Hypoxia induces lineage modulation of Ewing?s sarcoma tumor cells into EWS-FLI-1+ vascular pericytes

Author Info

Eugenie S. Kleinerman Yuanzheng Yang Zhichao Zhou

Corresponding Author

Eugenie S. Kleinerman
Department of Pediatrics, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

A B S T R A C T

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.

Article Info

Article Type

Research Article

Publication history

Received: Tue 12, Feb 2019
Accepted: Thu 07, Mar 2019
Published: Fri 29, Mar 2019

Copyright

© 2023 Eugenie S. Kleinerman. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.COR.2019.01.006