Models of Gastroenteropancreatic Neuroendocrine Neoplasms: Current Status and Future Directions

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare, heterogeneous group of tumors that originate from the endocrine system of the gastrointestinal tract and pancreas. GEP-NENs are subdivided according to their differentiation into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Since GEP-NENs represent rare diseases, only limited data from large prospective, randomized clinical trials are available, and recommendations for treatment of GEP-NEN are in part based on data from retrospective analyses or case series. In this context, tractable disease models that reflect the situation in humans and that allow to recapitulate the different clinical aspects and disease stages of GEP-NET or GEP-NEC are urgently needed. In this review, we highlight available data on mouse models for GEP-NEN. We discuss how these models reflect tumor biology of human disease and whether these models could serve as a tool for understanding the pathogenesis of GEP-NEN and for disease modeling and pharmacosensitivity assays, facilitating prediction of treatment response in patients. In addition, open issues applicable for future developments will be discussed.

Establishment of Novel Neuroendocrine Carcinoma Patient-Derived Xenograft Models for Receptor Peptide-Targeted Therapy

“…Several lung NEC lines 36,37 and colon NEC lines such as the HROC47, SS-2, NEC-DUE1 & 2 36,[38][39][40] have been established but few pancreas and small bowel NEC have been reported. 39 Considering the rarity of GEP NEC PDX and cell models, the NEC913 and NEC1452 PDX models developed in this study could be tremendously valuable for a variety of pre-clinical experiments.…”

“…Several lung NEC lines 36,37 and colon NEC lines such as the HROC47, SS-2, NEC-DUE1 & 2 36,[38][39][40] have been established but few pancreas and small bowel NEC have been reported. 39 Considering the rarity of GEP NEC PDX and cell models, the NEC913 and NEC1452 PDX models developed in this study could be tremendously valuable for a variety of pre-clinical experiments. Here, we showed that the NEC913 line can be useful in confirming the target specificity of NIR-TOC with fluorescence imaging in a clinically relevant model, suggesting high translational potential (Figure 4).…”

Clinicopathological Features of Neuroendocrine Tumors in Gastroenteropancreatic Tract: A Single Center Study

“…GEP-NETs are an uncommon heterogeneous category of tumors that develop from the secretory cells of the gastrointestinal tract and pancreatic endocrine systems [ 7 ]. GEP-NETs can manifest as hormonally functional or nonfunctional tumors, with varying clinical characteristics depending on the site of origin [ 8 ].…”

Human Immunocompetent Model of Neuroendocrine Liver Metastases Recapitulates Patient-Specific Tumour Microenvironment

“…LM-NEN can lead to development of carcinoid syndrome and carcinoid heart disease. Regardless of the primary site, LM are a strong prognostic predictor of mortality, reducing considerably the overall survival compared to non-metastatic disease ( 4 , 5 ). Although medical treatments can relieve symptoms and/or delay progression, the response rates are low and complete resection of LM-NEN tumours, which is rarely a curative option, is reserved for a minority (7-15%) of patients ( 6 , 7 ).…”

“…No studies to date have explored the therapeutic potential of solCRs as autologous biologicals or as biomarkers for immunotherapeutic strategies in LM-NEN, partially due to the paucity of experimental models that allow the investigation of solCRs and the human TME. This is an urgent unmet research need that significantly thwarts the advancement of our understanding of LM-NEN pathogenesis and the development of effective therapies ( 5 , 23 ).…”