Platelet-derived growth factor receptor-? and -? promote cancer stem cell phenotypes in sarcomas.

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 ? and ? (PDGFR-?/?) play an important role in the maintenance of mesenchymal stem cells. Here we examine the role of PDGFR-?/? in sarcoma CSCs. PDGFR-?/? activity and the effects of PDGFR-?/? inhibition were examined in 3 human sarcoma cell lines using in vitro assays and mouse xenograft models. In all three cell lines, PDGFR-?/? 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-?/? 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-?/? 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-?/? activity is upregulated in sarcoma CSCs and promote CSC phenotypes including migration, invasion, and chemotherapy resistance. Thus, the PDGFR-?/? pathway represents a new potential therapeutic target to reduce metastatic potential and increase chemosensitivity.

SUBMITTER: Chang KK 

PROVIDER: S-EPMC6006341 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature