Chemotherapeutic drugs and human tumor cells cytokine network.

The ability of human tumor cell lines to produce various cytokines, chemokines, angiogenic and growth factors was investigated using Luminex multiplex technology. Media conditioned by tumor cells protected tumor cells from drug-induced apoptosis and stimulated tumor cell proliferation. Antibodies neutralizing IL-6, CXCL8, CCL2 and CCL5 blocked this stimulation. Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of IL-6, CXCL8, CCL2, CCL5, BFGF, G-CSF and VEGF. This stimulation was associated with drug-induced activation of NF-kappaB, AP-1, AP-2, CREB, HIF-1, STAT-1, STAT-3, STAT-5 and ATF-2 transcription factors and upregulation of IL-6, CXCL8, FGF-2, CSF-3 and CCL5 gene expression. Treatment of tumor cells with doxorubicin and antibodies neutralizing G-CSF, CCL2 or CCL5 had higher inhibitory effects than each modality used alone. These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug-mediated destruction. Clinical studies showed that antibodies neutralizing VEGF (Avastin/Bevacizumab) or blocking HER2/neu signaling (Herceptin/Trastuzumab) could increase the efficacy of chemotherapy, although these beneficial effects have been limited. It is possible that drug-stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy. In addition, numerous growth factors and chemokines share angiogenic and growth-stimulating properties, and thus reduction of a single factor is insufficient to completely block tumor growth. Thus, a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy.