{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T23:41:34Z","timestamp":1773963694770,"version":"3.50.1"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,7,14]],"date-time":"2016-07-14T00:00:00Z","timestamp":1468454400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,7,14]],"date-time":"2016-07-14T00:00:00Z","timestamp":1468454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The ability to rapidly assess the efficacy of therapeutic strategies for incurable bone metastatic prostate cancer is an urgent need. Pre-clinical <jats:italic>in vivo<\/jats:italic> models are limited in their ability to define the temporal effects of therapies on simultaneous multicellular interactions in the cancer-bone microenvironment. Integrating biological and computational modeling approaches can overcome this limitation. Here, we generated a biologically driven discrete hybrid cellular automaton (HCA) model of bone metastatic prostate cancer to identify the optimal therapeutic window for putative targeted therapies. As proof of principle, we focused on TGF\u03b2 because of its known pleiotropic cellular effects. HCA simulations predict an optimal effect for TGF\u03b2 inhibition in a pre-metastatic setting with quantitative outputs indicating a significant impact on prostate cancer cell viability, osteoclast formation and osteoblast differentiation. <jats:italic>In silico<\/jats:italic> predictions were validated <jats:italic>in vivo<\/jats:italic> with models of bone metastatic prostate cancer (PAIII and C4-2B). Analysis of human bone metastatic prostate cancer specimens reveals heterogeneous cancer cell use of TGF\u03b2. Patient specific information was seeded into the HCA model to predict the effect of TGF\u03b2 inhibitor treatment on disease evolution. Collectively, we demonstrate how an integrated computational\/biological approach can rapidly optimize the efficacy of potential targeted therapies on bone metastatic prostate cancer.<\/jats:p>","DOI":"10.1038\/srep29384","type":"journal-article","created":{"date-parts":[[2016,7,14]],"date-time":"2016-07-14T11:17:45Z","timestamp":1468495065000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Predictive computational modeling to define effective treatment strategies for bone metastatic prostate cancer"],"prefix":"10.1038","volume":"6","author":[{"given":"Leah M.","family":"Cook","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arturo","family":"Araujo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julio M.","family":"Pow-Sang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikalai M.","family":"Budzevich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Basanta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conor C.","family":"Lynch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,7,14]]},"reference":[{"key":"BFsrep29384_CR1","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1177\/107327481502200114","volume":"22","author":"JS Frieling","year":"2015","unstructured":"Frieling, J. S., Basanta, D. & Lynch, C. C. Current and emerging therapies for bone metastatic castration-resistant prostate cancer. Cancer control: journal of the Moffitt Cancer Center 22, 109\u2013120 (2015).","journal-title":"Cancer control: journal of the Moffitt Cancer Center"},{"key":"BFsrep29384_CR2","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/j.ctrv.2014.04.003","volume":"40","author":"X Deng","year":"2014","unstructured":"Deng, X. et al. Recent advances in bone-targeted therapies of metastatic prostate cancer. Cancer Treat Rev 40, 730\u2013738, doi: 10.1016\/j.ctrv.2014.04.003 (2014).","journal-title":"Cancer Treat Rev"},{"key":"BFsrep29384_CR3","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/bonekey.2015.10","volume":"4","author":"PD Ottewell","year":"2015","unstructured":"Ottewell, P. D., O\u2019Donnell, L. & Holen, I. Molecular alterations that drive breast cancer metastasis to bone. BoneKEy