Open AccessAdenosine deaminase inhibition suppresses progression of 4T1 murine breast cancer by adenosine receptor‐dependent mechanisms
Author(s) -
KutrybZajac Barbara,
Koszalka Patrycja,
Mierzejewska Paulina,
Bulinska Alicja,
Zabielska Magdalena A.,
Brodzik Karolina,
Skrzypkowska Aleksandra,
Zelazek Lukasz,
PelikantMalecka Iwona,
Slominska Ewa M.,
Smolenski Ryszard T.
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13864
Subject(s) - adenosine , adenosine deaminase , adenosine receptor , cancer research , purinergic signalling , cancer cell , biology , endocrinology , chemistry , medicine , receptor , cancer , agonist
The activity of a cell‐surface ecto‐adenosine deaminase ( eADA ) is markedly increased in the endothelial activation and vascular inflammation leading to decreased adenosine concentration and alterations in adenosine signalling. Depending on the specific pathway activated, extracellular purines mediate host cell response or regulate growth and cytotoxicity on tumour cells. The aim of this study was to test the effects of adenosine deaminase inhibition by 2′deoxycoformycin ( dCF ) on the breast cancer development. dCF treatment decreased a tumour growth and a final tumour mass in female BALB /c mice injected orthotopically with 4T1 cancer cells. dCF also counteracted cancer‐induced endothelial dysfunction in orthotopic and intravenous 4T1 mouse breast cancer models. In turn, this low dCF dose had a minor effect on immune stimulation exerted by 4T1 cell implantation. In vitro studies revealed that dCF suppressed migration and invasion of 4T1 cells via A2a and A3 adenosine receptor activation as well as 4T1 cell adhesion and transmigration through the endothelial cell layer via A2a receptor stimulation. Similar effects of dCF were observed in human breast cancer cells. Moreover, dCF improved a barrier function of endothelial cells decreasing its permeability. This study highlights beneficial effects of adenosine deaminase inhibition on breast cancer development. The inhibition of adenosine deaminase activity by dCF reduced tumour size that was closely related to the decreased aggressiveness of tumour cells by adenosine receptor‐dependent mechanisms and endothelial protection.