Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer.
Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer.
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DOI：
10.1158/1078-0432.ccr-08-2004
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发表时间：
2009-04-01
期刊：
影响因子：
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通讯作者：
Feldmann G
中科院分区：
文献类型：
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作者：
Mullendore ME;Koorstra JB;Li YM;Offerhaus GJ;Fan X;Henderson CM;Matsui W;Eberhart CG;Maitra A;Feldmann G
Notch信号通路的异常激活通常在人胰腺癌中观察到，尽管这种激活的机制尚未阐明。对一组20种人胰腺癌细胞系进行Notch途径相关配体、受体和靶基因的表达谱分析。细胞内Notch信号传导的破坏-通过靶向N 0 TCH 1的RNA干扰遗传地或通过γ分泌酶抑制剂GSI-18靶向N 0 TCH 1的RNA干扰遗传地，用于评估胰腺癌起始和维持中Notch信号传导的需要。在绝大多数胰腺癌细胞系中可检测到Notch配体转录物的显著过表达，最显著的是JAGGED 2（18/20例; 90%）和DLL 4（10/20例; 50%）。在两个细胞系中，观察到DLL 3基因座的基因组扩增，反映了DLL 3转录物的过表达。相反，没有观察到NOTCH 1或NOTCH 2的编码区突变。Notch信号传导的遗传和药理学抑制减轻了胰腺癌细胞中的锚定非依赖性生长，证实了持续的Notch活化是胰腺癌维持的要求。此外，用GSI-18短暂预处理胰腺癌细胞导致肿瘤起始醛脱氢酶（ALDH）表达亚群的比例耗尽，并且与体外集落形成和体内异种移植物植入的抑制相关，强调了胰腺癌起始中对Notch依赖性ALDH表达细胞的需要。我们的研究证实，在胰腺癌中Notch激活几乎总是配体依赖性的，并且抑制Notch信号传导是这种恶性肿瘤中有希望的治疗策略。
Aberrant activation of the Notch signaling pathway is commonly observed in human pancreatic cancer, although the mechanisms for this activation have not been elucidated. A panel of 20 human pancreatic cancer cell lines was profiled for the expression of Notch pathway related ligands, receptors and target genes. Disruption of intracellular Notch signaling – either genetically by RNA interference targeting NOTCH1 or pharmacologically by means of the gamma secretase inhibitor GSI-18, was used for assessing requirement of Notch signaling in pancreatic cancer initiation and maintenance. Striking overexpression of Notch ligand transcripts was detectable in the vast majority of pancreatic cancer cell lines, most prominently, JAGGED2 (18/20 cases; 90%) and DLL4 (10/20 cases; 50%). In two cell lines, genomic amplification of the DLL3 locus was observed, mirrored by overexpression of DLL3 transcripts. In contrast, coding region mutations of NOTCH1 or NOTCH2 were not observed. Genetic and pharmacological inhibition of Notch signaling mitigated anchorage independent growth in pancreatic cancer cells, confirming that sustained Notch activation is a requirement for pancreatic cancer maintenance. Further, transient pre-treatment of pancreatic cancer cells with GSI-18 resulted in depletion in the proportion of tumor-initiating aldehyde dehydrogenase (ALDH)-expressing subpopulation, and was associated with inhibition of colony formation in vitro and xenograft engraftment in vivo, underscoring a requirement for the Notch-dependent ALDH-expressing cells in pancreatic cancer initiation. Our studies confirm that Notch activation is almost always ligand-dependent in pancreatic cancer, and inhibition of Notch signaling is a promising therapeutic strategy in this malignancy.