Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany.
Sci Adv. 2021 Mar 17;7(12). doi: 10.1126/sciadv.abf2283. Print 2021 Mar.
Breast cancer frequently metastasizes to bone, causing osteolytic lesions. However, how factors secreted by primary tumors affect the bone microenvironment before the osteolytic phase of metastatic tumor growth remains unclear. Understanding these changes is critical as they may regulate metastatic dissemination and progression. To mimic premetastatic bone adaptation, immunocompromised mice were injected with MDA-MB-231-conditioned medium [tumor-conditioned media (TCM)]. Subsequently, the bones of these mice were subjected to multiscale, correlative analysis including RNA sequencing, histology, micro-computed tomography, x-ray scattering analysis, and Raman imaging. In contrast to overt metastasis causing osteolysis, TCM treatment induced new bone formation that was characterized by increased mineral apposition rate relative to control bones, altered bone quality with less matrix and more carbonate substitution, and the deposition of disoriented mineral near the growth plate. Our study suggests that breast cancer-secreted factors may promote perturbed bone growth before metastasis, which could affect initial seeding of tumor cells.
乳腺癌常转移至骨骼，引发溶骨性病变。然而，原发肿瘤分泌的因子如何在转移性肿瘤生长的溶骨性阶段之前影响骨微环境尚不清楚。了解这些变化至关重要，因为它们可能调节转移的扩散和进展。为了模拟转移前的骨骼适应，免疫功能低下的小鼠被注射 MDA-MB-231 条件培养基[肿瘤条件培养基（TCM）]。随后，对这些小鼠的骨骼进行多尺度相关分析，包括 RNA 测序、组织学、微计算机断层扫描、X 射线散射分析和拉曼成像。与导致溶骨性的明显转移不同，TCM 处理诱导新骨形成，其特征是与对照骨相比，矿化速率增加，骨质量改变，基质减少，碳酸盐取代增加，生长板附近无序矿化的沉积。我们的研究表明，乳腺癌分泌的因子可能在转移前促进骨骼生长紊乱，这可能会影响肿瘤细胞的初始播种。
