Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells.
Scavenging of CXCL12 by CXCR7 promotes tumor growth and metastasis of CXCR4-positive breast cancer cells.
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DOI：
10.1038/onc.2011.633
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发表时间：
2012-11-08
期刊：
影响因子：
8
通讯作者：
Luker, G. D.
中科院分区：
文献类型：
--
作者：
Luker, K. E.;Lewin, S. A.;Mihalko, L. A.;Schmidt, B. T.;Winkler, J. S.;Coggins, N. L.;Thomas, D. G.;Luker, G. D.
趋化因子CXCL 12和受体CXCR 4控制乳腺癌和20多种其他人类恶性肿瘤原发肿瘤生长和转移的多个步骤。调节肿瘤微环境中CXCL 12可用性的机制将显著影响癌症进展和靶向CXCL 12-CXCR 4通路用于癌症化疗的持续努力。我们使用双荧光素酶成像来研究体内乳腺肿瘤中CXCL 12的CXCR 7依赖性清除，并量化CXCR 7对单独的CXCR 4+乳腺癌细胞群体的肿瘤生长和转移的影响。在人乳腺癌的小鼠异种移植模型中，体内成像显示，表达CXCR 7的恶性细胞减少了原发性肿瘤微环境中分泌的生物发光CXCL 12。利用生物发光CXCL 12的灵敏检测，我们还证明了CXCR 7+细胞减少了从原位肿瘤释放到循环中的趋化因子的量。免疫荧光染色显示，约30%的人原发性乳腺癌细胞表达CXCR 4和CXCR 7。在大多数情况下，CXCR 4和CXCR 7主要在肿瘤中的不同恶性细胞群上表达。我们通过将肿瘤异种移植物与CXCR 4+乳腺癌细胞、分泌CXCL 12的人乳腺成纤维细胞和CXCR 7+或对照乳腺癌细胞共植入来模拟这些人乳腺癌病例。生物发光成像显示，CXCR 7+乳腺癌细胞增强原位肿瘤和自发转移中CXCR 4+乳腺癌细胞的增殖。用清除CXCR 7趋化因子的小分子抑制剂治疗限制了CXCR 4+乳腺癌细胞在也含有恶性CXCR 7+细胞的肿瘤中的生长。这些研究建立了一种新的体内成像方法来量化肿瘤微环境中CXCR 7对趋化因子的清除，并确定CXCR 7+细胞促进CXCR 4+乳腺癌细胞的生长和转移。
Chemokine CXCL12 and receptor CXCR4 control multiple steps in primary tumor growth and metastasis in breast cancer and more than 20 other human malignancies. Mechanisms that regulate availability of CXCL12 in tumor microenvironments will substantially impact cancer progression and ongoing efforts to target the CXCL12-CXCR4 pathway for cancer chemotherapy. We used dual luciferase imaging to investigate CXCR7 dependent scavenging of CXCL12 in breast tumors in vivo and quantify effects of CXCR7 on tumor growth and metastasis of a separate population of CXCR4+ breast cancer cells. In a mouse xenograft model of human breast cancer, in vivo imaging showed that malignant cells expressing CXCR7 reduced bioluminescent CXCL12 secreted in the primary tumor microenvironment. Capitalizing on sensitive detection of bioluminescent CXCL12, we also demonstrated that CXCR7+ cells reduced amounts of chemokine released from orthotopic tumors into the circulation. Immunofluorescence staining of human primary breast cancers showed expression of CXCR4 and CXCR7 on malignant cells in ≈ 30% of cases. In most cases, CXCR4 and CXCR7 predominantly were expressed on separate populations of malignant cells in a tumor. We modeled these cases of human breast cancer by co-implanting tumor xenografts with CXCR4+ breast cancer cells, human mammary fibroblasts secreting CXCL12, and CXCR7+ or control breast cancer cells. Bioluminescence imaging showed that CXCR7+ breast cancer cells enhanced proliferation of CXCR4+ breast cancer cells in orthotopic tumors and spontaneous metastases. Treatment with a small molecule inhibitor of CXCR7 chemokine scavenging limited growth of CXCR4+ breast cancer cells in tumors that also contained malignant CXCR7+ cells. These studies establish a new in vivo imaging method to quantify chemokine scavenging by CXCR7 in the tumor microenvironment and identify that CXCR7+ cells promote growth and metastasis of CXCR4+ breast cancer cells.
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