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 A2B AR on GB compared with
sham, and its activation induced
matrix metalloproteinase-2, which enhanced GB pathogenesis. Inhibition of A2B 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 A2B AR signaling potently increased GB cell death induced by the chemotherapeutic drug
temozolomide. Together, these findings suggest that CD73 and A2B AR play a multifaceted role in GB pathogenesis and progression and that targeting the CD73-A2B AR axis can benefit GB patients and inform new approaches for
therapy to treat GB patients.SIGNIFICANCE STATEMENT
Glioblastoma (GB) is the most devastating
primary brain tumor. GB patients' median survival is 16 months even with treatment. It is critical that we develop prophylaxes to advance GB treatment and improve patient survival. CD73-generated
adenosine has been implicated in
cancer pathogenesis, but its role in GB was not ascertained. Here, we demonstrated that host CD73 plays a prominent role in multiple areas of
glioblastoma pathogenesis, including promoting GB growth, its angiogenesis, and its invasiveness. We found a 20-fold increase in A2B
adenosine receptor (AR) expression on GB compared with
sham, and its inhibition increased GB chemosensitivity to
temozolomide. These findings strongly indicate that blockade or inhibition of CD73 and the A2B AR are prime targets for future GB
therapy.