TY - JOUR
AR - COR-2019-1-106
TI - Hypoxia induces lineage modulation of Ewing?s sarcoma tumor cells into EWS-FLI-1+ vascular pericytes
AU - Eugenie S. , Kleinerman
AU - Yuanzheng , Yang
AU - Zhichao , Zhou
JO - Clinical Oncology and Research
PY - 2019
DA - Fri 29, Mar 2019
SN - 2613-4942
DO - http://dx.doi.org/10.31487/j.COR.2019.01.006
UR - https://www.sciencerepository.org/hypoxia-induces-lineage-modulation-of-Ewings-sarcoma-tumor-cells-into-ews-fli-1-vascular-pericytes_COR-2019-1-106 
KW - Hypoxia, lineage modulation, Ewing’s sarcoma, Pericytes, stem cell
AB - Background: Vasculogenesis and angiogenesis are required for expansion of the Ewing’s sarcoma
vasculature. Our previous studies demonstrated that pericytes and DLL4 Notch signaling pathway are
critical to the formation of new tumor vessels, but how tumor microenvironment regulates tumor vasculature
is not well understood.
Methods: Using unique EWS-FLI-1 fusion protein as tumor hallmark to determine tumor cell phenotype
in pericytes. Investigate that hypoxia induced Ewing’s sarcoma (ES) tumor cells express stem cell
characteristics and transdifferentiated into pericytes. Identify pericyte property in ES tumor cells by
transfection of special Desmin promoter-driven GFP vector.
Results: We discovered that a subset of tumor vascular pericytes expressed EWS-FLI-1 in Ewing’s sarcoma
patient tumor samples and xenograft mouse tumor vessels suggesting that these pericytes originated from
Ewing’s sarcoma tumor cells. These EWS-FLI-1
+ pericytes were in hypoxic areas. Culturing TC71 and
A4573 Ewing’s sarcoma cells under hypoxic condition induced sphere formation, and up-regulation of stem
cell and pericyte markers. This hypoxia-induced lineage modulation was in the CD133+ tumor cells,
enhanced by DLL4 and inhibited by a ɣ-secretase inhibitor. To confirm that Ewing’s tumor cells
transdifferentiated into pericytes, TC71 and A4573 cells were transfected with a Desmin promoter-driven
GFP vector. Culturing these transfected cells under hypoxic condition resulted in GFP expression
confirming differentiation into a pericyte lineage. Injecting transfected cells into mice resulted in a subset
of tumor vascular pericytes that expressed GFP.
Conclusion: This is the first to demonstrate that hypoxic tumor microenvironment triggers Ewing’s sarcoma
tumor cells transdifferentiated into pericytes that contribute to tumor vessel formation. These novel findings
suggest that an additional therapeutic approach may inhibit tumor vascular expansion, tumor growth and
metastasis.