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 49 条

[1] Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma [J].

Aguirre, AJ ;

Bardeesy, N ;

Sinha, M ;

Lopez, L ;

Tuveson, DA ;

Horner, J ;

Redston, MS ;

DePinho, RA .

GENES & DEVELOPMENT, 2003, 17 (24) :3112-3126

[2] Notch signalling controls pancreatic cell differentiation [J].

Apelqvist, Å ;

Li, H ;

Sommer, L ;

Beatus, P ;

Anderson, DJ ;

Honjo, T ;

de Angelis, MH ;

Lendahl, U ;

Edlund, H .

NATURE, 1999, 400 (6747) :877-881

[3] Notch signaling: Cell fate control and signal integration in development [J].

Artavanis-Tsakonas, S ;

Rand, MD ;

Lake, RJ .

SCIENCE, 1999, 284 (5415) :770-776

[4] Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse [J].

Bardeesy, N ;

Aguirre, AJ ;

Chu, GC ;

Cheng, KH ;

Lopez, LV ;

Hezel, AF ;

Feng, B ;

Brennan, C ;

Weissleder, R ;

Mahmood, U ;

Hanahan, D ;

Redston, MS ;

Chin, L ;

DePinho, RA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (15) :5947-5952

[5] The Notch signaling pathway is related to neurovascular progression of pancreatic cancer [J].

Büchler, P ;

Gazdhar, A ;

Schubert, M ;

Giese, N ;

Reber, HA ;

Hines, OJ ;

Giese, T ;

Ceyhan, GO ;

Müller, M ;

Büchler, MW ;

Friess, H .

ANNALS OF SURGERY, 2005, 242 (06) :791-801

[6] Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial [J].

Burris, HA ;

Moore, MJ ;

Andersen, J ;

Green, MR ;

Rothenberg, ML ;

Madiano, MR ;

Cripps, MC ;

Portenoy, RK ;

Storniolo, AM ;

Tarassoff, P ;

Nelson, R ;

Dorr, FA ;

Stephens, CD ;

VanHoff, DD .

JOURNAL OF CLINICAL ONCOLOGY, 1997, 15 (06) :2403-2413

[7] Ras family signaling - Therapeutic targeting [J].

Cox, AD ;

Der, CJ .

CANCER BIOLOGY & THERAPY, 2002, 1 (06) :599-606

[8] Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance [J].

Duncan, AW ;

Rattis, FM ;

DiMascio, LN ;

Congdon, KL ;

Pazianos, G ;

Zhao, C ;

Yoon, K ;

Cook, JM ;

Willert, K ;

Gaiano, N ;

Reya, T .

NATURE IMMUNOLOGY, 2005, 6 (03) :314-322

[9] Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas [J].

Esni, F ;

Ghosh, B ;

Biankin, AV ;

Lin, JW ;

Albert, MA ;

Yu, XB ;

MacDonald, RJ ;

Civin, CI ;

Real, FX ;

Pack, MA ;

Ball, DW ;

Leach, SD .

DEVELOPMENT, 2004, 131 (17) :4213-4224

[10] Biogenesis and metabolism of Alzheimer's disease Aβ amyloid peptides [J].

Evin, G ;

Weidemann, A .

PEPTIDES, 2002, 23 (07) :1285-1297

← 1 2 3 4 5 →