Autocrine PDGFR signaling promotes mammary cancer metastasis

被引:282
作者
Jechlinger, Martin
Sommer, Andreas
Moriggl, Richard
Seither, Peter
Kraut, Norbert
Capodiecci, Paola
Donovan, Michael
Cordon-Cardo, Carlos
Beug, Hartmut
Gruenert, Stefan
机构
[1] Res Inst Mol Pathol, A-1030 Vienna, Austria
[2] Boehringer Ingelheim KG, Gen Grp, Biberach, Germany
[3] Boehringer Ingn Austria GmbH, Dept Lead Discovery, Vienna, Austria
[4] Aureon Labs, New York, NY USA
[5] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA
关键词
D O I
10.1172/JCI24652
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Metastasis is the major cause of cancer morbidity, but strategies for direct interference with invasion processes are lacking. Dedifferentiated, late-stage tumor cells secrete multiple factors that represent attractive targets for therapeutic intervention. Here we show that metastatic potential of oncogenic mammary epithelial cells requires an autocrine PDGF/PDGFR loop, which is established as a consequence of TGF-beta-induced epithelial-mesenchymal transition (EMT), a faithful in vitro correlate of metastasis. The cooperation of autocrine PDGFR signaling with oncogenic Ras hyperactivates PI3K and is required for survival during EMT. Autocrine PDGFR signaling also contributes to maintenance of EMT, possibly through activation of STAT1 and other distinct pathways. Inhibition of PDGFR signaling interfered with EMT and caused apoptosis in murine and human mammary carcinoma cell lines. Consequently, overexpression of a dominant-negative PDGFR or application of the established cancer drug STI571 interfered with experimental metastasis in mice. Similarly, in mouse mammary tumor virus-Neu (MMTV-Neu) transgenic mice, TGF-beta enhanced metastasis of mammary tumors, induced EMT, and elevated PDGFR signaling. Finally, expression of PDGFR alpha and -beta correlated with invasive behavior in human mammary carcinomas. Thus, autocrine PDGFR signaling plays an essential role during cancer progression, suggesting a novel application of STI571 to therapeutically interfere with metastasis.
引用
收藏
页码:1561 / 1570
页数:10
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