Mullendore Michael E, Koorstra Jan-Bart, Li Yue-Ming, Offerhaus G Johan, Fan Xing, Henderson Clark M, Matsui William, Eberhart Charles G, Maitra Anirban, Feldmann Georg
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Clin Cancer Res. 2009 Apr 1;15(7):2291-301. doi: 10.1158/1078-0432.CCR-08-2004. Epub 2009 Mar 3.
Aberrant activation of the Notch signaling pathway is commonly observed in human pancreatic cancer, although the mechanism(s) for this activation has 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 of 20 cases, 90%) and DLL4 (10 of 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 pharmacologic 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 pretreatment of pancreatic cancer cells with GSI-18 resulted in depletion in the proportion of tumor-initiating aldehyde dehydrogenase-expressing subpopulation and was associated with inhibition of colony formation in vitro and xenograft engraftment in vivo, underscoring a requirement for the Notch-dependent aldehyde dehydrogenase-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.
尽管尚未阐明Notch信号通路激活的机制，但在人类胰腺癌中普遍观察到该信号通路的异常激活。
对一组20种人类胰腺癌细胞系进行Notch信号通路相关配体、受体和靶基因表达分析。通过靶向NOTCH1的RNA干扰进行基因干扰，或使用γ-分泌酶抑制剂GSI-18进行药理学干扰，以破坏细胞内Notch信号，用于评估Notch信号在胰腺癌起始和维持中的需求。
在绝大多数胰腺癌细胞系中可检测到Notch配体转录本的显著过表达，最明显的是JAGGED2（20例中的18例，90%）和DLL4（20例中的10例，50%）。在两个细胞系中，观察到DLL3基因座的基因组扩增，同时伴有DLL3转录本的过表达。相比之下，未观察到NOTCH1或NOTCH2的编码区突变。Notch信号的基因和药理学抑制减轻了胰腺癌细胞的非锚定依赖性生长，证实持续的Notch激活是胰腺癌维持所必需的。此外，用GSI-18对胰腺癌细胞进行短暂预处理导致表达醛脱氢酶的肿瘤起始亚群比例减少，并与体外集落形成抑制和体内异种移植植入抑制相关，强调了表达Notch依赖性醛脱氢酶的细胞在胰腺癌起始中的需求。
我们的研究证实，在胰腺癌中Notch激活几乎总是依赖配体的，并且抑制Notch信号是这种恶性肿瘤中有前景的治疗策略。
