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 immunecompetent 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. (Cancer Res 2006; 66(15): 7701-7)

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

“…Moreover, CXCL10 has been shown to be one of the Ras targets, and overexpressed in many cases of colorectal cancer (Zhang et al, 1997). Notably, a small molecular antagonist of CXCR3 has been recently reported to inhibit lung metastasis of breast cancer in a murine model, although they did not examine the metastatic potential to LNs (Walser et al, 2006). Thus, our present results suggest that CXCR3 can be a novel therapeutic target to suppress LN metastasis of colon and other CXCR3-expressing cancer cells.…”

“…Notably, CXCL9, CXCL10 and CCL21 play additional roles in the tumor microenvironment. For example, CXCL9 and CXCL10 activate RhoA and Rac1, induce actin reorganization, and trigger migration and invasion of melanoma, malignant B-lymphocyte, and lung and breast cancers (Trentin et al, 1999;Robledo et al, 2001;Soejima and Rollins, 2001;Kawada et al, 2004;Walser et al, 2006). Here, we have demonstrated that CXCR3 plays a critical role in colon cancer cell metastasis to LNs by inducing diverse cellular effects such as cytoskeletal rearrangement, migration, invasion, MMP-2/9 expression and cell survival through activation of ERK1/2 and Akt/PKB pathways.…”

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

“…It is worth noting that systemic administration of a small molecular inhibitor of CXCR3, AMG487, inhibits lung metastasis of HT29 CRC cells and breast cancer cells in a mouse model. 8,14 In addition, CXCR4-knockdown clones also significantly decreased metastasis to LNs, liver and lungs 6 weeks after inoculation, although its effect on LN metastasis was less. However, 2 weeks after inoculation, CXCR4-knockdown clones disseminated to LNs, liver and lungs at a similar frequency to that of the control clones, which was consistent with a previous report that CXCR4 is required for outgrowth of CRC micrometastases.…”

“…[6][7][8][9][13][14][15] In CRC, it was reported that CXCR3 expression is upregulated in metastatic colon cancer cells, but not in their primary lesions, and that the CXCL10/CXCR3 axis…”

“…16 It is notable that systemic administration of a CXCR3 inhibitor, AMG487, was recently reported to inhibit lung metastasis of CRC and breast cancer in a mouse model. 8,14 We previously demonstrated that forced expression of CXCR3 promotes colon cancer metastasis preferentially to the draining lymph nodes (LNs) with poor prognosis. 6 In 92 human colon cancer specimens, CXCR3 was expressed in 31 (34%) cases, and correlated with the metastatic frequencies to LNs and distant organs.…”