Location matters: osteoblast and osteoclast distribution is modified by the presence and proximity to breast cancer cells in vivo
Location matters: osteoblast and osteoclast distribution is modified by the presence and proximity to breast cancer cells in vivo
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DOI：
10.1007/s10585-012-9481-5
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发表时间：
2012-12-01
影响因子：
4
通讯作者：
Holen, I.
中科院分区：
文献类型：
--
作者：
Brown, H. K.;Ottewell, P. D.;Holen, I.
骨转移是乳腺癌常见的不可治愈的并发症，影响约70%的晚期乳腺癌患者。为了改善这些患者的预后，需要建立骨转移的细胞和分子机制。迄今为止，大多数研究都集中在终末期疾病上，对骨初始肿瘤细胞定植后发生的事件知之甚少。在这里，我们报告了一项纵向研究的结果，该研究详细分析了骨转移进展过程中骨和癌细胞之间的空间和时间关系。通过在免疫受损小鼠中心脏内接种MDA-MB-231-GFP乳腺癌细胞来启动骨中的肿瘤生长。区分与肿瘤直接接触的骨区域和远离癌细胞但在肿瘤承载骨内的区域，我们对破骨细胞和成骨细胞的数量和分布进行了全面分析。从第10天开始，在骨中可检测到肿瘤集落，而从第19天开始，骨小梁体积明显减少。癌症引起的成骨细胞和破骨细胞数量的变化基本上取决于细胞是否与肿瘤直接接触。与未经处理的对照组相比，与肿瘤直接接触的骨区域成骨细胞显著减少，但破骨细胞数量增加，而在远端区域则相反。我们的数据表明，肿瘤细胞诱导骨病变的出现之前，骨微环境的实质性变化，这表明，可能需要早期治疗干预，以反对肿瘤诱导的微环境的变化，从而肿瘤的进展。
Bone metastasis is a common incurable complication of breast cancer affecting around 70% of patients with advanced disease. In order to improve outcomes for these patients, the cellular and molecular mechanisms underlying bone metastasis need to be established. The majority of studies to date have focused on end-stage disease and little is known about the events taking place following initial tumour cell colonisation of bone. Here we report the results of a longitudinal study that provides detailed analysis of the spatial and temporal relationship between bone and cancer cells during progression of bone metastasis. Tumour growth in bone was initiated by intra-cardiac inoculation of MDA-MB-231-GFP breast cancer cells in immunocompromised mice. Differentiating between areas of bone in direct contact with the tumour and areas distal to the cancer cells but within the tumour bearing bone, we performed comprehensive analyses of the number and distribution of osteoclasts and osteoblasts. Tumour colonies were detectable in bone from day 10, while reduced trabecular bone volume was apparent from day 19 onwards. Cancer-induced changes in osteoblast and osteoclast numbers differed substantially depending on whether or not the cells were in direct contact with the tumour. Compared to na < ve controls, areas of bone in direct contact with the tumour had significantly reduced osteoblast but increased osteoclast numbers, whereas the reverse was found in distal areas. Our data demonstrate that tumour cells induce substantial changes in the bone microenvironment prior to the appearance of bone lesions, suggesting that early therapeutic intervention may be required to oppose the tumour-induced changes to the microenvironment und thus tumour progression.