Resistance of muscle to tumor metastases: A role for A3 adenosine receptoragonists

Tumor metastases are extremely rare in striated muscles, Lately, we have fo und that muscle cell conditioned medium (MCM) inhibits the proliferation of various tumor cells while maintaining the growth of normal murine bone mar row cells, This dual activity was confirmed in vivo when the MCM was admini stered orally, i.e., it inhibited the development of tumor growth in mice a nd prevented the myelotoxic effects of chemotherapy. Adenosine was found to be one of the active components of MCM, inhibiting tumor cell growth while maintaining bone marrow cell proliferation in vitro, Adenosine is known to act as an important regulatory molecule through its binding to specific G- protein-associated A1, A(2a), A(2b) and A3 cell surface receptors. In disti nction from MCM, adenosine did not suppress tumor development in mice and w as not active as a chemoprotective agent when administered orally or intrav enously, Thus, the in vivo activity of MCM could not be attributed to adeno sine, In this study, MCM from which adenosine was enzymatically removed sti ll retained its dual activity that was also found to be mediated through th e A3 adenosine receptor (A3AR). This result led to the conclusion that natu ral agonists to A3AR were responsible for the activity of MCM. We further t ested synthetic agonist to the A3AR and demonstrated that it possessed the same in vitro and in vivo activity profile as MCM. Taken together, muscle c ells, in addition to adenosine, secrete natural agonists to A3AR. These ago nists are stable nondegradable molecules and may contribute to the systemic anticancer and chemoprotective activity exerted by MCM. This group of mole cules may account for the rarity of tumor metastases in muscle.