Figure 7.

Possible pathways connecting NTPDase2 overexpression to ADP generation, platelet recruitment, and glioma progression. Overexpression of NTPDase2, due to its preference for ATP over ADP, would strongly favor ADP accumulation in the tumor periphery and vascular interface and consequently induce endothelial cell migration and platelet activation via ADP‐dependent P2Y receptors. Upon activation, platelets release a variety of substances from alpha‐granules, which stimulate angiogenesis, recruitment of immune cells, and tumor proliferation. In our experimental model, clopidogrel, a P2Y₁₂ antagonist and inhibitor of ADP‐mediated platelet activation, markedly reduced glioma growth and angiogenesis. We hypothesize that the overexpression of NTPDase2 in glioma cells produces accumulating amounts of ADP around the tumor and this activates ADP‐dependent receptors on platelets, which may play an important role in the increased malignancy of C6‐EYFP/NTPDase2 gliomas. bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; PDGF, platelet‐derived growth factor; VEGF, vascular endothelial growth factor.