title: Bone microenvironment-mediated resistance of cancer cells to bisphosphonates and impact on bone osteocytes/stem cells.
abstract: 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.
authors.affiliation: Department of Periodontology, Goldman School of Dental Medicine, Boston University, 650 Albany Street, Boston, MA, 02118, USA.
authors.forename: Abeer
authors.initials: A
authors.lastname: Alasmari
authors.affiliation: Department of Periodontology, Goldman School of Dental Medicine, Boston University, 650 Albany Street, Boston, MA, 02118, USA.
authors.forename: Shih-Chun
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Department of Periodontology, Goldman School of Dental Medicine, Boston University, 650 Albany Street, Boston, MA, 02118, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Dibart
authors.affiliation: Department of Periodontology, Goldman School of Dental Medicine, Boston University, 650 Albany Street, Boston, MA, 02118, USA. Salih@bu.edu.
authors.forename: Erdjan
authors.initials: E
authors.lastname: Salih
mesh_terms: D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary*; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy / Q000473:pathology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D010011:Osteocytes / Q000187:drug effects / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates
keywords: Alendronate (Fosamax); Biomineralization; Bisphosphonates; Bone resorption/formation; Cancer-bone metastasis, prostate and breast cancer cells; Ex-vivo three-dimensional models; Osteocytes; Osteoporosis; Stem cells