Abstract
Tumor-associated macrophages are known to influence cancer progression by modulation of immune function, angiogenesis, and cell metastasis, however, little is known about the chemokine signaling networks that regulate this process. Utilizing CT26 colon cancer cells and RAW 264.7 macrophages as a model cellular system, we demonstrate that treatment of CT26 cells with RAW 264.7 conditioned medium induces cell migration, invasion and metastasis. Inflammatory gene microarray analysis indicated CT26-stimulated RAW 264.7 macrophages upregulate SDF-1α and VEGF, and that these cytokines contribute to CT26 migration in vitro. RAW 264.7 macrophages also showed a robust chemotactic response towards CT26-derived chemokines. In particular, microarray analysis and functional testing revealed CSF-1 as the major chemoattractant for RAW 264.7 macrophages. Interestingly, in the chick CAM model of cancer progression, RAW 264.7 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. In support of these findings, hypoxic conditions down regulated CSF-1 production in several tumor cell lines and decreased RAW 264.7 macrophage migration in vitro. Together our findings suggest a model where normoxic tumor cells release CSF-1 to recruit macrophages to the tumor periphery where they secrete motility and angiogenic factors that facilitate tumor cell invasion and metastasis.
Highlights
The propensity for tumors to progress and metastasize reflects the oncogenic mutations in the cancer cells and dynamic interactions involving non-malignant cells in the tumor cell microenvironment
In chick chorioallantoic membrane (CAM) inoculated with tumor cells, RAW 264.7 macrophages localize to the tumor periphery, where they facilitate vascular remodeling and potentiate tumor cell metastasis to the chick lungs
The expectation was that the microarray analysis would serve as a resource for identifying and testing specific signaling pathways activated in alternative macrophage/tumor cell interactions during cancer progression
Summary
The propensity for tumors to progress and metastasize reflects the oncogenic mutations in the cancer cells and dynamic interactions involving non-malignant cells in the tumor cell microenvironment. Compared to classically activated macrophages (M1) that function as primary effector cells in the innate immune system, M2 TAMs support tumor survival by promoting local angiogenesis and tissue remodeling, while suppressing the immune response [5]. TAMs localize to the invasive areas of the tumor where they secrete a variety of cytokines and proteases involved in tumor cell invasion and metastasis [6,7]. In this role, TAMs actively contribute to tumor progression and the transition to malignancy that often correlates with poor clinical outcome. Deciphering the tumor-cell chemokine networks that regulate cancer progression in vivo remains a major challenge
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