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 7

dnP and STI571 (Gleevec) prevent metastasis of EpRas cells in a cell-autonomous fashion.

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dnP and STI571 (Gleevec) prevent metastasis of EpRas cells in a cell-aut...
(A) EpRas cells expressing empty GFP vector (EpRas) or dnP (EpRas-dnP) were injected into the tail veins of nude mice (5 × 105 cells per mouse). Photographs of respective lungs are shown. (B) Mean numbers of lung metastases per lung (3 lungs per cell type) were quantitated by serial sectioning. (C and D) Mixtures of EpRas cells (no GFP) and GFP-expressing EpRas (43% GFP+ cells) or EpRas-GFP-dnP cells (37% GFP+ cells) were injected (5 × 105 cells) into the tail veins of nude mice. After 3 weeks, cells were recultivated from individual lungs and analyzed for GFP by FACS. One day after injection, 1 mouse per group was analyzed for injected cells initially reaching the lungs, yielding 8% (EpRas/EpRas-GFP) and 12% (EpRas/EpRas-GFP-dnP) GFP+ cells. (C) FACS profiles of lung cell cultures from representative mice of the 2 groups. (D) Percentage of GFP+ cells for individual mice. (E) Nude mice were treated or not treated for 6 days with STI571 and tail vein–injected with EpRas cells or CT26 cells (5 × 105 cells per animal) 1 day after start of STI571 treatment. All mice were sacrificed when controls were moribund (~3 weeks), and lungs were photographed. Lung metastases were quantified either by determining mean total lung weights from a total of 6–9 lungs each (F; mean weight ± SD) or by serial sectioning to determine mean numbers of metastases per lung (G; mean ± SD from 3 lungs total).