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.
- 16.Mitsiades CS, McMillin DW, Klippel S, Hideshima T, Chauhan D, Richardson PG, Munshi NC, Anderson KC (2007) The role of the bone marrow microenvironment in the pathophysiology of myeloma and its significance in the development of more effective therapies. Hematol Oncol Clin North Am 21:1007–1034CrossRefPubMedGoogle Scholar
- 23.Selander KS, Monkkonen J, Karhukorpi EK, Harkonen P, Hannuniemi R, Vaananen HK (1996) Characteristics of clodronate-induced apoptosis in osteoclasts and macrophages. Mol Pharmacol 5:1127–1138Google Scholar
- 24.Murakami H, Takahashi N, Sasaki T, Udagawa N, Tanaka S, Nakamura I, Zhang D, Barbier A, Suda T (1995) A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders. Bone 17(2):137–144CrossRefPubMedGoogle Scholar
- 29.Giuliani N, Pedrazzoni M, Negri G, Passeri G, Impicciatore M, Girasole G (1998) Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo. Bone 22:455–461CrossRefPubMedGoogle Scholar
- 37.Hue TF, Cummings SR, Cauley JA, Bauer DC, Ensrud KE, Barrett-Connor E, Black DM (2014) Effect of bisphosphonate use on risk of postmenopausal breast cancer results from the randomized clinical trials of alendronate and zoledronic acid. JAMA Intern Med 174:1550–1557CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Coleman R et al (2013) Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomized trials. In: San Antonio breast cancer symposium, San Antonio, TX (Abstract S4-07)Google Scholar
- 46.Wang N, Docherty FE, Brown HK, Reeves KJ, Fowles AC, Ottewell PD, Dear TN, Holen I, Croucher PI, Eaton CL (2014) Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis—evidence from in vivo models. J Bone Miner Res 29:2688–2696CrossRefPubMedGoogle Scholar
- 52.Powles T, Paterson A, McCloskey E, Schein P, Scheffler B, Tidy A, Ashley S, Smith I, Ottestad L, Kanis J (2006) Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8:R13CrossRefPubMedPubMedCentralGoogle Scholar
- 56.Lochter A, Galosy S, Muschler J, Freedman N, Werb Z, Bissell MJ (1997) Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol 139:1861–1872CrossRefPubMedPubMedCentralGoogle Scholar