Oncotarget

Research Papers:

CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity

Guiquan Zhu, H. Hannah Yan, Yanli Pang, Jiang Jian, Bhagelu R. Achyut, Xinhua Liang, Jonathan M. Weiss, Robert H. Wiltrout, M. Christine Hollander and Li Yang _

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Oncotarget. 2015; 6:43408-43419. https://doi.org/10.18632/oncotarget.6125

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Abstract

Guiquan Zhu1,2, H. Hannah Yan1,*, Yanli Pang1,3,*, Jiang Jian1,4, Bhagelu R. Achyut1, Xinhua Liang4, Jonathan M. Weiss5, Robert H. Wiltrout5, M. Christine Hollander1, Li Yang1

1Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA

2Department of Head and Neck Surgery, Sichuan Cancer Hospital, Sichuan University, Chengdu, P. R. China

3Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, P. R. China

4Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, P. R. China

5Cancer and Inflammation Program, National Cancer Institute, Frederick, MD, USA

*These authors have contributed equally to this work

Correspondence to:

Li Yang, e-mail: yangl3@mail.nih.gov

Keywords: CXCR3, tumor metastasis, migration, host immunity, drug treatment

Received: August 07, 2015     Accepted: October 10, 2015     Published: October 15, 2015

ABSTRACT

Chemokines and chemokine receptors have critical roles in cancer metastasis and have emerged as one of the targeting options in cancer therapy. However, the treatment efficacy on both tumor and host compartments needs to be carefully evaluated. Here we report that targeting CXCR3 decreased tumor cell migration and at the same time improved host anti-tumor immunity. We observed an increased expression of CXCR3 in metastatic tumor cells compared to those from non-metastatic tumor cells. Knockdown (KD) of CXCR3 in metastatic tumor cells suppressed tumor cell migration and metastasis. Importantly, CXCR3 expression in clinical breast cancer samples correlated with progression and metastasis. For the host compartment, deletion of CXCR3 in all host cells in 4T1 mammary tumor model significantly decreased metastasis. The underlying mechanisms involve a decreased expression of IL-4, IL-10, iNOs, and Arg-1 in myeloid cells and an increased T cell response. IFN-γ neutralization diminished the metastasis inhibition in the CXCR3 knockout (KO) mice bearing 4T1 tumors, suggesting a critical role of host CXCR3 in immune suppression. Consistently, targeting CXCR3 using a small molecular inhibitor (AMG487) significantly suppressed metastasis and improved host anti-tumor immunity. Our findings demonstrate that targeting CXCR3 is effective in both tumor and host compartments, and suggest that CXCR3 inhibition is likely to avoid adverse effects on host cells.


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