CD73 Promotes Glioblastoma Pathogenesis and Enhances Its Chemoresistance via A_2BAdenosine Receptor Signaling

Abstract

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 Ϫ/Ϫ mice. This allowed us to elucidate the mechanism of host CD73 versus GB-expressed CD73 by comparing GB pathogenesis in WT, CD73 Ϫ/Ϫ , and CD73-FLK mice. GB in CD73 Ϫ/Ϫ 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 findings suggest that CD73 and A 2B AR play a multifaceted role in GB pathogenesis and progression and that targeting the CD73-A 2B AR axis can benefit GB patients and inform new approaches for therapy to treat GB patients.

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Multiple studies using syngeneic and/or spontaneous tumor models show tumor growth and metastasis is significantly reduced by genetic deletion or pharmacological blockade of CD73 or A2AR; this effect is largely due to restoring antitumor immunity (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(67)(68)(69)(70). These mice also benefit from increased chemotherapy sensitivity (36,71) and reduced angiogenesis (71,72). In line with these studies, many human tumors overexpress CD73 and associates with poor prognosis (36,(73)(74)(75)(76)(77)(78).…”

High Adenosine Extracellular Levels Induce Glioblastoma Aggressive Traits Modulating the Mesenchymal Stromal Cell Secretome

“…Studies on the nucleoside influence on different tumor cell lines and on the other cells of the TME are still conflicting. Some literature data indicate that ADO plays a prominent role in multiple areas of glioma pathogenesis, including promoting cell growth, angiogenesis and invasiveness [ 33 , 34 , 35 ]. Our results demonstrate that the chronic exposure of up to micromolar extracellular ADO concentration does not significantly modify glioblastoma cell proliferation.…”

“…Our results demonstrate that the chronic exposure of up to micromolar extracellular ADO concentration does not significantly modify glioblastoma cell proliferation. The reduction of ADO production by the CD73 inhibition causes the decrease of glioma proliferation in vitro and in vivo [ 33 , 76 ]. Similarly, a single administration of 100 µM ADO concentration enhances the human U138MG glioma cell proliferation in vitro [ 77 ].…”

“…Emerging evidences report the prominent role of adenosinergic signaling in multiple aspects of GBM aggressiveness, including GBM growth, angiogenesis and invasiveness [ 33 , 34 , 35 , 36 ]. The inhibition of CD73 activity and the pharmacological blockade of ARs decreased cell adhesion to the extracellular matrix of U138MG glioblastoma cells, demonstrating the pivotal role played by extracellular adenosine in controlling aggressive traits of GBM [ 37 , 38 ].…”

CD73 positive adipose derived mesenchymal stem cells enhance cardiac repair with experimental myocardial infarction by promoting angiogenesis

“…CD73 hydrolyzes 5'-adenosine monophosphate (AMP) into adenosine and phosphoric acid and then interacts with adenosine receptors on the cell surface to regulate many biological effects [26]. CD73 also has non-hydrolase function, which is also a signal and adhesion molecule that regulate cell-extracellular matrix interaction [27]. However, our understanding of the role of CD73 in the biology of MSCs is rather limited.…”