Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer.

Tumor cells aberrantly express chemokines and/or chemokine receptors, and some may promote tumor growth and metastasis. We examined the expression and function of chemokine receptor CXCR3 in a syngeneic murine model of metastatic breast cancer. By flow cytometry, CXCR3 was detected in all murine mammary tumor cell lines examined. All human breast cancer cell lines examined also expressed CXCR3, as did the immortalized but nontumorigenic MCF-10A cell line. Interaction of CXCR3 ligands, CXCL9, CXCL10, and CXCL11, with CXCR3 on the highly malignant murine mammary tumor cell line 66.1 resulted in intracellular calcium mobilization and chemotaxis in vitro. To test the hypothesis that tumor metastasis is facilitated by CXCR3 expressed by tumor cells, we employed a small molecular weight antagonist of CXCR3, AMG487. 66.1 tumor cells were pretreated with AMG487 prior to i.v. injection into immune-competent female mice. Antagonism of CXCR3 on 66.1 tumor cells inhibited experimental lung metastasis, and this antimetastatic activity was compromised in mice depleted of natural killer cells. Systemic administration of AMG487 also inhibited experimental lung metastasis. In contrast to the antimetastatic effect of AMG487, local growth of 66.1 mammary tumors was not affected by receptor antagonism. These studies indicate that murine mammary tumor cells express CXCR3 which facilitates the development of lung metastases. These studies also indicate for the first time that a small molecular weight antagonist of CXCR3 has the potential to inhibit tumor metastasis.

[1]  D. Jonas,et al.  Prostate tumor CXC-chemokine profile correlates with cell adhesion to endothelium and extracellular matrix. , 2006, Life sciences.

[2]  M. Smyth,et al.  CD27 Dissects Mature NK Cells into Two Subsets with Distinct Responsiveness and Migratory Capacity1 , 2006, The Journal of Immunology.

[3]  Y. Nakazawa,et al.  Significance of chemokine receptor expression in aggressive NK cell leukemia , 2005, Leukemia.

[4]  P. di Sant'Agnese,et al.  Differential expression of interleukin-8 and its receptors in the neuroendocrine and non-neuroendocrine compartments of prostate cancer. , 2005, The American journal of pathology.

[5]  R. Catarino,et al.  Protective role of the polymorphism CCR2-64I in the progression from squamous intraepithelial lesions to invasive cervical carcinoma. , 2005, Gynecologic oncology.

[6]  T. Meshel,et al.  Cellular characteristics of neuroblastoma cells: regulation by the ELR--CXC chemokine CXCL10 and expression of a CXCR3-like receptor. , 2005, Cytokine.

[7]  Lieve Moons,et al.  CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. , 2005, Cancer research.

[8]  D. Piwnica-Worms,et al.  CXCR4 Regulates Growth of Both Primary and Metastatic Breast Cancer , 2004, Cancer Research.

[9]  T. Manabe,et al.  Pivotal Role of CXCR3 in Melanoma Cell Metastasis to Lymph Nodes , 2004, Cancer Research.

[10]  D. Spandidos,et al.  Significant involvement of CCR2–64I and CXCL12–3a in the development of sporadic breast cancer , 2004, Journal of Medical Genetics.

[11]  T. Meshel,et al.  The expression of the chemokine receptor CXCR3 and its ligand, CXCL10, in human breast adenocarcinoma cell lines. , 2004, Immunology letters.

[12]  R. Bachelder,et al.  Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. , 2002, Cancer research.

[13]  Gordon Stamp,et al.  Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. , 2002, Cancer research.

[14]  Giovanni Martinelli,et al.  CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin's lymphoma. , 2002, Cancer research.

[15]  N. Longo,et al.  Expression of Functional Chemokine Receptors CXCR3 and CXCR4 on Human Melanoma Cells* , 2001, The Journal of Biological Chemistry.

[16]  F. Balkwill,et al.  Epithelial cancer cell migration: a role for chemokine receptors? , 2001, Cancer research.

[17]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[18]  D. Dorfman,et al.  The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia. , 2000, Blood.

[19]  L. Trentin,et al.  The chemokine receptor CXCR3 is expressed on malignant B cells and mediates chemotaxis. , 1999, The Journal of clinical investigation.

[20]  A. Fulton,et al.  Interleukin-10 inhibits tumor metastasis, downregulates MHC class I, and enhances NK lysis. , 1997, Cellular immunology.

[21]  T. Beaty,et al.  Antimetastatic and antitumor activities of interleukin 10 in a murine model of breast cancer. , 1996, Journal of the National Cancer Institute.

[22]  D. Dexter,et al.  Heterogeneity of tumor cells from a single mouse mammary tumor. , 1978, Cancer research.