Templeton Zach S, Lie Wen-Rong, Wang Weiqi, Rosenberg-Hasson Yael, Alluri Rajiv V, Tamaresis John S, Bachmann Michael H, Lee Kitty, Maloney William J, Contag Christopher H, King Bonnie L
Department of Pediatrics, 150E Clark Center, 318 Campus Drive, Stanford University School of Medicine, Stanford, CA 94305-5427.
EMD Millipore Corporation, 14 Research Park Drive, St Charles, MO 63304-5618.
Neoplasia. 2015 Dec;17(12):849-861. doi: 10.1016/j.neo.2015.11.005.
BACKGROUND/OBJECTIVES: Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche.
Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry.
Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment.
Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche.
背景/目的：骨是乳腺癌转移的常见部位，这表明存在吸引并促进乳腺癌细胞生长的组织特异性特征。我们试图确定与乳腺癌细胞骨嗜性及转移龛中定植相关的人骨组织参数。
研究了MDA-MB-231-fLuc-EGFP（荧光素酶增强型绿色荧光蛋白）和MCF-7-fLuc-EGFP乳腺癌细胞与从14例髋关节置换术中分离出的松质骨组织碎片共培养时的迁移和定植模式。使用生物发光成像在Transwell迁移小室中测量乳腺癌细胞向组织及组织条件培养基的迁移情况，并作为通过多重免疫测定法测量的分泌因子的函数进行分析。用荧光显微镜和免疫组织化学评估乳腺癌细胞的定植模式。
在14个标本中的12个中观察到MDA-MB-231-fLuc-EGFP乳腺癌细胞向骨条件培养基而非对照培养基的迁移增强（P = 0.0014），在单变量和多变量回归分析中，这与脂肪因子/细胞因子瘦素（P = 0.006）和IL-1β（P = 0.001）水平升高显著相关。碎片的荧光显微镜检查和免疫组织化学强调了成人骨组织的极度肥胖，并揭示了骨髓脂肪组织隔室内广泛的乳腺癌细胞定植。
我们的结果表明，乳腺癌细胞迁移至人骨组织条件培养基与瘦素和IL-1β水平升高有关，并在培养碎片的骨髓脂肪组织隔室内定植。骨髓脂肪组织及其分子信号可能是乳腺癌转移龛中重要但研究不足的组成部分。
