The Chemokine CCL2 Increases Prostate Tumor Growth and Bone Metastasis through Macrophage and Osteoclast Recruitment
The Chemokine CCL2 Increases Prostate Tumor Growth and Bone Metastasis through Macrophage and Osteoclast Recruitment
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DOI：
10.1593/neo.09988
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发表时间：
2009-11-01
期刊：
影响因子：
4.8
通讯作者：
Pienta, Kenneth J.
中科院分区：
文献类型：
--
作者：
Mizutani, Kosuke;Sud, Sudha;Pienta, Kenneth J.
CC趋化因子配体2（CCL 2，也称为单核细胞趋化蛋白-1）已被证明可以将单核细胞募集到肿瘤部位。单核细胞能够分化为肿瘤相关巨噬细胞（TAM）和破骨细胞（OC）。TAM已被证明在几种癌症类型中促进肿瘤生长。破骨细胞也被认为在癌症骨转移中起重要作用。为了研究CCL 2对肿瘤发生的影响及其对人前列腺癌骨转移的潜在影响，将CCL 2过表达到经内切酶标记的人前列腺癌细胞系PC-3中。在体外，与来自PC-3（lucMock）的条件培养基相比，过表达CCL 2的PC-3luc细胞（PC-3（lucCCL 2））的条件培养基是小鼠单核细胞的有效化学引诱物。此外，CCL 2过表达增加了移植的异种移植物的生长，并增加了体内巨噬细胞的积累。在肿瘤扩散模型中，PC-3（lucCCL 2）增强了骨转移的生长，这与更多功能性OC相关。靶向人和小鼠CCL 2的中和抗体抑制PC-3（luc）的生长，这伴随着巨噬细胞向肿瘤的募集减少。这些发现表明，CCL 2通过将巨噬细胞和OC募集到肿瘤部位来增加肿瘤生长和骨转移。
CC chemokine ligand 2 (CCL2, also known as monocyte chemoattractant protein-1) has been demonstrated to recruit monocytes to tumor sites. Monocytes are capable of being differentiated into tumor-associated macrophages (TAMs) and osteoclasts (OCs). TAMs have been shown to promote tumor growth in several cancer types. Osteoclasts have also been known to play an important role in cancer bone metastasis. To investigate the effects of CCL2 on tumorigenesis and its potential effects on bone metastasis of human prostate cancer, CCL2 was overexpressed into a luciferase-tagged human prostate cancer cell line PC-3. In vitro, the conditioned medium of CCL2 overexpressing PC-3luc cells (PC-3(lucCCL2)) was a potent chemoattractant for mouse monocytes in comparison to a conditioned medium from PC-3(lucMock). In addition, CCL2 overexpression increased the growth of transplanted xenografts and increased the accumulation of macrophages in vivo. In a tumor dissemination model, PC-3(lucCCL2) enhanced the growth of bone metastasis, which was associated with more functional OCs. Neutralizing antibodies targeting both human and mouse CCL2 inhibited the growth of PC-3(luc), which was accompanied by a decrease in macrophage recruitment to the tumor. These findings suggest that CCL2 increases tumor growth and bone metastasis through recruitment of macrophages and OCs to the tumor site.