The ectonucleoside
triphosphate diphosphohydrolases (E-NTPDases) are a family of ectoenzymes that hydrolyze extracellular
nucleotides, thereby modulating purinergic signaling.
Gliomas have low expression of all E-NTPDases, particularly
NTPDase2, when compared to astrocytes in culture.
Nucleotides induce
glioma proliferation and
ATP, although potentially neurotoxic, does not evoke cytotoxic action on the majority of
glioma cultures. We have previously shown that the co-injection of
apyrase with
gliomas decreases
glioma progression. Here, we tested whether selective re-establishment of
NTPDase2 expression would affect
glioma growth.
NTPDase2 overexpression in C6
glioma cells had no effect on in vitro proliferation but dramatically increased
tumor growth and malignant characteristics in vivo. Additionally, a sizable platelet sequestration in the
tumor area and an increase in CD31 or
platelet/endothelial cell adhesion molecule-1 (PECAM-1),
vascular endothelial growth factor and OX-42 immunostaining were observed in C6-Enhanced Yellow Fluorescent
Protein (EYFP)/
NTPDase2-derived
gliomas when compared to controls. Treatment with
clopidogrel, a P2Y(12) antagonist with anti-platelet properties, decreased these parameters to control levels. These data suggest that the
ADP derived from
NTPDase2 activity stimulates platelet migration to the
tumor area and that
NTPDase2, by regulating angiogenesis and
inflammation, seems to play an important role in
tumor progression. In conclusion, our results point to the involvement of purinergic signaling in
glioma progression.