| Abstract |
The aim of this project was to characterize the newly established
pancreatic NET cell line NT-3 and to study its behavior in direct
comparison to the existing cell lines (QGP-1 and BON), upon treatment with
therapeutics and as a xenograft animal model. This is to evaluate if NT-3
provides a representative, well-differentiated neuroendocrine tumor model
for targeted and significant research on this tumor entity. Research on
new therapies for pancreatic neuroendocrine tumors (pNET) has been
hampered by the absence of a clinically relevant tumor model system. The
neuroendocrine identity of NT-3 was verified by the expression of multiple
NET-specific markers, which were highly expressed in NT-3 compared with
BON and QGP-1. As a sign of functional activity, we were able to detect
the expression and secretion of insulin in NT-3, corresponding to the
clinical insulinoma of the patient providing the tumor that NT-3 was
derived from. Until now, this well-differentiated phenotype is stable
since 58 passages. The proliferative labeling index 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%). Moreover, NT-3 showed high
expression of somatostatin receptors (SSTRs: 1, 2, 3, and 5), which are
targets of therapeutics successfully used in the treatment of pancreatic
NETs. In vivo growth was assessed in a xenograft mouse model. 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. Morphology and neuroendocrine marker expression of
xenograft tumors resembled the original human tumor. These outstanding
characteristics qualify NT-3 as a relevant model to study neuroendocrine
tumor biology and to develop new NET treatments.
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