Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer
Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer
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DOI：
10.1158/0008-5472.can-06-0709
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Fulton, Amy M.
中科院分区：
文献类型：
--
作者：
Walser, Tonya C.;Rifat, Salah;Fulton, Amy M.
肿瘤细胞异常表达趋化因子和/或趋化因子受体，并且一些趋化因子和/或趋化因子受体可促进肿瘤生长和转移。我们研究了趋化因子受体CXCR 3在同基因小鼠转移性乳腺癌模型中的表达和功能。通过流式细胞术，在所有检查的小鼠乳腺肿瘤细胞系中均检测到CXCR 3。所有检测的人乳腺癌细胞系也表达CXCR 3，永生化但非致瘤性MCF-10A细胞系也表达CXCR 3。CXCR 3配体CXCL 9、CXCL 10和CXCL 11与高度恶性小鼠乳腺肿瘤细胞系66.1上的CXCR 3的相互作用导致细胞内钙动员和体外趋化性。为了检验肿瘤细胞表达的CXCR 3促进肿瘤转移的假设，我们采用了CXCR 3的小分子量拮抗剂AMG 487。66.1在静脉内注射到免疫活性雌性小鼠中之前，用AMG 487预处理肿瘤细胞。CXCR 3对66.1肿瘤细胞的拮抗作用抑制了实验性肺转移，并且这种抗转移活性在自然杀伤细胞耗尽的小鼠中受到损害。AMG 487的全身给药也抑制了实验性肺转移。与AMG 487的抗转移作用相反，66.1乳腺肿瘤的局部生长不受受体拮抗作用的影响。这些研究表明，小鼠乳腺肿瘤细胞表达CXCR 3，这有助于肺转移的发展。这些研究还首次表明CXCR 3的小分子量拮抗剂具有抑制肿瘤转移的潜力。
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.