Department of Materials Science and Engineering, Cornell University, Ithaca, NY, USA.
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
Biomaterials. 2018 Oct;179:71-82. doi: 10.1016/j.biomaterials.2018.06.030. Epub 2018 Jun 22.
Microcalcifications serve as diagnostic markers for breast cancer, yet their formation pathway(s) and role in cancer progression are debated due in part to a lack of relevant 3D culture models that allow studying the extent of cellular regulation over mineralization. Previous studies have suggested processes ranging from dystrophic mineralization associated with cell death to bone-like mineral deposition. Here, we evaluated microcalcification formation in 3D multicellular spheroids, generated from non-malignant, pre-cancer, and invasive cell lines from the MCF10A human breast tumor progression series. The spheroids with greater malignancy potential developed necrotic cores, thus recapitulating spatially distinct viable and non-viable areas known to regulate cellular behavior in tumors in vivo. The spatial distribution of the microcalcifications, as well as their compositions, were characterized using nanoCT, electron-microscopy, and X-ray spectroscopy. Apatite microcalcifications were primarily detected within the viable cell regions and their number and size increased with malignancy potential of the spheroids. Levels of alkaline phosphatase decreased with malignancy potential, whereas levels of osteopontin increased. These findings support a mineralization pathway in which cancer cells induce mineralization in a manner that is linked to their malignancy potential, but that is distinct from physiological osteogenic mineralization.
微钙化被用作乳腺癌的诊断标志物，但由于缺乏相关的 3D 培养模型，无法研究细胞对矿化的调控程度，其形成途径及其在癌症进展中的作用仍存在争议。先前的研究表明，其过程范围从与细胞死亡相关的营养不良性矿化到骨样矿物质沉积。在这里，我们评估了来自 MCF10A 人乳腺癌肿瘤进展系列的非恶性、癌前和侵袭性细胞系的 3D 多细胞球体中的微钙化形成。具有更高恶性潜能的球体形成了坏死核心，从而再现了体内已知调节肿瘤中细胞行为的空间上不同的存活和非存活区域。使用纳米 CT、电子显微镜和 X 射线光谱学来表征微钙化的空间分布及其组成。磷灰石微钙化主要存在于活细胞区域内，其数量和大小随球体的恶性潜能增加而增加。碱性磷酸酶的水平随恶性潜能的增加而降低，而骨桥蛋白的水平则增加。这些发现支持一种矿化途径，其中癌细胞以与恶性潜能相关的方式诱导矿化，但与生理成骨矿化不同。
