CD73 promotes glioblastoma pathogenesis and enhances its chemoresistance via A adenosine receptor signaling.

Glioblastoma (GB) is one of the deadliest brain cancers to afflict humans, and it has a very poor survival rate even with treatment. The extracellular adenosine-generating enzyme CD73 is involved in many cellular functions that can be usurped by tumors, including cell adhesion, proliferation, invasion, and angiogenesis. We set out to determine the role of CD73 in GB pathogenesis. To do this, we established a unique GB mouse model (CD73-FLK) in which we spatially expressed CD73 on endothelial cells in CD73(-/-) mice. This allowed us to elucidate the mechanism of host CD73 versus GB-expressed CD73 by comparing GB pathogenesis in WT, CD73(-/-) and CD73-FLK mice. GB in CD73(-/-) mice had decreased tumor size, decreased tumor vessel density, and reduced tumor invasiveness compared with GB in WT mice. Interestingly, GBs in CD73-FLK mice were much more invasive and caused complete distortion of the brain morphology. We showed a 20-fold upregulation of A(2B) AR on GB compared with sham, and its activation induced matrix metalloproteinase-2, which enhanced GB pathogenesis. Inhibition of A(2B) AR signaling decreased multidrug resistance transporter protein expression, including permeability glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). Further, we showed that blockade of A(2B) AR signaling potently increased GB cell death induced by the chemotherapeutic drug temozolomide. Together, these fmdings suggest that CD73 and A(2B) AR play a multifaceted role in GB pathogenesis and progress ion and that targeting the CD73-A(2B) AR axis can benefit GB patients and inform new approaches for therapy to treat GB patients.