Abstract
Sarcomas are malignant tumors derived from mesenchymal tissues and may harbor a subset of cells with cancer stem-like cell (CSC) properties. Platelet-derived growth factor receptors α and β (PDGFR-α/β) play an important role in the maintenance of mesenchymal stem cells. Here we examine the role of PDGFR-α/β in sarcoma CSCs. PDGFR-α/β activity and the effects of PDGFR-α/β inhibition were examined in 3 human sarcoma cell lines using in vitro assays and mouse xenograft models. In all three cell lines, PDGFR-α/β 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 4.2-fold greater migration and invasion and resistance to doxorubicin chemotherapy. Inhibition of PDGFR-α/β 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-α/β inhibition (using shRNA or imatinib) with doxorubicin had a more-than-additive effect in blocking tumor growth, with enhanced apoptosis, especially in CD133(+) cells. These results indicate that PDGFR-α/β activity is upregulated in sarcoma CSCs and promote CSC phenotypes including migration, invasion, and chemotherapy resistance. Thus, the PDGFR-α/β pathway represents a new potential therapeutic target to reduce metastatic potential and increase chemosensitivity.
Highlights
Mesenchymal tissues are derived from the mesoderm and include the musculoskeletal system, circulatory and lymphatic systems, and connective tissues
CD133 is a marker of sarcoma cancer stemlike cell (CSC)
The role of PDGFR signaling in mesenchymal stem cell biology has been well described, and PDGFR-α and PDGFR-β have been shown to be expressed on both sarcoma cells and mesenchymal stromal cells in the tumor microenvironment[22,23]
Summary
Mesenchymal tissues are derived from the mesoderm (i.e., middle layer of the embryo) and include the musculoskeletal system, circulatory and lymphatic systems, and connective tissues. Sarcomas are malignant tumors of mesenchymal tissues. These tumors are diagnosed in over 15,000 people in the United States annually, and are fatal for ~40% of patients due to either locoregional disease or distant metastasis[1]. The treatment of primary tumors typically includes aggressive surgical resection and radiation therapy, but local recurrence remains a significant problem for tumors in difficult locations such as the head and neck, paraspinal region, retroperitoneum, and pelvis. Up to half of patients with large, high-grade sarcomas develop distant metastases, most frequently to the lung[2]. The efficacy of chemotherapy in treating local and distant recurrence is modest at best, and for the minority of patients who do respond, most eventually develop chemotherapy resistance[3]
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