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The multifaceted roles of the chemokines CCL2 and CXCL12 in osteophilic metastatic cancers

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Abstract

Breast and prostate cancers have a great propensity to metastasize to long bones. The development of bone metastases is life-threatening, incurable, and drastically reduces patients’ quality of life. The chemokines CCL2 and CXCL12 and their respective receptors, CCR2 and CXCR4, are central instigators involved in all stages leading to cancer cell dissemination and secondary tumor formation in distant target organs. They orchestrate tumor cell survival, growth and migration, tumor invasion and angiogenesis, and the formation of micrometastases in the bone marrow. The bone niche is of particular importance in metastasis formation, as it expresses high levels of CCL2 and CXCL12, which attract tumor cells and contribute to malignancy. The limited number of available effective treatment strategies highlights the need to better understand the pathophysiology of bone metastases and reduce the skeletal tumor burden in patients diagnosed with metastatic bone disease. This review focuses on the involvement of the CCL2/CCR2 and CXCL12/CXCR4 chemokine axes in the formation and development of bone metastases, as well as on therapeutic perspectives aimed at targeting these chemokine-receptor pairs.

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Acknowledgements

PS holds a Canada Research Chair in Neurophysiopharmacology of Chronic Pain. Figures were created with BioRender.com.

Funding

ÉM is supported by a research scholarship awarded by the Fonds de recherche du Québec – Santé (FRQ-S). This work was supported by a Canadian Institutes of Health Research (CIHR) grant (FDN-148413).

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  1. Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, QC, Canada

    Élora Midavaine, Jérôme Côté & Philippe Sarret

  2. Centre de recherche du Centre hospitalier universitaire de Sherbrooke, CIUSSS de l’Estrie – CHUS, Sherbrooke, QC, Canada

    Élora Midavaine, Jérôme Côté & Philippe Sarret

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E.M. designed the review, carried out the literature search, and wrote the manuscript with critical revisions provided by P.S., and J.C. P.S. acquired funding. All authors approved the final version of the manuscript.

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Midavaine, É., Côté, J. & Sarret, P. The multifaceted roles of the chemokines CCL2 and CXCL12 in osteophilic metastatic cancers. Cancer Metastasis Rev 40, 427–445 (2021). https://doi.org/10.1007/s10555-021-09974-2

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