Platelet-derived growth factor receptor-α and -β promote cancer stem cell phenotypes in sarcomas

Sarcomas are malignant tumors derived from mesenchymal tissues and may harbor a subset of cells with cancer stemlike cell (CSC) properties. Platelet-derived growth factor receptors alpha and beta (PDGFR-alpha/beta play an important role in the maintenance of mesenchymal stem cells. Here we examine the role of PDGFR-alpha/beta in sarcoma CSCs. PDGFR-alpha/beta activity and the effects of PDGFR-alpha/beta inhibition were examined in 3 human sarcoma cell lines using in vitro assays and mouse xenograft models. In all three cell lines, PDGFR-alpha/beta activity was significantly higher in cells grown as spheroids (to enrich for CSCs) and in cells sorted for CD133 expression (a marker of sarcoma CSCs). Self-renewal transcription factors Nanog, Oct4, and Slug and epithelial-to-mesenchymal transition (EMT) proteins Snail, Slug, and Zeb1 were also significantly higher in spheroids cells and CD133((+)) cells. Spheroid cells and CD133((+)) cells demonstrated 2.9- to 42-fold greater migration and invasion and resistance to doxorubicin chemotherapy. Inhibition of PDGER-alpha/beta in CSCs using shRNA or pharmacologic inhibitors reduced expression of certain self-renewal and EMT proteins, reduced spheroid formation by 74-82%, reduced migration and invasion by 73-80%, and reversed chemotherapy resistance. In mouse xenograft models, combining PDGFR-alpha/beta inhibition (using shRNA or imatinib) with doxorubicin had a morethan-additive effect in blocking tumor growth, with enhanced apoptosis, especially in CD133((+)) cells. These results indicate that PDGFR-alpha/beta activity is upregulated in sarcoma CSCs and promote CSC phenotypes including migration, invasion, and chemotherapy resistance. Thus, the PDGFR-alpha/beta pathway represents a new potential therapeutic target to reduce metastatic potential and increase chemosensitivity.