| 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-b-induced epithelialmesenchymal 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-b enhanced metastasis of mammary tumors, induced EMT, and elevated PDGFR signaling. Finally, expression of PDGFRa and -b 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. |
| Keywords: |
signal transduction; platelet derived growth factor; controlled study; cancer growth; nonhuman; antineoplastic agents; animal cell; mouse; animals; mice; imatinib; gene overexpression; receptor, platelet-derived growth factor alpha; stat1 protein; apoptosis; breast cancer; transforming growth factor beta; cell differentiation; cancer cell culture; enzyme activation; cell line, tumor; platelet derived growth factor receptor; pyrimidines; breast neoplasms; phosphatidylinositol 3 kinase; transgenic mouse; mice, transgenic; protein kinase inhibitors; correlation analysis; recombinant fusion proteins; mice, nude; carcinogenicity; 1-phosphatidylinositol 3-kinase; neoplasm metastasis; autocrine effect; epithelial cells; autocrine communication; ras protein; piperazines; ras proteins; mouse strain; breast metastasis; mesoderm; mesenchyme; mammary neoplasms, experimental; receptor, platelet-derived growth factor beta; mouse mammary tumor oncovirus; mammary tumor virus, mouse
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