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The role of macrophage chemoattractant signaling in cancer cell migration, metastasis and neovascularization


Tumor-associated macrophages possess the potential to contribute to cancer progression by modulation of immune function, angiogenesis, and cell metastasis. However, understanding of the chemokine signaling networks that regulate this process is unclear. Here, we demonstrate that treatment of CT26 colon cancer cells with RAW 264.7 macrophage conditioned media induces cancer cell migration, invasion and metastasis. Genetic profiling indicated that chemokines SDF-1[alpha] and VEGF are upregulated in tumor- stimulated macrophages and contribute to tumor cell migration in vitro. Macrophages also showed a robust chemotactic response towards tumor-derived chemokines. Microarray analysis and functional testing revealed CSF-1 as the major chemoattractant for macrophages. In the in vivo CAM model, RAW macrophages localized specifically to the tumor periphery where they were found to increase CT26 tumor growth, microvascular density, vascular disruption, and lung metastasis suggesting these cells home to actively invading areas of the tumor, but not the hypoxic core of the tumor mass. Additionally, hypoxic conditions down-regulated CSF-1 production in several tumor cell lines and decreased macrophage migration in vitro. Taken together our findings suggest that normoxic tumor cells release CSF-1 to recruit macrophages to the tumor periphery where they secrete mitogenic and angiogenic factors that facilitate tumor cell proliferation, invasion and metastasis

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