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PMID: 16741576 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Autocrine PDGFR signaling promotes mammary cancer metastasis.

The Journal of clinical investigation ·Vol. 116 ·No. 6 ·2006-06-00 ·Pages 1561-70

Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, Donovan M, Cordon-Cardo C, Beug H, Grünert S

Abstract

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 PDGFRalpha 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.

MeSH Terms
Animals Antineoplastic Agents/metabolism Apoptosis Autocrine Communication Benzamides Breast Neoplasms/metabolism,pathology Cell Differentiation/physiology Cell Line, Tumor Enzyme Activation Epithelial Cells/cytology,physiology Female Humans Imatinib Mesylate Mammary Neoplasms, Experimental/metabolism,pathology Mammary Tumor Virus, Mouse/genetics,metabolism Mesoderm/physiology Mice Mice, Nude Mice, Transgenic Neoplasm Metastasis Phosphatidylinositol 3-Kinases/metabolism Piperazines/metabolism Protein Kinase Inhibitors/metabolism Pyrimidines/metabolism Receptor, Platelet-Derived Growth Factor alpha/metabolism Receptor, Platelet-Derived Growth Factor beta/metabolism Recombinant Fusion Proteins/genetics,metabolism Signal Transduction/physiology Transforming Growth Factor beta/genetics,metabolism ras Proteins/metabolism
Chemicals
Antineoplastic Agents Benzamides Piperazines Protein Kinase Inhibitors Pyrimidines Recombinant Fusion Proteins Transforming Growth Factor beta Imatinib Mesylate Phosphatidylinositol 3-Kinases Receptor, Platelet-Derived Growth Factor alpha Receptor, Platelet-Derived Growth Factor beta ras Proteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Jechlinger Martin
Research Institute for Molecular Pathology, Vienna, Austria.
Sommer Andreas
Moriggl Richard
Seither Peter
Kraut Norbert
Capodiecci Paola
Donovan Michael
Cordon-Cardo Carlos
Beug Hartmut
Grünert Stefan
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI24652
Published
2006-06-00
Pages
1561-70
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1469776
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI24652 PMC Full Text View journal details
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