Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Oncogene. 2012 Nov 8;31(45):4750-8. doi: 10.1038/onc.2011.633. Epub 2012 Jan 23.
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 limited the 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.
趋化因子 CXCL12 和受体 CXCR4 控制乳腺癌和 20 多种其他人类恶性肿瘤中原发性肿瘤生长和转移的多个步骤。调节肿瘤微环境中 CXCL12 可用性的机制将极大地影响癌症进展和当前针对 CXCL12-CXCR4 途径进行癌症化疗的努力。我们使用双荧光素酶成像来研究体内乳腺癌肿瘤中 CXCR7 依赖性的 CXCL12 清除，并定量分析 CXCR7 对另一群 CXCR4+乳腺癌细胞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 CXCR7 的恶性细胞减少了原发性肿瘤微环境中分泌的生物发光 CXCL12。利用对生物发光 CXCL12 的敏感检测，我们还证明 CXCR7+细胞减少了从原位肿瘤释放到循环中的趋化因子的量。对人原发性乳腺癌的免疫荧光染色显示，约 30%的病例中恶性细胞表达 CXCR4 和 CXCR7。在大多数情况下，CXCR4 和 CXCR7 主要在肿瘤中恶性细胞的不同群体上表达。我们通过共同植入携带 CXCR4+乳腺癌细胞、分泌 CXCL12 的人乳腺成纤维细胞和 CXCR7+或对照乳腺癌细胞的肿瘤异种移植物来模拟这些人乳腺癌病例。生物发光成像显示，CXCR7+乳腺癌细胞增强了原位肿瘤中 CXCR4+乳腺癌细胞的增殖和自发转移。用 CXCR7 趋化因子的小分子抑制剂治疗可限制含有恶性 CXCR7+细胞的肿瘤中 CXCR4+乳腺癌细胞的生长。这些研究建立了一种新的体内成像方法，用于定量测量肿瘤微环境中 CXCR7 对趋化因子的清除，并确定 CXCR7+细胞促进 CXCR4+乳腺癌细胞的生长和转移。
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