Autocrine PDGFR signaling promotes mammary cancer metastasis
Martin Jechlinger, … , Hartmut Beug, Stefan Grünert
Martin Jechlinger, … , Hartmut Beug, Stefan Grünert
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1561-1570. https://doi.org/10.1172/JCI24652.
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Research Article Oncology

Autocrine PDGFR signaling promotes mammary cancer metastasis

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-β–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-β enhanced metastasis of mammary tumors, induced EMT, and elevated PDGFR signaling. Finally, expression of PDGFRα and -β 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.

Authors

Martin Jechlinger, Andreas Sommer, Richard Moriggl, Peter Seither, Norbert Kraut, Paola Capodiecci, Michael Donovan, Carlos Cordon-Cardo, Hartmut Beug, Stefan Grünert

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Figure 4

Interference with autocrine PDGF signaling in EpRas cells prevents EMT by causing apoptosis.

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Interference with autocrine PDGF signaling in EpRas cells prevents EMT b...
(A) EpRas and EpRasXT cells were treated with PDGF, VEGF (control, VEGFR pathway not altered in EpRasXT cells), PDGF-neutralizing antibodies (α-PDGF-Ab), 2 nonimmune control antibodies (Contr. Ab 1 and 2), the tumor drug STI571, or a specific PDGFR tyrosine kinase inhibitor (PDGFR inh; see Methods). Levels of p-AKT were determined by Western blot analysis. For normalization, blots were stripped and reprobed for total AKT. Signals were quantified by densitometry, normalized to levels of untreated EpRas cells, and shown as histograms. Data from 3 independent experiments are represented as mean ± SD. (B) EpRas cells were seeded into collagen gels and induced or not induced to undergo EMT by addition of TGF-β, in the presence or absence of neutralizing PDGF antibodies (α-PDGF), no immune antibodies (Contr. Ab), or STI571. Cultures were photographed after 7 days. (C) Similar collagen cultures were subjected to in situ TUNEL staining (green) and counterstaining for DNA (red). Lumina of polarized epithelial structures (yellow arrows), spindle-shaped mesenchymal cells (white arrows), and TUNEL-positive nuclei (green arrows) are indicated. Original magnification, ×10 (B) and ×40 (C). (D) Quantification of the data in B (>300 cells from several gel structures were evaluated for TUNEL and DAPI staining).