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The CXCR3/CXCL3 Axis in Cancer

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Chemokine Receptors in Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

CXCR3 is a G protein-coupled receptor that binds the chemokines CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-Tac). The murine receptor also binds CCL21. CXCR3 is expressed on activated T cells, B cells, Natural Killer (NK) cells, dendritic cells, mast cells, and endothelial cells, and has now been reported on many malignant cells. There are several CXCR3 variants: CXCR3-A promotes chemotaxis and also plays a role in cell survival, CXCR3-B activation leads to inhibited DNA synthesis and apoptosis but less is known regarding the pathophysiologic role of CXCR3-alt. Melanoma, breast, and colon cancer cell lines express CXCR3, however, expression levels are not correlated with metastatic potential. Nevertheless, gene silencing of CXCR3 reduces the number of lymph node metastases from implanted melanoma or colon cancers without affecting expansion of the primary tumor implant or dissemination to the lungs. Gene silencing or antagonism of CXCR3 with a small molecular weight (m.w.) antagonist also inhibits breast cancer metastasis but in this setting, pulmonary metastases are reduced by receptor blockade. In all three histologic types, CXCR3 expression is associated with a poorer prognosis. In clear cell renal carcinoma and in chronic lymphocytic leukemia the opposite correlation is observed, where low CXCR3 is associated with shorter survival. In spite of the demonstrated contribution of tumor-expressed CXCR3 in promoting tumor metastasis in several disease settings, local overexpression of CXCR3 ligands leads to tumor inhibition in several cancer models. Antiangiogenic properties of CXCR3 ligands as well as the ability to attract CXCR3+ T lymphocytes and NK cells to the tumor contribute to the protective mechanisms. Manipulation of the CXCR3/CXCL3 axis should be considered as a potential therapeutic approach to prevent cancer progression.

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  1. Marlene and Stewart Greenebaum Cancer Center and Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA

    Yanchun Li & Amy M. Fulton

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  1. Yanchun Li
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Correspondence to Amy M. Fulton .

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    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

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    Li, Y., Fulton, A.M. (2009). The CXCR3/CXCL3 Axis in Cancer. In: Fulton, A. (eds) Chemokine Receptors in Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-60327-267-4_5

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    • DOI: https://doi.org/10.1007/978-1-60327-267-4_5

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