We focused influences of stress-related neurotransmitters/hormones on two components of tumor microenvironment, osteosarcoma (OS) cells and mesenchymal stem cells (MSCs), under hypoxic stress. Epinephline, norepinephrine or isoproterenol increased cellular proliferation of rat OS cell line COS1NR and rat MSCs in a dose-dependent manner, which was inhibited by a β2AR selective inhibitor. While MSCs showed significant proliferative effect of isoproterenol under normoxic and even hypoxic conditions, COS1NR cells did not show the effect under hypoxic conditions. The β2AR sensitivity assay revealed that hypoxia impaired the sensitivity in COS1NR cells, but not affected in MSCs. HIF-1a immunoassay showed no significant change of HIF-1a expression in COS1NR cells, but 115% increment in MSCs. However, co-cultured with MSCs, isoproterenol caused a significant increment of COS1NR proliferation under hypoxic condition. Interestingly, this effect was inhibited by adding the anti-IL-6 antibody. The in vivo rat assay showed that the intravenous injection of MSCs enhanced β2AR-mediated tumor growth. There exists the heterogeneity of response to hypoxia in components of tumor microenvironment. Hypoxia causes the desentization of β2AR in COS1NR cells alone, but the heterogeneity may supports tumor progress.