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Oncology: Theory & Practice
Oncology: Theory & Practice
iConcept Press

Chapter 8

Oncology: Theory & Practice

The Complex Role of Chemokines in Cancer: The Case of the CX3CL1/CX3CR1 Axis

by Manuel Tardáguila and Santos Mañes

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Tumor progression is intimately bound to the external cues provided by the tumor microenvironment, a complex assembly of cells and molecules that help enable and sustain most of the hallmarks of cancer. Among the many factors present in the tumor milieu, chemokines have received increasing attention, as these chemotactic factors direct leukocyte infiltration to sites of inflammation and neoplasia, and mediate leukocyte activation in the anti-tumor response. The role of the chemokine ligand-receptor system in cancer is nonetheless complex; chemokine signaling can promote or inhibit cell transformation, as well as angiogenesis. Moreover, the hijacking of infiltrated immune cells by malignant cells accelerates tumor progression, whereas de novo expression of chemokine receptors in tumor cells enhances invasiveness. It is thus not surprising that different cancer cell types and cancer-associated cells express chemokines and chemokine receptors. A chemokine-receptor pair that has recently attracted attention in the context of tumor progression is CX3CL1-CX3CR1. CX3CL1, also termed fractalkine, is expressed as a transmembrane protein able to mediate cell adhesion, and as a soluble form that attracts cells expressing its sole receptor, CX3CR1. Recognition of CX3CL1 by its receptor activates, among other signaling routes, survival and proliferation pathways in the target cell. Although initial studies showed that CX3CL1 overexpression in tumor cells triggers a potent anti-tumor response mediated by recruitment of immune effector cells, the CX3CL1-CX3CR1 chemokine-receptor pair has also been implicated in the progression of various cancer types, including pancreatic, prostate, breast and ovarian tumors. It can also enhance tumor cell dissemination, as shown for pancreatic adenocarcinoma as well as prostate and breast cancer cells. The role of the CX3CL1-CX3CR1 axis in tumors is thus complex, as its effects range from tumor eradication by the immune system to the acceleration of tumor progression through activation of survival and mitogenic pathways, and by enhancing metastatic potential. Analysis of the role of CX3CL1 in the biology of a given tumor type therefore requires the development of preclinical models that closely recapitulate the evolution of human malignancies. We recently addressed this question using the Her2/ErbB2/neu transgenic mouse model of spontaneous breast carcinogenesis to analyze the role of CX3CL1 in de novo tumor formation. We found that CX3CL1 showed tumor promoter activity, which correlated with its ability to transactivate ErbB receptors, leading to induction of the mitogenic ERK pathway. The importance of CX3CL1-induced ErbB transactivation in breast carcinogenesis was demonstrated by a significant delay in cancer onset and reduced tumor number in CX3CL1-deficient transgenic mice. These results highlight the concerted effect of CX3CL1 and ErbB receptors in promoting breast cancer. CX3CL1 is thus a paradigm that illustrates the complexity of the interplay between sporadic tumors and the immune system. Tumor cells not only induce a tolerogenic response to tumor antigens that allows them to pass largely unnoticed, but also subvert an integral element of the immune system, a chemokine, to promote their own growth. Since a central goal of tumor immunologists is to harness and augment immune responses to tumors, these intricacies must be taken into account to avoid unanticipated adverse effects.

Author Details

Manuel Tardáguila
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB/CSIC), Madrid, Spain, Spain
Santos Mañes
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB/CSIC), Madrid, Spain, Spain


Manuel Tardáguila and Santos Mañes. The Complex Role of Chemokines in Cancer: The Case of the CX3CL1/CX3CR1 Axis. In Oncology: Theory & Practice. ISBN:978-1-922227-80-5. iConcept Press. 2014.