晚期乳腺癌骨转移前究竟发生了什么
晚期乳腺癌远处转移最常见于骨骼，大约占65%～75%，可引起溶骨病变。虽然双膦酸盐可预防或减轻乳腺癌骨转移后晚期溶骨病变，但是效果不佳或不持久，故有必要探索晚期乳腺癌骨转移前究竟发生了什么，以采取相应措施进行预防。
2021年3月17日，美国科学促进会《科学》旗下《科学进展》在线发表美国康奈尔大学、德国马克斯普朗克胶体界面研究所的研究报告，探讨了三阴性乳腺癌在原发肿瘤转移溶骨前对骨骼微环境的影响，及其对转移扩散和疾病进展的调节机制。
为了模拟乳腺癌骨转移前的骨骼变化，该研究首先将培养过人类三阴性乳腺癌细胞MDA-MB-231的肿瘤条件培养液（内含肿瘤细胞分泌的活性物质，包括少量生长因子）注入免疫受损小鼠体内。随后，对这些小鼠的骨骼进行多种分析，包括核糖核酸（RNA）测序、组织学分析、微型CT成像、X射线散射电子显微镜分析、激光扫描显微镜分析、拉曼显微镜成像。
结果发现，血液循环中的肿瘤分泌因子并不影响小鼠生长或骨骼细胞活性。与乳腺癌骨转移后引起骨质溶解相反，肿瘤条件培养液在乳腺癌骨转移前可诱发新的骨质形成，与对照骨骼相比，其特征为矿物质沉积速率增加、骨质改变、基质减少、碳酸盐增加、骨骺与骨干交界部位的生长板附近矿物质沉积。
因此，该研究结果表明，乳腺癌分泌的生长因子可干扰转移前骨骼生长，这可能影响肿瘤细胞启动播种，并为进一步开发预防乳腺癌骨转移的靶向药物奠定了基础。
Sci Adv. 2021 Mar 17;7(12):eabf2283.
Breast cancer-secreted factors perturb murine bone growth in regions prone to metastasis.
Aaron E. Chiou, Chuang Liu, Inés Moreno-Jiménez, Tengteng Tang, Wolfgang Wagermaier, Mason N. Dean, Claudia Fischbach, Peter Fratzl.
Cornell University, Ithaca, NY, USA; Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.
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.
DOI: 10.1126/sciadv.abf2283