Notch2-positive progenitors with the intrinsic ability to give rise to pancreatic ductal cells
Notch2-positive progenitors with the intrinsic ability to give rise to pancreatic ductal cells
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DOI：
10.1038/labinvest.3700298
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发表时间：
2005-08-01
影响因子：
5
通讯作者：
Ouellette, MM
中科院分区：
文献类型：
--
作者：
Lee, KM;Yasuda, H;Ouellette, MM
胰腺腺癌显示胰腺导管细胞标记阳性的导管样结构灶。这些肿瘤的发展是由导致腺泡到导管化生的条件促进的，腺泡细胞被导管细胞取代的过程。腺泡-导管化生最近被证明是通过表达Nestin的中间细胞进行的。为了建立一个研究胰腺癌的体外系统，我们使用hTERT cDNA使人胰腺的原代细胞永生化。在这份报告中，我们表明，永生化细胞，称为hTERT-HPNE细胞，有能力分化为胰腺导管细胞。将hTERT-HPNE细胞暴露于丁酸钠和5-氮杂-2 '-脱氧胞苷导致胰腺导管细胞的形成，其通过MDR-1、碳酸酐酶II和细胞角蛋白7、8和19的表达来标记。发现hTERT-HPNE细胞具有在腺泡-导管化生期间形成的中间细胞的性质，其包括它们的未分化表型、巢蛋白表达、活性Notch信号传导的证据以及分化为胰腺导管细胞的能力。这些结果为成年胰腺中存在导管细胞的前体提供了进一步的证据。hTERT-HPNE细胞应该提供一个有用的模型来研究腺泡-导管化生以及该过程在胰腺癌发展中所起的作用。
Pancreatic adenocarcinomas display foci of duct-like structures that are positive for markers of pancreatic ductal cells. The development of these tumors is promoted by conditions leading to acinar-to-ductal metaplasia, a process by which acinar cells are replaced by ductal cells. Acinar-to-ductal metaplasia has recently been shown to proceed through intermediary cells expressing Nestin. To create an in vitro system to study pancreatic adenocarcinomas, we had used an hTERT cDNA to immortalize primary cells of the human pancreas. In this report, we show that the immortalized cells, termed hTERT-HPNE cells, have the ability to differentiate to pancreatic ductal cells. Exposing hTERT-HPNE cells to sodium butyrate and 5-aza-2'-deoxycytidine lead to the formation of pancreatic ductal cells marked by the expression of MDR-1, carbonic anhydrase II, and the cytokeratins 7, 8, and 19. hTERT-HPNE cells were found to have properties of the intermediary cells formed during acinar-to-ductal metaplasia, which included their undifferentiated phenotype, expression of Nestin, evidence of active Notch signaling, and ability to differentiate to pancreatic ductal cells. These results provide further evidence for the presence in the adult pancreas of a precursor of ductal cells. hTERT-HPNE cells should provide a useful model to study acinar-to-ductal metaplasia and the role played by this process in pancreatic cancer development.