Homeostatic chemokines are expressed in certain tissues constitutively and direct cell recruitment under resting conditions.
These homeostatic chemokines define 'cellular highways' that guide cells to specific organs in the body.
Evidence that homeostatic chemokines determine metastatic destinations has come from mouse models, in which blocking certain homeostatic chemokine receptors blocks metastasis, and from retrospective human studies, in which the expression of a chemokine receptor is associated with metastasis to a given organ and/or poor prognosis.
Several homeostatic chemokine receptors have been associated with metastasis. CXC-chemokine receptor 4 (CXCR4) is the most widely expressed chemokine receptor in many cancers and probably mediates metastasis to the lung, liver, brain and bone marrow.
CC-chemokine receptor 7 (CCR7) probably determines metastasis to lymph nodes, and CCR9 mediates rare metastases to the small intestine when expressed in some melanoma cases.
There are many other ways in which chemokines can affect cancer progression. For example, chemokines can promote angiogenesis, promote growth of metastatic cells in their new 'niche' and inhibit the immune system from developing strong antitumour immune responses.
It has been 10 years since the role of a chemokine receptor, CXCR4, in breast cancer metastasis was first documented. Since then, the field of chemokines and cancer has grown significantly, so it is timely to review the progress, analyse the studies to date and identify future challenges facing this field. Metastasis is the major factor that limits survival in most patients with cancer. Therefore, understanding the molecular mechanisms that control the metastatic behaviour of tumour cells is pivotal for treating cancer successfully. Substantial experimental and clinical evidence supports the conclusion that molecular mechanisms control organ-specific metastasis. One of the most important mechanisms operating in metastasis involves homeostatic chemokines and their receptors. Here, we review this field and propose a model of 'cellular highways' to explain the effects of homeostatic chemokines on cancer cells and how they influence metastasis.
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A.Z. is supported by a grant from the US National Institute of Allergy and Infectious Diseases (NIAID) (R21 AI083540-01). A.M.B. is the recipient of grant T32 AI60573 from NIAID. We apologize to those colleagues whose work could not be cited here owing to space limitations.
The authors declare no competing financial interests.
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Zlotnik, A., Burkhardt, A. & Homey, B. Homeostatic chemokine receptors and organ-specific metastasis. Nat Rev Immunol 11, 597–606 (2011). https://doi.org/10.1038/nri3049
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