The microstructure of metastatic bone lesions suggests tumor mediated alterations in bone mineralization

Breast, prostate and lung cancer cells frequently metastasize to bone, leading to disruption of the bone microstructure. This study utilized mechanical testing coupled with micro-CT imaging, digital volume correlation (DVC), and atomic force microscopy (AFM) nanomechanical testing to examine the mechanical property variations in mouse long bones (tibia) with metastatic lung cancer cell involvement, spanning from the whole-bone scale to the microstructural level. In addition, we also investigated how metastatic invasion alters the morphology of hydroxyapatite nanocrystals in bone at the nanometer scale. The biochemical composition within metastatic lesions was assessed using Raman spectroscopy and correlated with AFM mechanical testing data. Our results demonstrate that lung cancer bone metastasis induces region-specific demineralization and microarchitectural alterations, which likely depend on the local bone matrix structure before tumor invasion. In particular, lamellar cortical bone in the lung cancer cell metastatic region exhibits demineralization both within and between mineralized collagen fibrils, as well as increased porosity. In the tibial crest region, which naturally lacks organized lamellar architecture, demineralization occurs in a spatially nonuniform manner, resulting in the formation of clustered regions with varying mechanical stiffness. These localized differences in mineral and organic content, along with microstructural organization, may contribute to spatial heterogeneity in the mechanical integrity of the tumor-bearing bone, leading to impaired mechanical strength. These findings offer new insights into microstructural alterations within the tumor-bone microenvironment during metastatic progression.