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

Abstract

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.

• Authors: Tonya C Walser, Salah Rifat, Xinrong Ma, Namita Kundu, Chris Ward, Olga Goloubeva, Michael G Johnson, Julio C Medina, Tassie L Collins, Amy M Fulton
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 15 Pg. 7701-7 (Aug 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16885372 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR3 protein, human
• Cxcr3 protein, mouse
• Receptors, CXCR3
• Receptors, Chemokine

Topics

• Adenocarcinoma (immunology, prevention & control, secondary)
• Animals
• Breast Neoplasms (immunology, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Humans
• Lung Neoplasms (immunology, prevention & control, secondary)
• Mammary Neoplasms, Experimental (immunology, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Mice, SCID
• Receptors, CXCR3
• Receptors, Chemokine (antagonists & inhibitors, biosynthesis, immunology)