Chemokine receptor CX3CR1 contributes to macrophage survival in tumor metastasis

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.

The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination

“…Supporting the observation made in human samples, in the mouse model of colitis-associated cancer, a limited number of infiltrating leukocytes expressed CX 3 CR1, especially in the peritumoral areas. Of note, a recent paper described that CD68 + macrophages infiltrating human CRC expressed CX 3 CR1, which was markedly increased in advanced patients (46). This discrepancy could be explained by the use of different anti-CX 3 CR1 reagents and the fact that our case list of samples mostly comprised early stage tumors.…”

AMP-activated Protein Kinase α2 Protects against Liver Injury from Metastasized Tumors via Reduced Glucose Deprivation-induced Oxidative Stress

“…Mouse Tumor Models-A liver metastasis model was carried out as described previously (20). SL4, a mouse colon carcinoma cell line with high incidence of experimental hepatic metastasis, was used for this model (20).…”

“…SL4, a mouse colon carcinoma cell line with high incidence of experimental hepatic metastasis, was used for this model (20). We transfected the SL4 cell line with a vector expressing luciferase, and G418 was used for screening the stably transfected cell strain.…”

Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration

“…The enhanced infiltration of inflammatory cells in C5aR-deficient mice suggests the possibility that C5a has immunomodulatory functions in tumor metastasis. Several studies with animal experimental models, as well as studies in humans, have demonstrated a crucial function for inflammatory cells in tumor immunity (24,48,49). Infiltration of leukocytes and macrophages are molecular signatures linked to a poor prognosis in cancer patients (50).…”