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

TY - JOUR

T1 - Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model

AU - Benten, Daniel

AU - Behrang, Yasmin

AU - Unrau, Ludmilla

AU - Weissmann, Victoria

AU - Wolters-Eisfeld, Gerrit

AU - Burdak-Rothkamm, Susanne

AU - Stahl, Felix R

AU - Anlauf, Martin

AU - Grabowski, Patricia

AU - Möbs, Markus

AU - Dieckhoff, Jan

AU - Sipos, Bence

AU - Fahl, Martina

AU - Eggers, Corinna

AU - Perez, Daniel

AU - Bockhorn, Maximilian

AU - Izbicki, Jakob R

AU - Lohse, Ansgar W

AU - Schrader, Jörg

N1 - ©2018 American Association for Cancer Research.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative in vitro and in vivo 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. In vivo 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.Implications: 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. Mol Cancer Res; 16(3); 496-507. ©2018 AACR.

AB - Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative in vitro and in vivo 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. In vivo 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.Implications: 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. Mol Cancer Res; 16(3); 496-507. ©2018 AACR.

KW - Journal Article

U2 - 10.1158/1541-7786.MCR-17-0163

DO - 10.1158/1541-7786.MCR-17-0163

M3 - SCORING: Journal article

C2 - 29330294

VL - 16

SP - 496

EP - 507

JO - MOL CANCER RES

JF - MOL CANCER RES

SN - 1541-7786

IS - 3

ER -