Ecto-5'-Nucleotidase Overexpression Reduces Tumor Growth in a Xenograph Medulloblastoma Model.
BACKGROUND
Ecto-5'-nucleotidase/CD73 (ecto-5'-NT) participates in extracellular ATP catabolism by converting adenosine monophosphate (AMP) into adenosine. This enzyme affects the progression and invasiveness of different tumors. Furthermore, the expression of ecto-5'-NT has also been suggested as a favorable prognostic marker, attributing to this enzyme contradictory functions in cancer. Medulloblastoma (MB) is the most common brain tumor of the cerebellum and affects mainly children.


METHODS
The effects of ecto-5'-NT overexpression on human MB tumor growth were studied in an in vivo model. Balb/c immunodeficient (nude) 6 to 14-week-old mice were used for dorsal subcutaneous xenograph tumor implant. Tumor development was evaluated by pathophysiological analysis. In addition, the expression patterns of adenosine receptors were verified.


RESULTS
The human MB cell line D283, transfected with ecto-5'-NT (D283hCD73), revealed reduced tumor growth compared to the original cell line transfected with an empty vector. D283hCD73 generated tumors with a reduced proliferative index, lower vascularization, the presence of differentiated cells and increased active caspase-3 expression. Prominent A1 adenosine receptor expression rates were detected in MB cells overexpressing ecto-5'-NT.


CONCLUSIONS
This work suggests that ecto-5'-NT promotes reduced tumor growth to reduce cell proliferation and vascularization, promote higher differentiation rates and initiate apoptosis, supposedly by accumulating adenosine, which then acts through A1 adenosine receptors. Therefore, ecto-5'-NT might be considered an important prognostic marker, being associated with good prognosis and used as a potential target for therapy.
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Angélica R
AR
Cappellari
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
Micheli M
MM
Pillat
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
Hellio D N
HD
Souza
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Fabrícia
F
Dietrich
Serviço de Patologia, Hospital de Clínicas de Porto Alegre, UFRGS, Porto Alegre, RS, Brazil.
Francine H
FH
Oliveira
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Fabrício
F
Figueiró
Laboratório de Pesquisa em Câncer, Hospital de Clínicas de Porto Alegre, UFRGS, Porto Alegre, RS, Brazil; Instituto do Câncer Infantil do RS, ICI-RS, Porto Alegre, RS, Brazil.
Ana L
AL
Abujamra
Laboratório de Pesquisa em Câncer, Hospital de Clínicas de Porto Alegre, UFRGS, Porto Alegre, RS, Brazil; Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil; Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, UFRGS, Porto Alegre, RS, Brazil.
Rafael
R
Roesler
Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, G1V 0A6, QC, Canada; Centre de recherche du CHU de Québec, Québec, G1V 4G2, QC, Canada.
Joanna
J
Lecka
Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, G1V 0A6, QC, Canada; Centre de recherche du CHU de Québec, Québec, G1V 4G2, QC, Canada.
Jean
J
Sévigny
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas e da Saúde, UFRGS, Porto Alegre, RS, Brazil.
Ana Maria O
AM
Battastini
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
Henning
H
Ulrich
D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D006801:Humans; D008527:Medulloblastoma / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D043682:Receptor, Adenosine A1; D000249:Adenosine Monophosphate; D015720:5'-Nucleotidase