Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model
Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model
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DOI：
10.1158/1541-7786.mcr-17-0163
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发表时间：
2018-03-01
影响因子：
5.2
通讯作者：
Schrader, Joerg
中科院分区：
文献类型：
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作者：
Benten, Daniel;Behrang, Yasmin;Schrader, Joerg
神经内分泌肿瘤(Net)系统治疗的临床选择有限。新药的开发需要具有代表性的体内外模型系统。到目前为止，缺乏具有良好分化表型和典型生长特征的人类模型已经损害了Net的临床前研究。在此，我们建立并鉴定了一个来自分化良好的胰腺网络男性患者的淋巴结来源的细胞系(NT-3)。将神经内分泌分化和肿瘤生物学与现有的网络细胞系Bon和QGP-1进行比较。在异种移植小鼠模型中评估体内生长情况。多个Net特异性标志物的表达证实了NT-3的神经内分泌特性，与Bon和QGP-1相比，NT-3在NT-3中高表达。此外，NT-3还表达和分泌胰岛素。到目前为止，这种分化良好的表型自58代以来一直是稳定的。Ki-67测定的增殖标记指数在NT-3中为14.6%+/-1.0%，与原始肿瘤相似(15%-20%)，低于BON(80.6%+/-3.3%)和QGP-1(82.6%+/-1.0%)。NT-3高表达生长抑素受体(SSTRs：1、2、3和5)。将NT-3细胞皮下移植后，受体小鼠在4周内形成肿瘤，有效成瘤率为94%，生长率为139%+/-13%。重要的是，异种移植瘤的形态和神经内分泌标志物的表达与原始人类肿瘤相似。
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.