Recombinant
erythropoietin (EPO) is a
growth factor used in the treatment of
chemotherapy-induced
anemia, but recent studies suggest that EPO may accelerate
cancer growth. Although several
cancers express EPO receptors (EPORs), the mechanism by which EPOR promotes
tumor growth remains poorly understood.
Glioblastomas display a cellular hierarchy of self-renewal and
tumor propagation restricted to
glioma stem cells (GSCs). We find that GSCs express higher levels of EPOR than matched non-stem
glioma cells. Prospective enrichment for EPOR on GSCs increased neurosphere formation, suggesting that EPOR can select for a subset of GSCs with increased self-renewal capacity. Targeting EPOR expression with lentiviral mediated
short hairpin RNA (
shRNA) reduced GSC growth, survival, and neurosphere formation capacity, defining a crucial role for EPOR in GSC maintenance. We further find that STAT3 is an important mediator of EPOR signals in GSCs. EPOR knockdown attenuated the basal activation of STAT3 present in GSCs, and a small molecule inhibitor of STAT3 reduced GSC growth and survival. EPOR signaling was critical for survival in vivo, as targeting EPOR expression decreased GSC tumorigenic potential. Elevated EPOR expression also associated with poor patient outcome. Thus, EPOR on GSCs promotes
tumor growth and may explain the poor survival of
cancer patients treated with EPO.