EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis

被引：442

作者：

Ardito, Christine M. ^{[1
]}

Gruener, Barbara M. ^{[2
]}

Takeuchi, Kenneth K. ^{[3
]}

Lubeseder-Martellato, Clara ^{[2
]}

Teichmann, Nicole ^{[2
]}

Mazur, Pawel K. ^{[4
,5
]}

DelGiorno, Kathleen E. ^{[3
]}

Carpenter, Eileen S. ^{[1
]}

Halbrook, Christopher J. ^{[1
,3
]}

Hall, Jason C. ^{[1
,3
]}

Pal, Debjani ^{[1
]}

Briel, Thomas ^{[2
]}

Herner, Alexander ^{[2
]}

Trajkovic-Arsic, Marija ^{[2
]}

Sipos, Bence ^{[6
]}

Liou, Geou-Yarh ^{[3
]}

Storz, Peter ^{[3
]}

Murray, Nicole R. ^{[3
]}

Threadgill, David W. ^{[7
]}

Sibilia, Maria ^{[8
]}

Washington, M. Kay ^{[9
]}

Wilson, Carole L. ^{[10
]}

Schmid, Roland M. ^{[2
]}

Raines, Elaine W. ^{[10
]}

Crawford, Howard C. ^{[1
,3
,11
]}

Siveke, Jens T. ^{[2
]}

机构：

[1] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA

[2] Tech Univ Munich, Klinikum Rechts Isar, Med Klin 2, D-81675 Munich, Germany

[3] Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA

[4] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[6] Univ Tubingen Hosp, Dept Pathol, D-72076 Tubingen, Germany

[7] N Carolina State Univ, Dept Genet, Raleigh, NC 27599 USA

[8] Med Univ Vienna, Ctr Comprehens Canc, Inst Canc Res, Dept Med 1, A-1090 Vienna, Austria

[9] Vanderbilt Univ, Dept Pathol, Med Ctr, Nashville, TN 37232 USA

[10] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[11] Vet Affairs Med Ctr, Dept Res, Northport, NY 11768 USA

来源：

CANCER CELL | 2012年 / 22卷 / 03期

基金：

奥地利科学基金会; 美国国家卫生研究院;

关键词：

EPIDERMAL-GROWTH-FACTOR; ONCOGENIC K-RAS; IN-VIVO; DUCTAL ADENOCARCINOMA; TGF-ALPHA; CANCER; EXPRESSION; CELLS; ACTIVATION; INDUCTION;

D O I：

10.1016/j.ccr.2012.07.024

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.

引用

页码：304 / 317

页数：14

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