Bone microenvironment-mediated resistance of cancer cells to bisphosphonates and impact on bone osteocytes/stem cells
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Anti-resorptive bisphosphonates (BPs) have been clinically used to prevent cancer-bone metastasis and cancer-induced bone pathologies despite the fact that the phenotypic response of the cancer-bone interactions to BP exposure is “uncharted territory”. This study offers unique insights into the interplay between cancer stem cells and osteocytes/osteoblasts and mesenchymal stem cells using a three-dimensional (3D) live cancer-bone interactive model. We provide extraordinary cryptic details of the biological events that occur as a result of alendronate (ALN) treatment using 3D live cancer-bone model systems under specific bone remodeling stages. While cancer cells are susceptible to BP treatment in the absence of bone, they are totally unaffected in the presence of bone. Cancer cells colonize live bone irrespective of whether the bone is committed to bone resorption or formation and hence, cancer-bone metastasis/interactions are though to be “independent of bone remodeling stages”. In our 3D live bone model systems, ALN inhibited bone resorption at the osteoclast differentiation level through effects of mineral-bound ALN on osteocytes and osteoblasts. The mineral-bound ALN rendered bone incapable of osteoblast differentiation, while cancer cells colonize the bone with striking morphological adaptations which led to a conclusion that a direct anti-cancer effect of BPs in a “live or in vivo” bone microenvironment is implausible. The above studies were complemented with mass spectrometric analysis of the media from cancer-bone organ cultures in the absence and presence of ALN. The mineral-bound ALN impacts the bone organs by limiting transformation of mesenchymal stem cells to osteoblasts and leads to diminished endosteal cell population and degenerated osteocytes within the mineralized bone matrix.
KeywordsEx-vivo three-dimensional models Cancer-bone metastasis, prostate and breast cancer cells Bone resorption/formation Osteocytes Stem cells Osteoporosis Bisphosphonates Alendronate (Fosamax) Biomineralization
The work was made possible by private funds of Dr. Salih, and support from The Department of Periodontology, Goldman School of Dental Medicine, Boston University and was not supported by NIH/NIDCR funds. The authors thank Professor M. Kirber for use of the LSM 710 2-photon confocal microscope in the BUMC “Cellular Imaging Core Facility”; and Professor J. Pudney (Department of Obstetrics and Gynecology) and Professor Steven Borkan (Department of Medicine), Boston University School of Medicine for pre-submission review of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors have declared that no conflict of interest exists.
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