Abstract
Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and propagating cells we used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma. We found that SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithramycin (MTM) analog (mithralog) with enhanced anti-tumor activity and highly improved safety. EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPα. SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to the chemotherapeutic drug doxorubicin, repressed the expression of many genes responsible for the TIC/CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFκB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. These data suggest that EC-8042 could constitute an effective treatment against both TIC and CSC subpopulations in sarcoma.
Highlights
Sarcomas often show a limited clinical response to cytotoxic drugs which still remain as the most utilized agents for generalized treatment of soft tissue sarcomas [1]
We have previously developed and characterized sarcoma models using human bone marrow-derived MSCs (hBMSCs) sequentially mutated with up to 5 oncogenic events
Immunohistochemical analysis showed a highly increased expression of P16-INK4A, a key regulator of cellular senescence, in EC-8042-treated tumors (Supplementary Figure S7). These results indicate that the in vivo sarcoma growth inhibition induced by EC-8042 is due to the induction of a senescent-state, while the antitumor effects of doxorubicin are mainly caused by the promotion of apoptotic cell death
Summary
Sarcomas often show a limited clinical response to cytotoxic drugs which still remain as the most utilized agents for generalized treatment of soft tissue sarcomas [1]. A hypothesis to explain the resistance of sarcomas to chemotherapy is the existence of drug-resistant CSCs, which are responsible of tumor progression and propagation. These subpopulations of CSCs emerge during tumor evolution from the cell-of-origin or TICs, which are the normal cells that acquire the first cancerpromoting mutations and initiate tumor formation [2]. Many efforts have been undertaken to produce models of sarcomas based on MSCs transformed with relevant oncogenic events This kind of models constitutes unparalleled systems to unravel the mechanisms underlying sarcomagenesis from the cell of www.impactjournals.com/oncotarget origin, to explore the evolution of CSCs subpopulations and to search for specific therapies able to eliminate these populations
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
