Disruption of Collagen Matrix Alignment in Osteolytic Bone Metastasis Induced by Breast Cancer

Abstract

Breast cancer is highly metastatic to bone tissue and causes osteolytic lesions through osteoclast activation. Although the effects of osteolytic metastasis on bone quantity have been well studied, whether osteoclast activation induced by cancer bone metastasis affects the bone microstructure, a notable aspect of the bone quality, remains uncertain. The aim of this study was to clarify the effect of osteolytic bone metastasis in breast cancer on the microstructure of the bone matrix, particularly the integrity of collagen bril orientation. Osteolytic breast cancer cells induced hyperactivation of osteoclasts both in vivo and in vitro. Osteoclasts differentiated by culture of monocytes in the cancer cell-derived conditioned medium had an increased number of nuclei; more speci c podosome structures were organized compared to osteoclasts differentiated in the control medium. These observations suggest that the resorptive capacity of a single osteoclast was abnormally upregulated in the cancer-involving environment, causing geometrically irregular resorption cavities. Histological studies on mouse femurs with metastasis of breast cancer MDA-MB-231 cells revealed that the osteoclasts in the metastatic bone were abnormally large and they generated resorption cavities that are irregular both in size and in shape. Notably, collagen matrix in newly formed bone in metastatic bone exhibited a signi cantly disorganized architecture. To the best of our knowledge, this is the rst report demonstrating that osteolytic bone metastasis induces the disruption of bone matrix alignment, which determines the mechanical function of bone in both intact and diseased bone tissue.

Dynamic Collision Behavior Between Osteoblasts and Tumor Cells Regulates the Disordered Arrangement of Collagen Fiber/Apatite Crystals in Metastasized Bone

“…We have clarified that apatite orientation is the dominant determiner of bony mechanical function [ 19 ]. The ex vivo tumor-invaded bone showed a significantly disrupted alignment of apatite crystals ( Figure 2 ), which is consistent with our previous in vivo reports [ 7 , 8 , 20 ]. Our ex vivo model can represent the alteration of bone apatite orientation in response to the external loading conditions [ 21 ].…”

“…Intact bone tissue exhibits a characteristic anisotropic microstructure based on collagen fiber alignment and the related c -axis orientation of apatite crystals [ 4 , 5 ], which is derived from the intercellular molecular events mediating the cellular arrangement [ 6 ]. We recently discovered that the disorganized, less-aligned collagen/apatite microstructure in cancer-bearing bone is a dominant determiner in the disruption of bone mechanical function [ 7 , 8 ]. However, the biological scenarios that stimulate the disorganization of metastasized bone microstructures are not fully understood.…”

The Bone Extracellular Matrix as an Ideal Milieu for Cancer Cell Metastases

“…In bone metastatic cancers, type I collagen production and orientation is known to be altered [66,68]. There is increased collagen production at the bone metastatic site, whereby secreted collagen molecules are dense, misaligned, and disorganized, further disrupting bone mechanical function (Figure 5b) [66,75]. Liu et al identified that metastatic breast cancer cells secreted miR-218 which directly regulated type I collagen secretion from osteoblasts in the bone niche [76].…”

Alteration of osteoblast arrangement via direct attack by cancer cells: New insights into bone metastasis

“…Tumor invasion and metastasis effect dynamic changes in targeted organs both histologically and genetically 3 . Interestingly, our recent study revealed that cancer cells alter the anisotropic microstructure of metastasized bone 4 5 . Homing of cancer cells to bone induces disrupted mechanical function derived from the disorganized microstructure associated with the less aligned crystallographic structure of apatite c -axis with the hexagonal lattice of the P6 3 /m space group.…”

“…Recently, we had established a bone-mimetic anisotropic culture model by controlling the orientation of the substrate collagen 11 . Further development of the culture model by combining the artificially-controlled anisotropic culture substrate with the cancer-bone coculture system is necessary to study the cellular mechanisms behind the metastasis-mediated disorganization of the anisotropic bone microstructure 4 5 . Here, focusing on the cellular orientation in response to the collagen molecular anisotropy, coculture of cancer cells and osteoblasts was performed on an artificially controlled oriented collagen scaffold.…”