Tumor rates in Drosophila melanogaster are regulated by extracellular adenosine

Adenosine (Ado) is a purine nucleoside that modulates many physiological processes in the body. It plays a prominent role as a paracrine signal of metabolic imbalance within tissues and serves as a signaling mechanism to coordinate tissue activity. Ado exerts a broad range of cytoprotective, growth-promoting, and immunosuppressive effects and was observed at a high concentration in a number of human tumors, it was therefore suggested to be an important factor regulating tumor growth. We developed a method for the measurement of the Ado effect on tumor growth in Drosophila melanogaster using the modification of somatic mutation and recombination test (SMART). In this report, we examined the effect of three Drosophila genes involved in Ado signaling on the incidence of somatic mosaic clones, including adenosine receptor (AdoR), adenosine transporter (Ent2), and adenosine deaminase Adgf-A. We show that genetic manipulations with these genes do not affect control clones, but cause dramatic changes in the frequency of hyperplastic clones established by the loss of heterozygosity (LOH) of the warts (wts) tumor suppressor gene(wts homolog in humans is called LATS1 and its down-regulation has been reported in a number of tumors). The loss of AdoR function also decreases the frequency of dco tumor clones (human homolog of dco is called CK1δ). Our data show that adenosine and warts signaling pathways interact and adenosine signaling plays an important role in growth and survival of homozygous wts^- cells.

Sidorov R., Kucerova L., Kiss I., Zurovec M. (2014) Mutation in the Drosophila melanogaster adenosine receptor gene selectively decreases the mosaic hyperplastic epithelial outgrowth rates in wts or dco heterozygous flies. Purinergic Signalling. Published online: 21 Dec. 2014. DOI: 10.1007/s11302-014-9435-2