Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model

Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative and model systems. So far, the unavailability of a human model with a well-differentiated phenotype and typical growth characteristics has impaired preclinical...

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Bibliographic Details
Published in:	Molecular cancer research Vol. 16; no. 3; pp. 496 - 507
Main Authors:	Benten, Daniel, Behrang, Yasmin, Unrau, Ludmilla, Weissmann, Victoria, Wolters-Eisfeld, Gerrit, Burdak-Rothkamm, Susanne, Stahl, Felix R, Anlauf, Martin, Grabowski, Patricia, Möbs, Markus, Dieckhoff, Jan, Sipos, Bence, Fahl, Martina, Eggers, Corinna, Perez, Daniel, Bockhorn, Maximillian, Izbicki, Jakob R, Lohse, Ansgar W, Schrader, Jörg
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research Inc 01-03-2018
Subjects:	Animals Biology Cancer Cell Differentiation - physiology Cell Proliferation - physiology Disease Models, Animal Drug development Genotype & phenotype Genotyping Techniques - methods Growth rate Heterografts Humans Immunosuppressive agents Insulin Lymph nodes Male Mice Neuroendocrine tumors Neuroendocrine Tumors - diagnosis Neuroendocrine Tumors - genetics Neuroendocrine Tumors - pathology Neurotrophin 3 Pancreas Pancreatic Neoplasms - diagnosis Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Phenotypes Receptors Somatostatin Somatostatin receptors Transplantation Tumors Xenografts Xenotransplantation
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Summary:	Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative and model systems. So far, the unavailability of a human model with a well-differentiated phenotype and typical growth characteristics has impaired preclinical research in NET. Herein, we establish and characterize a lymph node-derived cell line (NT-3) from a male patient with well-differentiated pancreatic NET. Neuroendocrine differentiation and tumor biology was compared with existing NET cell lines BON and QGP-1. growth was assessed in a xenograft mouse model. The neuroendocrine identity of NT-3 was verified by expression of multiple NET-specific markers, which were highly expressed in NT-3 compared with BON and QGP-1. In addition, NT-3 expressed and secreted insulin. Until now, this well-differentiated phenotype is stable since 58 passages. The proliferative labeling index, measured by Ki-67, of 14.6% ± 1.0% in NT-3 is akin to the original tumor (15%-20%), and was lower than in BON (80.6% ± 3.3%) and QGP-1 (82.6% ± 1.0%). NT-3 highly expressed somatostatin receptors (SSTRs: 1, 2, 3, and 5). Upon subcutaneous transplantation of NT-3 cells, recipient mice developed tumors with an efficient tumor take rate (94%) and growth rate (139% ± 13%) by 4 weeks. Importantly, morphology and neuroendocrine marker expression of xenograft tumors resembled the original human tumor. High expression of somatostatin receptors and a well-differentiated phenotype as well as a slow growth rate qualify the new cell line as a relevant model to study neuroendocrine tumor biology and to develop new tumor treatments. .
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ISSN:	1541-7786 1557-3125
DOI:	10.1158/1541-7786.mcr-17-0163