Breast Cancer Cells Induce Osteolytic Bone Lesions In vivo through a Reduction in Osteoblast Activity in Mice

Abstract

Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients.

Three-Dimensional Mechanical Loading Modulates the Osteogenic Response of Mesenchymal Stem Cells to Tumor-Derived Soluble Signals

“…While most research on osteolytic breast cancer metastasis focuses on osteoclasts, osteoblasts are similarly critical as they can provide factors triggering osteoclastogenesis. 34 Yet breast cancer is generally accepted to inhibit osteogenic differentiation, 16,27,35,36 suppress numbers of mature osteoblasts, [37][38][39] reduce bone-forming activity and adhesion, 16,36,40 and increase osteoblast apoptosis. 15,39 Our results, in contrast, suggest enhanced osteogenic differentiation, which may be related to the stage of osteogenic differentiation at the time of exposure to tumor-derived factors.…”

Validating of the pre-clinical mouse model for metastatic breast cancer to the mandible

“…In this model, cancer cells are inserted extra-capsulary through the tibial crest, epiphysis, and growth plate and then cells are sequentially injected into the bone marrow space. The intra-tibia model does not precisely reflect the characteristics of bone-invasive OSCC 8 , 13 . Thus, it fails to address certain aspects of the clinical situation.…”

Osteoblasts are “educated” by crosstalk with metastatic breast cancer cells in the bone tumor microenvironment

“…2), we proceeded with the use of these cells for in vivo studies. MDA-MB-231 cells are a human triple-negative breast cancer cell line that frequently metastasize to and colonize the bone [44,[74][75][76]. MDA-MB-231GFP/Luc2 breast cancer cells were admixed with either EO-231 cells or vehicle-treated osteoblasts prior to intratibial injection.…”