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Human Neuroendocrine Tumor Cell Lines as a Three-Dimensional Model for the Study of Human Neuroendocrine Tumor Therapy

Human Neuroendocrine Tumor Cell Lines as a Three-Dimensional Model for the Study of Human Neuroendocrine Tumor Therapy

Published on: August 14, 2012

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

Daniel Benten^1,2, Yasmin Behrang¹, Ludmilla Unrau³

¹I. Medical Department - Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Molecular Cancer Research : MCR

|January 14, 2018

Abstract:

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.

Insights

Researchers developed a new human cell line, NT-3, from pancreatic neuroendocrine tumors (NET). This well-differentiated NET model expresses key markers and somatostatin receptors, aiding preclinical drug development.

Area of Science:

Oncology
Cell Biology
Translational Research

Background:

Clinical treatment options for neuroendocrine tumors (NET) are limited.
Effective preclinical research requires representative in vitro and in vivo models.
A human model with a well-differentiated phenotype and typical growth characteristics for NET has been lacking.

Purpose of the Study:

To establish and characterize a novel human cell line derived from a well-differentiated pancreatic neuroendocrine tumor.
To compare the neuroendocrine differentiation and tumor biology of the new cell line with existing NET models.
To evaluate the in vivo growth potential of the new cell line in a xenograft mouse model.

Main Methods:

Establishment and characterization of a lymph node-derived cell line (NT-3) from a pancreatic NET patient.
Assessment of neuroendocrine marker expression (including Ki-67) and insulin secretion.
Comparison of NT-3 with existing NET cell lines (BON, QGP-1) for differentiation and proliferation.
In vivo evaluation using a subcutaneous xenograft mouse model.

Main Results:

The NT-3 cell line demonstrated stable, well-differentiated neuroendocrine phenotype over 58 passages.
NT-3 exhibited high expression of NET-specific markers and insulin secretion, surpassing BON and QGP-1.
NT-3 showed a low Ki-67 proliferation index (14.6%) similar to the original tumor.
NT-3 expressed multiple somatostatin receptor subtypes (SSTRs 1, 2, 3, and 5).
Xenografts derived from NT-3 cells showed a high tumor take rate (94%) and resembled the original human tumor's morphology and marker expression.

Conclusions:

The novel NT-3 cell line represents a valuable human model for studying well-differentiated pancreatic neuroendocrine tumors.
High somatostatin receptor expression, stable differentiation, and slow growth rate make NT-3 suitable for preclinical research.
This model system will facilitate the development of new therapeutic strategies for neuroendocrine tumors.

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