Inhibition of γ-Secretase Activity Inhibits Tumor Progression in a Mouse Model of Pancreatic Ductal Adenocarcinoma

被引：143

作者：

Plentz, Ruben ^{[1
]}

Park, Ji-Sun ^{[1
]}

Rhim, Andrew D. ^{[2
,3
]}

Abravanel, Daniel ^{[2
,3
]}

Hezel, Aram F. ^{[1
]}

Sharma, Sreenath V. ^{[1
,4
]}

Gurumurthy, Sushma ^{[1
]}

Deshpande, Vikram ^{[5
]}

Kenific, Candia ^{[6
]}

Settleman, Jeffrey ^{[1
,4
]}

Majumder, Pradip K. ^{[7
]}

Stanger, Ben Z. ^{[2
,3
]}

Bardeesy, Nabeel ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Canc Ctr, Boston, MA 02114 USA

[2] Univ Penn, Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USA

[3] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA

[4] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Therapeut, Boston, MA 02114 USA

[5] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[6] Merck Res Labs, Dept Neuropharmacol, Boston, MA USA

[7] Merck Res Labs, Dept Oncol Pharmacol, Boston, MA USA

来源：

GASTROENTEROLOGY | 2009年 / 136卷 / 05期

关键词：

CELL EXPANSION; ACINAR-CELLS; NOTCH; CANCER; GROWTH; ACTIVATION; DIFFERENTIATION; INDUCTION; FATE; RAS;

D O I：

10.1053/j.gastro.2009.01.008

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background & Aim: 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. Methods: 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). Results: 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 tumorderived 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, chi(2) test; compared with mice exposed to vehicle). Conclusions: These results suggest that Notch signaling is required for PDAC progression. Pharmacologic targeting of this pathway offers therapeutic potential in this treatment-refractory malignancy.

引用

页码：1741 / 1749

页数：9

共 50 条

[11] VGF-Derived TLQP-21 Ameliorates Tumor Progression, Pain, and Depression-Like Behaviors in an Orthotopic Mouse Model of Pancreatic Ductal Adenocarcinoma [J].

Huang, Shuying ;

Xia, Pei ;

Chen, Qiuyi ;

Zeng, Yixiu ;

Cheng, Xin ;

Cao, Qianyi ;

Cai, Wenbao ;

Yang, Yuying ;

Ouyang, Yang ;

Wang, Xinyu ;

Li, Yiyi ;

Chen, Jun ;

Lin, Wei-Jye ;

Ye, Xiaojing .

FASEB JOURNAL, 2025, 39 (14)

[12] Mouse Models of Pancreatic Ductal Adenocarcinoma [J].

Ponz-Sarvise, Mariano ;

Tuveson, David A. ;

Yu, Kenneth H. .

HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA, 2015, 29 (04) :609-+

[13] Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression [J].

Laklai, Hanane ;

Miroshnikova, Yekaterina A. ;

Pickup, Michael W. ;

Collisson, Eric A. ;

Kim, Grace E. ;

Barrett, Alex S. ;

Hill, Ryan C. ;

Lakins, Johnathon N. ;

Schlaepfer, David D. ;

Mouw, Janna K. ;

LeBleu, Valerie S. ;

Roy, Nilotpal ;

Novitskiy, Sergey V. ;

Johansen, Julia S. ;

Poli, Valeria ;

Kalluri, Raghu ;

Iacobuzio-Donahue, Christine A. ;

Wood, Laura D. ;

Hebrok, Matthias ;

Hansen, Kirk ;

Moses, Harold L. ;

Weaver, Valerie M. .

NATURE MEDICINE, 2016, 22 (05) :497-505

[14] A Biomimetic Tumor Model of Heterogeneous Invasion in Pancreatic Ductal Adenocarcinoma [J].

Bradney, Michael J. ;

Venis, Stephanie M. ;

Yang, Yi ;

Konieczny, Stephen F. ;

Han, Bumsoo .

SMALL, 2020, 16 (10)

[15] Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model [J].

Dhar, Animesh ;

Mehta, Smita ;

Dhar, Gopal ;

Dhar, Kakali ;

Banerjee, Snigdha ;

Van Veldhuizen, Peter ;

Campbell, Donald R. ;

Banerjee, Sushanta K. .

MOLECULAR CANCER THERAPEUTICS, 2009, 8 (02) :315-323

[16] Controversy on the time to progression of pancreatic ductal adenocarcinoma [J].

Gallmeier, Eike ;

Hernaez, Ruben ;

Gress, Thomas M. .

GUT, 2015, 64 (11) :1676-1677

[17] The Anti-Tumor Activity of Afatinib in Pancreatic Ductal Adenocarcinoma Cells [J].

Ye, Zhenyu ;

Li, Yecheng ;

Xie, Jiaming ;

Feng, Zhenyu ;

Yang, Xiaodong ;

Wu, Yong ;

Zhao, Kui ;

Pu, Yuwei ;

Xu, Xiangrong ;

Zhu, Zhaobi ;

Li, Wei ;

Pan, Jun ;

Chen, Wei ;

Xing, Chungen .

ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, 2020, 20 (12) :1447-1458

[18] SRC-3 inhibition blocks tumor growth of pancreatic ductal adenocarcinoma [J].

Song, Xianzhou ;

Chen, Hui ;

Zhang, Chengwei ;

Yu, Yang ;

Chen, Zhongyuan ;

Liang, Han ;

Van Buren, George, II ;

McElhany, Amy L. ;

Fisher, William E. ;

Lonard, David M. ;

O'Malley, Bert W. ;

Wang, Jin .

CANCER LETTERS, 2019, 442 :310-319

[19] A mouse model for pain and neuroplastic changes associated with pancreatic ductal adenocarcinoma [J].

Selvaraj, Deepitha ;

Hirth, Michael ;

Gandla, Jagadeesh ;

Kuner, Rohini .

PAIN, 2017, 158 (08) :1609-1621

[20] ID1 marks the tumorigenesis of pancreatic ductal adenocarcinoma in mouse and human [J].

Tang, Yuanxin ;

Zhang, Sheng ;

Li, Jiazi ;

Wu, Chunli ;

Fan, Qing .

SCIENTIFIC REPORTS, 2022, 12 (01)

← 1 2 3 4 5 →