, may arise from more than one type of lung cell and may involve identity shifts as the cancer develops. This may help explain differences in behavior and treatment response compared with lung NETs.
Small intestine
Small intestinal NETs are generally thought to begin in specialized hormone-signaling cells in the gut lining. The review highlights newer research suggesting there may be more than one “starting pattern” in small intestinal NETs. Some tumors look more like mature gut hormone cells, while others look less mature or more mixed, which could affect how they grow and spread.
What this means for patients
If researchers can reliably identify where different NEN subtypes begin, and how they change over time, it could lead to:
- more precise classification beyond what is seen under the microscope
- better risk prediction, including which tumors are more likely to act aggressively
- treatment strategies matched to the tumor’s underlying biology, including vulnerabilities tied to its origin and evolution
NETRF perspective, and NETRF support
One of the review’s authors, Nicolas Alcala, PhD, is a 2023 NETRF awardee through a NETRF Mentored Research Award. His funded work focuses on reconstructing how neuroendocrine tumor subtypes evolve, which closely connects to this review’s central theme: understanding origins and identity shifts to enable better, more personalized care. Learn more.