CD14+CD16+单核细胞亚群在乳腺癌骨转移中的作用及机制研究

Osteolytic bone destruction is a major clinical problem in bone metastases of breast cancer. CD14+CD16+monocytes are a potential cytological marker of circulating osteoclast precursors in multiple myeloma. In our previous study, a high percentage of CD14+CD16+ monocyte subpopulation was detected in peripheral blood of breast cancer patients with bone metastasis. We speculate that CD14+CD16+ monocyte expanded in breast cancer patients with bone metastasis may play a role as precursors of osteoclasts. Previous study in breast caner bone metastasis indicated that MCP-1 can promote osteoclast differentiation and induce osteolytic bone destruction. High level of MCP-1 expression was observed in breast cancer patients with bone metastasis in our study. MCP-1 may play a key role in the process of CD14+CD16+monocyte-to-osteoclast differentiation. Recent studies suggest that osteoclast precursor can differentiate into osteoclast via OPG-RANKL-RANK pathway. Based on these results, we will detect the level of CD14+CD16+ monocyte and MCP-1 in breast cancer patients with bone metastasis, and investigate the roles of OPG-RANKL-RANK pathway in the process of CD14+CD16+monocyte-to-osteoclast differentiation. Through the research of this subject, we will further reveal the additional mechanism of the breast caner bone metastasis and provide new strategies and targets for prevention and treatment of breast caner bone metastasis.

破骨细胞的激活在乳腺癌溶骨性骨转移中发挥着关键作用。人CD14+单核细胞为破骨细胞前体细胞。多发性骨髓瘤患者外周血的CD14+CD16+单核细胞具有分化为破骨细胞的潜能，提示其可能是破骨细胞前体细胞，我们研究发现CD14+CD16+单核细胞在乳腺癌骨转移患者外周血中明显增高，然而其是否可以向破骨细胞分化尚不明确。在乳腺癌骨转移中MCP-1等可以通过诱导破骨细胞分化促进骨破坏，我们研究发现乳腺癌骨转移患者血清MCP-1表达水平明显增高。研究发现在破骨前体细胞向破骨细胞分化过程中，OPG-RANKL-RANK信号通路发挥着关键作用。基于以上分析，本课题拟在前期研究的基础上，首次分析CD14+CD16+单核细胞以及MCP-1在乳腺癌骨转移中的表达水平，并围绕OPG-RANKL-RANK通路探讨MCP-1诱导CD14+CD16+单核细胞向破骨细胞分化的机制，为乳腺癌骨转移的防治提供新的策略及靶点。

人CD14+单核细胞为破骨细胞前体细胞。多发性骨髓瘤患者外周血的CD14+CD16+单核细胞具有分化为破骨细胞的潜能，提示其可能是破骨细胞前体细胞。我们研究发现CD14+CD16+单核细胞在乳腺癌骨转移患者外周血中明显增高。进一步研究发现乳腺癌细胞培养上清可以诱导CD14+CD16+单核细胞分化为破骨细胞。同时，研究发现乳腺癌骨转移患者血清MCP-1表达水平明显增高，在乳腺癌骨转移中MCP-1在CD14+CD16+单核细胞向破骨细胞分化中发挥着关键作用，进而可以诱导并促进骨转移的发生。作为本课题研究充分的补充和扩展，相似的结果在肺癌骨转移患者中同样被发现。进一步研究发现RANKL-RANK信号通路在MCP-1诱导CD14+CD16+单核细胞向破骨细胞分化过程中发挥着关键作用。总之，本研究从多角度探究了MCP-1诱导CD14+CD16+单核细胞向破骨细胞分化在肿瘤骨转移中发挥的核心作用。并发现RANKL-RANK信号通路在其中发挥的重要作用。为恶性肿瘤骨转移相关机制的理解做出了有价值的补充，提供了新的靶点。