Abstract
BackgroundMacrophages, the key component of the tumor microenvironment, are differentiated mononuclear phagocyte lineage cells that are characterized by specific phenotypic characteristics that have been implicated in tumor growth, angiogenesis, and invasion. CX3CR1, the chemoattractant cytokine CX3CL1 receptor, plays an important role in modulating inflammatory responses, including monocyte homeostasis and macrophage phenotype and function. However, the role of CX3CR1 in the regulation of the tumor inflammatory microenvironment is not fully understood.MethodsUsing in vivo hepatic metastasis model, human colon carcinoma specimens, immunohistochemical staining, TUNEL staining, flow cytometry analysis, Western blotting assay and co-culture in three-dimensional peptide gel, we determined the effects of CX3CR1 on angiogenic macrophage survival and tumor metastasis.ResultsIn this study, we found that CX3CR1 was expressed in human colon carcinomas in a histologic grade- and stage-dependent manner, and CX3CR1 upregulation in TAMs was correlated with poor prognosis. Furthermore, we showed that in a microenvironment lacking CX3CR1, the liver metastasis of colon cancer cells was significantly inhibited. The underlying mechanism is associated with decrease accumulation of angiogenic macrophages that can be partly attributed to increased apoptosis in the tumor microenvironment, thus leading to impaired tumor angiogenesis in the liver and suppressed tumor metastasis.ConclusionsOur results suggest a role of CX3CR1 in angiogenic macrophage survival in the tumor microenvironment contributing to tumor metastasis.
Highlights
Macrophages, the key component of the tumor microenvironment, are differentiated mononuclear phagocyte lineage cells that are characterized by specific phenotypic characteristics that have been implicated in tumor growth, angiogenesis, and invasion
We explored whether CX3CR1, a chemoattractant cytokines receptor, regulates the the article associated macrophages (TAMs) subtypes in the tumor microenvironment, for several reasons
Expression of CX3CR1 in TAMs is increased along with colon carcinoma development Because the treatment and prognosis of colorectal cancer patients depends on the tumor grade and tumor-node-metastasis stage, we first measured the CX3CR1 expression levels in normal colon tissues and human colon cancer tissue
Summary
Macrophages, the key component of the tumor microenvironment, are differentiated mononuclear phagocyte lineage cells that are characterized by specific phenotypic characteristics that have been implicated in tumor growth, angiogenesis, and invasion. CX3CR1, the chemoattractant cytokine CX3CL1 receptor, plays an important role in modulating inflammatory responses, including monocyte homeostasis and macrophage phenotype and function. The role of CX3CR1 in the regulation of the tumor inflammatory microenvironment is not fully understood. In addition to genetic complexity, it has become increasingly apparent that the tumor inflammatory microenvironment plays an active role in promoting all stages of tumor progression [1,2,3]. We explored whether CX3CR1, a chemoattractant cytokines receptor, regulates the TAMs subtypes in the tumor microenvironment, for several reasons. Fourth, increasing evidence indicates that CX3CR1 is required for monocyte homeostasis and differentiation and regulates the fate of monocyte-derived cells in other inflammatory diseases such as cardiovascular disease and liver fibrosis [13,14,15]. Precisely how CX3CR1 regulates TAMs subtypes in the tumor microenvironment remains unknown
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