Restoring epithelial HoxD10 also reduces VEGF ZD1839 molecular weight expression and restoring either HoxA5 or HoxD10 in epithelial cells also suppresses expression of several chemokines including CCL-2 and CxCL12 that in turn decrease recruitment of immune cells to tumors. In addition directly restoring expression of either HoxD10 or HoxA5 in angiogenic endothelial cells directly attenuates angiogenesis by reducing endothelial
cell invasion and stabilization of vascular structures. Thus, both HoxD10 and HoxA5 are potent breast tumor suppressors that coordinately stabilize the breast tumor microenvironment by inhibiting epithelial cell growth and invasion, directly impairing angiogenesis and suppressing leukocyte infiltration (inflammation). We are currently developing targeted approaches to restore expression of HoxD10 and/or HoxA5 to cells within mammary PR-171 in vitro tumor tissues in vivo. O78 Macrophages are an Important Component of Myeloma Microenvironment and Protect Myeloma Cells from Chemotherapy Drug-Induced Apoptosis Jing Yang 1 , Qing Yi1 1 Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA Multiple myeloma is a B-cell malignancy characterized
by proliferation of plasma cells in the bone marrow. It is the second most common JNK inhibitor nmr hematological malignancy and is still largely incurable. One of the major problems is that myeloma cells develop drug resistance upon interaction from with bone marrow stromal cells. To understand the importance of different stromal cell components in the bone marrow microenvironment, we examined the effects of macrophages on myeloma cell survival and response to chemotherapy. We report here that macrophages, in particular tumor-associated macrophages obtained by culturing macrophages with myeloma cell culture supernatants, are a protector of myeloma cells. Macrophages protected both
myeloma cell lines and primary myeloma cells, isolated from patients from spontaneous and chemotherapy drug-induced apoptosis via attenuating the activation and cleavage of caspase-dependent apoptotic signaling. The protective effect was dependent on direct contact between macrophages and myeloma cells. However, the reduced numbers of apoptotic tumor cells in the cocultures were not the result of macrophage-uptake of apoptotic cells, because macrophages with or without the capacity to phagocytose apoptotic cells provide similar protection to myeloma cells against chemotherapy-induced apoptosis. Although tumor-associated macrophages secreted large amounts of IL-6, which is the most important survival factor for myeloma cells, our results show that IL-6 neutralizing antibodies failed to significantly affect the protective effects of tumor-associated macrophages, suggesting that other cytokines may be involved.