The ecto-nucleotidase activity is known to be utilized by the breast cancer cells to enhance their adhesion, migration and invasion via adenosine receptor-mediated pathways 20, 21, 49, 50. Targeting of CD73 by antibodies and siRNA attenuates the growth and metastasis of CD73+tumors in a T- and/or B-cell-dependent manner 49, 50. Interestingly, anti-CD73 therapy, which results in diminished adenosine production, was inefficient

against CD73− breast tumors 49. Our study is the first one to dissect the contribution of host CD73 in the progression of tumors. It strongly suggests that some of the beneficial effects seen in previous studies may actually be dependent on the inhibition of host CD73 rather than targeting the tumor. Moreover, our data show that the host CD73 is a potential Enzalutamide mw therapeutic target for controlling tumor

progression also in those cases in which tumor cells themselves lack or loose CD73 expression. The altered purinergic signaling cascade can offer new therapeutic targets for inhibiting tumor growth. We showed that the scavenging of extracellular ATP in tumors by soluble apyrase treatment or CD73 blockade by AMPCP retarded growth of CD73− tumors in NVP-LDE225 in vivo vivo. The phenotypes of apyrase-treated WT mice and that of control-treated CD73-deficient mice were virtually indistinguishable in terms of the kinetics of tumor growth and in the composition of intratumoral Treg and MR+ macrophage infiltrates. Moreover, apyrase treatment had no beneficial effect on tumor growth in CD73-deficient

mice, and it did not alter these intratumoral leukocyte isometheptene subpopulations either. CD73 is induced by HIF-1a under hypoxic conditions 51. Because larger tumors are typically hypoxic, induction of CD73 in the stromal cells is very likely in clinical settings. Hence, it may be useful to be able to counteract the effects of inducible CD73 on intratumoral leukocyte accumulation by altering the purinergic signaling by enzyme therapy. These findings also highlight the novel fact that mechanistically the increased ATPase and ADPase activities, together with the reduced adenosine production, in CD73-deficient mice are major players in the improved control of tumor growth. WT and CD73-deficient mice on a C57BL/6 background (kindly provided by Linda Thompson) have been described earlier 13, 18. Age- and sex-matched animals were used in all experiments. All animal experiments were approved by the local animal care committee. B16-F10 melanoma cells stably transfected with luciferase were obtained from Xenogen, and maintained in MEM/Earle’s balanced salts medium containing 10% FCS, 200 mM L-glutamine, 1 mM sodium pyruvate, 1 mM non-essential amino acids, MEM vitamin solution and penicillin and streptomycin.