Tumor-associated macrophage recruitment and regulation of angiogenesis
Date
2008
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Abstract
Tumors are no longer thought of as purely a mass of transformed cells. A major component of the cellular composition of a tumor is infiltrating immune cells. Macrophages can constitute a large proportion of infiltrating immune cells. In many cases, increased numbers of Tumor-Associated Macrophages (TAMs) can be associated with a poorer prognosis. Utilizing mice which lack a functional type I interferon receptor (IFN-α/βR-/-), we found that endogenous levels of type I IFNs control tumor growth and angiogenesis. We also determined that tumors grown in IFN-α/βR-/- mice have an increase in macrophage infiltrate. In vitro assays suggest that suppression of macrophage responsiveness to CSF-1 by type I IFNs was responsible for the increased macrophage accumulation in tumors of mice unable to respond to type I IFNs. These results indicate that endogenous production of type I IFNs by tumor cells or inflammatory cells may be an important means of suppressing the accumulation of TAMs and their subsequent induction of angiogenesis. The ability of TAMs to produce VEGF is one of the major means by which TAMs are known to induce tumor angiogenesis. Since VEGF expression is in part induced by hypoxia, it has been speculated that the hypoxic tumor environment is responsible for driving TAM VEGF production. As an alternative possibility we suggest that the engulfment of apoptotic tumor cells can stimulate TAM production of VEGF. We determined that the use of Liposome DNA-complex (LDC) therapy can induce anti-tumor immunity through the combined activation of systemic innate and adaptive immune responses. We show that LDC can traffic into macrophages and induce expression of activation markers. In vitro results show that LDC therapy can inhibit the production of VEGF by macrophages after their consumption of apoptotic cells, suggesting that LDC may be an effective way to circumvent the pro-tumor function of TAMs. Additionally, we determined that LDC combined with chemotherapy can be used as a safe and effective immunotherapy for the treatment of canine hemangiosarcoma. Taken together, these findings could uncover new avenues in which TAMs can be targeted and identified a novel immunotherapy as a potential candidate.
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Subject
angiogenesis
CSF-1
interferon
macrophages
migration
tumor
immunology