Plentz Ruben, Park Ji-Sun, Rhim Andrew D, Abravanel Daniel, Hezel Aram F, Sharma Sreenath V, Gurumurthy Sushma, Deshpande Vikram, Kenific Candia, Settleman Jeffrey, Majumder Pradip K, Stanger Ben Z, Bardeesy Nabeel
Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
Gastroenterology. 2009 May;136(5):1741-9.e6. doi: 10.1053/j.gastro.2009.01.008. Epub 2009 Jan 14.
BACKGROUND & AIMS: The Notch signaling pathway is required for the expansion of undifferentiated pancreatic progenitor cells during embryonic development and has been implicated in the progression of pancreatic ductal adenocarcinoma (PDAC). The interaction of Notch ligands with their receptors promotes a gamma-secretase-dependent cleavage of the Notch receptor and release of the Notch intracellular domain, which translocates to the nucleus and activates transcription. We investigated the role of this pathway in PDAC progression.
We tested the effects of a gamma-secretase inhibitor (GSI) that blocks Notch signaling in PDAC cell lines and a genetically engineered mouse model of PDAC (Kras p53 L/+ mice).
Notch signaling was activated in PDAC precursors and advanced tumors. The GSI inhibited the growth of premalignant pancreatic duct-derived cells in a Notch-dependent manner. Additionally, in a panel of over 400 human solid tumor-derived cell lines, PDAC cells, as a group, were more sensitive to the GSI than any other tumor type. Finally, the GSI completely inhibited tumor development in the genetically engineered model of invasive PDAC (P < .005, chi2 test; compared with mice exposed to vehicle).
These results suggest that Notch signaling is required for PDAC progression. Pharmacologic targeting of this pathway offers therapeutic potential in this treatment-refractory malignancy.
Notch信号通路在胚胎发育过程中对未分化胰腺祖细胞的扩增是必需的，并且与胰腺导管腺癌（PDAC）的进展有关。Notch配体与其受体的相互作用促进了Notch受体的γ-分泌酶依赖性切割以及Notch细胞内结构域的释放，该结构域易位至细胞核并激活转录。我们研究了该通路在PDAC进展中的作用。
我们测试了一种γ-分泌酶抑制剂（GSI）在PDAC细胞系以及一种基因工程化的PDAC小鼠模型（Kras p53 L/+小鼠）中阻断Notch信号的作用。
Notch信号在PDAC前体和进展期肿瘤中被激活。GSI以Notch依赖性方式抑制了癌前胰腺导管来源细胞的生长。此外，在一组超过400种人类实体瘤来源的细胞系中，PDAC细胞作为一个整体，比任何其他肿瘤类型对GSI更敏感。最后，GSI在侵袭性PDAC的基因工程模型中完全抑制了肿瘤发展（P <.005，卡方检验；与接受载体处理的小鼠相比）。
这些结果表明Notch信号是PDAC进展所必需的。对该通路进行药物靶向治疗在这种难治性恶性肿瘤中具有治疗潜力。
