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Chemokine Receptors Involved in Colon Cancer Progression, and Lymph Node Metastasis

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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

In this chapter, we focus on the roles of chemokines and their receptors on colon cancer invasion, and lymph node metastasis in two mouse models. First, inactivation of TGF-β family signaling within colon cancer epithelium increases chemokine CCL9, and promotes recruitment of the MMP-expressing stromal cells that carry CCR1, the cognate receptor for CCL9. Consistently, lack of CCR1 prevents the accumulation of MMP-expressing myeloid cells at the invasion front and suppresses tumor invasion. These results provide the possibility of a novel therapeutic strategy for advanced cancer; prevention of the recruitment of MMP-expressing myeloid cells by chemokine receptor antagonist; hence “cellular target therapy” instead of molecular target therapy. Second, we recently found that some human colon cancer cell lines express chemokine receptor CXCR3 constitutively. To evaluate its role in metastasis, we constructed colon cancer cells that expressed CXCR3 cDNA (DLD-1-CXCR3), and compared with non-expressing controls by rectal transplantation in nude mice. In 6 weeks, 59% of mice inoculated with DLD1-CXCR3 showed macroscopic metastasis in para-aortic lymph nodes, whereas only 14% of those with the control (P < 0.05). Metastasis to the liver or lung was rare, and unaffected by CXCR3 expression. In human colon cancer specimens, expression of CXCR3 was found in 34% cases, most of which had lymph node metastasis. Importantly, patients with CXCR3-positive colon cancer showed significantly poorer prognosis than those without CXCR3, or those expressing CXCR4 or CCR7. These results indicate that activation of CXCR3 stimulates colon cancer metastasis preferentially to the draining lymph nodes with poorer prognosis.

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  1. Department of Pharmacology, Graduate School of Medicine, Kyoto University, 606-8501, Sakyo, Kyoto, Japan

    Makoto Mark Taketo & Kenji Kawada

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  1. Makoto Mark Taketo
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Correspondence to Makoto Mark Taketo .

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    Taketo, M.M., Kawada, K. (2009). Chemokine Receptors Involved in Colon Cancer Progression, and Lymph Node Metastasis. 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_4

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    • DOI: https://doi.org/10.1007/978-1-60327-267-4_4

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