Abstract 2899: Hypoxia-inducible factor 1-α maintains sarcoma stem-like cells in hypoxic regions of tumors and promotes migration and invasion via upregulation of platelet-derived growth factor receptors
Authors: Chang Kevin K. , Yoon Changhwan , Yoon Sam S. 
Published: July 2017

Abstract
Introduction: Sarcomas often thrive in hypoxic conditions to proliferate and metastasize. To survive in such an environment, sarcomas upregulate hypoxia inducible factor-1α (HIF-1α), which enhances the transcription of over 150 genes mediating tumor metabolism, angiogenesis, and metastasis. HIF-1α may be important for the maintenance of a subset of tumor cells referred to as “sarcoma stem-like cells” or SSCs. Platelet-derived growth factor receptor (PDGFR) is important in mesenchymal biology and may be a potential target of HIF-1α.
Methods: Three human sarcoma cell lines were examined: HT1080 (fibrosarcoma), SK-LMS-1 (leiomyosarcoma), and DDLS8817 (dedifferentiated liposarcoma). Cell lines were grown as spheroids on ultra-low attachment dishes to enrich for SSCs. The roles of HIF-1α and PDGFR-α/β in promoting SSC phenotypes, such as migratory/invasive capacity, were assessed via several in vitro assays under hypoxic conditions.
Results: Sarcoma cell lines grown as spheroids had increased levels of HIF-1α and increased phosphorylation of PDGFR-α/β as compared to when grown as monolayers; these effects were even more pronounced when sarcoma spheroids were grown under hypoxic conditions. Hypoxic conditions also increased migratory and invasive capacity in spheroid cells by 65-73% as compared to normoxic conditions. HIF-1α knockdown using shRNA in the three cell lines decreased expression of self-renewal proteins and decreased spheroid formation by 67-80%. HIF-1α knockdown decreased expression of epithelial-mesenchymal transition (EMT) transcription factors and reduced migratory and invasive capacity by 80-87% under normoxic conditions and 85-87% under hypoxic conditions. Phosphorylation of PDGFR-α/β was decreased in sarcoma cell lines following HIF-1α knockdown under normoxic and hypoxic conditions. PDGFR-α/β inhibition with imatinib reversed chemotherapy resistance in normally resistant SSCs, and treatment of HT1080 xenografts with doxorubicin chemotherapy and imatinib reduced tumor formation by 85% as compared to control and by 77% as compared to chemotherapy alone.
Conclusions: The HIF-1α/PDGFR axis supports the maintenance of SSCs, especially under hypoxic conditions, and promotes SSC phenotypes such as migratory/invasive capacity and chemotherapy resistance. Combining chemotherapy with PDGFR-α/β inhibition may be a promising strategy to reverse chemotherapy resistance and prevent metastasis in sarcomas.
Note: This abstract was not presented at the meeting.
Citation Format: Kevin K. Chang, Changhwan Yoon, Sam S. Yoon. Hypoxia-inducible factor 1-α maintains sarcoma stem-like cells in hypoxic regions of tumors and promotes migration and invasion via upregulation of platelet-derived growth factor receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2899. doi:10.1158/1538-7445.AM2017-2899