Chemokine receptor CX3CR1 contributes to macrophage survival in tumor metastasis.
BACKGROUND
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. However, the role of CX3CR1 in the regulation of the tumor inflammatory microenvironment is not fully understood.


METHODS
Using 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.


RESULTS
In 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.


CONCLUSIONS
Our results suggest a role of CX3CR1 in angiogenic macrophage survival in the tumor microenvironment contributing to tumor metastasis.
Beijing Anzhen Hospital, Capital Medical University, Beijing, China. jdu@bcm.edu.
Jiao
J
Zheng
Min
M
Yang
Jianghua
J
Shao
Yanju
Y
Miao
Jiahuai
J
Han
Jie
J
Du
D000230:Adenocarcinoma / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D000818:Animals; D017209:Apoptosis; D000073883:CX3C Chemokine Receptor 1; D002470:Cell Survival; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000502:physiology*; D059016:Tumor Microenvironment
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D019707:Receptors, Chemokine