APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression

被引:255
作者
Janssen, Klaus-Peter
Alberici, Paola
Fsihi, Hafida
Gaspar, Claudia
Breukel, Cor
Franken, Patrick
Rosty, Christophe
Abal, Miguel
El Marjou, Fatima
Smits, Ron
Louvard, Daniel
Fodde, Riccardo
Robine, Sylvie
机构
[1] Inst Curie, CNRS UMR144, F-75248 Paris 05, France
[2] Tech Univ Munich, Klinikum Rechts Isar, D-8000 Munich, Germany
[3] Erasmus UMC, Josephine Nefkens Inst, Dept Pathol, Rotterdam, Netherlands
[4] LUMC, Ctr Human & Clin Genet, Leiden, Netherlands
[5] Inst Curie, Pathol Serv, Paris, France
基金
澳大利亚研究理事会;
关键词
D O I
10.1053/j.gastro.2006.08.011
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Synchronous activation of the Wnt signaling pathway, mostly because of loss of function of the APC tumor suppressor, and of the oncogenic KRAS-signaling pathway is very frequent in colorectal cancer and is associated with poor prognosis. Methods: We have generated a compound transgenic mouse model, KRAS(V12G)/Apc(+/1638N), to recapitulate the human disease and compared it with single transgenic littermates. Results: Compound mutant mice are characterized by a 10-fold increase in tumor multiplicity and by accelerated tumor progression, resulting in strongly enhanced morbidity and mortality. Tumors from compound mutant mice proliferate faster and show decreased levels of apoptosis. Several lines of evidence indicate that the observed increase in tumor multiplicity and malignant transformation is caused by the synergistic activation of Wnt signaling in cells with oncogenic KRAS and loss-of-function Apc mutations. Activated KRAS is known to induce tyrosine phosphorylation of beta-catenin, leading to its release from E-cadherin at the adherens junction. This results in an increased beta-catenin pool in the cytoplasma, its subsequent translocation to the nucleus, and the transcriptional activation of Wnt downstream target genes. Accordingly, intestinal tumors from KRAS(V12G)/AVC(+/1638N) mice show a significant increase in cells with nuclear accumulation of beta-catenin when compared with Apc(+/1638N) animals. Moreover, Apc/KRAS-mutant embryonic stem cells show a significantly enhanced beta-catenin/T-cell factor-mediated transcriptional activation, accompanied by increased beta-catenin nuclear localization. Conclusions: This KRAS-induced increase in Wnt/beta-catenin signaling may enhance the plasticity and self-renewal capacity of the tumor, thus resulting in the drastically augmented tumor multiplicity and malignant behavior in compound mutant animals.
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收藏
页码:1096 / 1109
页数:14
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