Overexpression of NTPDase2 in gliomas promotes systemic inflammation and pulmonary injury.
Gliomas are the most common and devastating type of primary brain tumor. Many non-neoplastic cells, including immune cells, comprise the tumor microenvironment where they create a milieu that appears to dictate cancer development. ATP and the phosphohydrolytic products ADP and adenosine by activating P2 and P1 receptors may participate in these interactions among malignant and immune cells. Purinergic receptor-mediated cell communication is closely regulated by ectonucleotidases, such as by members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family, which hydrolyze extracellular nucleotides. We have shown that gliomas, unlike astrocytes, exhibit low NTPDase activity. Furthermore, ATP induces glioma cell proliferation and the co-administration of apyrase decreases progression of injected cells in vivo. We have previously shown that NTPDase2 reconstitution dramatically increases tumor growth in vivo. Here we evaluated whether NTPDase2 reconstitution to gliomas modulates systemic inflammatory responses. We observed that NTPDase2 overexpression modulated pro-inflammatory cytokine production and platelet reactivity. Additionally, pathological alterations in the lungs were observed in rats bearing these tumors. Our results suggest that disruption of purinergic signaling via ADP accumulation creates an inflammatory state that may promote tumor spread and dictate clinical progression.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, RS, Brazil.
Elizandra
E
Braganhol
Rafael F
RF
Zanin
Andressa
A
Bernardi
Leticia S
LS
Bergamin
Angelica R
AR
Cappellari
Luis F
LF
Campesato
Fernanda B
FB
Morrone
Maria M
MM
Campos
João B
JB
Calixto
Maria Isabel A
MI
Edelweiss
Márcia R
MR
Wink
Jean
J
Sévigny
Simon C
SC
Robson
Ana Maria O
AM
Battastini
D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001081:Apyrase / Q000096:biosynthesis; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005910:Glioma / Q000201:enzymology* / Q000473:pathology; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology*; D055370:Lung Injury / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D018836:Inflammation Mediators; D000251:Adenosine Triphosphatases; C027201:ectoATPase; D001081:Apyrase