Effect of tumor producing cytokines on bone marrow proliferation

Many tumors produce cytokines. The purpose of this study was to determine whether cytokines produced by tumors can modulate the proliferation of bone marrow cells. ELISA was used to identify the amount of IL-3, IL-6, GM-CSF, and TNFα that are produced by a series of murine pancreatic tumor lines derived from Tg(Ela-1-SV40E)Bri18 transgenic mice. Conditioned media from these lines was then co-incubated for 3 days with 2e5 murine marrow cells in 96-well plates and a 4hr incorporation of 3H-thymidine into marrow cells was determined. The TGP47 line produces substantial GM-CSF (187 pg/ml) and the TGP49 and TGP50 lines produce large amounts of IL-6 (250 and 115 pg/ml, respectively). Conditioned media from all cell lines affected marrow proliferation; the greatest effect was observed with media from TGP-50, increasing 3H-TdR uptake 17.6-fold from 14.6 CPM/well to 257.4 CPM/well (using 200,000 cells). Media from TGP-48, which produces less IL-6 and GM-CSF than TGP-50, increases marrow proliferation 10.8-fold. Media from TGP-47, which has very high GM-CSF production but no IL-3 and slightly higher TNFα production, only stimulates marrow proliferation by 4.6-fold. These results provide proof of the concept that tumor cytokine production can affect marrow physiology. They further support ongoing in vitro studies to determine if the magnitude of change of marrow proliferation in response to tumor cytokines is consistent, independent of the time of day that marrow was collected. Additional in vivo studies are also in progress to determine whether baseline hematopoietic activity is altered in tumor-bearing mice and whether the profile of myelosuppression and myelorecovery in response to cytotoxic chemotherapy is influenced by tumor-produced cytokines. This studies could provide an understanding of bone marrow disruption by tumor cells.