reports 4, 643, doi: 10.1038\/bonekey.2015.10 (2015).","journal-title":"BoneKEy reports"},{"key":"BFsrep29384_CR4","doi-asserted-by":"publisher","first-page":"6213s","DOI":"10.1158\/1078-0432.CCR-06-1007","volume":"12","author":"TA Guise","year":"2006","unstructured":"Guise, T. A. et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res 12, 6213s\u20136216s, doi: 12\/20\/6213s (2006).","journal-title":"Clin Cancer Res"},{"key":"BFsrep29384_CR5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.bone.2010.08.004","volume":"48","author":"P Juarez","year":"2010","unstructured":"Juarez, P. & Guise, T. A. TGF-beta in cancer and bone: implications for treatment of bone metastases. Bone 48, 23\u201329, doi: S8756-3282(10)01401-8 (2010).","journal-title":"Bone"},{"key":"BFsrep29384_CR6","doi-asserted-by":"crossref","unstructured":"Anderson, A. R. & Quaranta, V. Integrative mathematical oncology. Nat Rev Cancer 8, 227\u2013234, doi: nrc2329 (2008).","DOI":"10.1038\/nrc2329"},{"key":"BFsrep29384_CR7","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1021\/mp200458e","volume":"9","author":"D Basanta","year":"2012","unstructured":"Basanta, D., Gatenby, R. A. & Anderson, A. R. Exploiting evolution to treat drug resistance: combination therapy and the double bind. Molecular pharmaceutics 9, 914\u2013921, doi: 10.1021\/mp200458e (2012).","journal-title":"Molecular pharmaceutics"},{"key":"BFsrep29384_CR8","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/1745-6150-5-24","volume":"5","author":"SE Eikenberry","year":"2010","unstructured":"Eikenberry, S. E., Nagy, J. D. & Kuang, Y. The evolutionary impact of androgen levels on prostate cancer in a multi-scale mathematical model. Biology direct 5, 24, doi: 10.1186\/1745-6150-5-24 (2010).","journal-title":"Biology direct"},{"key":"BFsrep29384_CR9","doi-asserted-by":"publisher","first-page":"4894","DOI":"10.1158\/0008-5472.CAN-08-3658","volume":"69","author":"RA Gatenby","year":"2009","unstructured":"Gatenby, R. A., Silva, A. S., Gillies, R. J. & Frieden, B. R. Adaptive therapy. Cancer Res 69, 4894\u20134903, doi: 10.1158\/0008-5472.CAN-08-3658 (2009).","journal-title":"Cancer Res"},{"key":"BFsrep29384_CR10","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1182\/blood-2012-07-441956","volume":"121","author":"M Horn","year":"2013","unstructured":"Horn, M. et al. Model-based decision rules reduce the risk of molecular relapse after cessation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Blood 121, 378\u2013384, doi: 10.1182\/blood-2012-07-441956 (2013).","journal-title":"Blood"},{"key":"BFsrep29384_CR11","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/j.cell.2013.12.029","volume":"156","author":"K Leder","year":"2014","unstructured":"Leder, K. et al. Mathematical modeling of PDGF-driven glioblastoma reveals optimized radiation dosing schedules. Cell 156, 603\u2013616, doi: 10.1016\/j.cell.2013.12.029 (2014).","journal-title":"Cell"},{"key":"BFsrep29384_CR12","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1007\/s00285-008-0219-6","volume":"58","author":"R Rockne","year":"2009","unstructured":"Rockne, R., Alvord, E. C., Jr., Rockhill, J. K. & Swanson, K. R. A mathematical model for brain tumor response to radiation therapy. J Math Biol 58, 561\u2013578, doi: 10.1007\/s00285-008-0219-6 (2009).","journal-title":"J Math Biol"},{"key":"BFsrep29384_CR13","doi-asserted-by":"publisher","first-page":"7366","DOI":"10.1158\/0008-5472.CAN-11-1399","volume":"71","author":"KR Swanson","year":"2011","unstructured":"Swanson, K. R. et al. Quantifying the role of angiogenesis in malignant progression of gliomas: in silico modeling integrates imaging and histology. Cancer Res 71, 7366\u20137375, doi: 10.1158\/0008-5472.CAN-11-1399 (2011).","journal-title":"Cancer Res"},{"key":"BFsrep29384_CR14","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/sj.bjc.6604125","volume":"98","author":"KR Swanson","year":"2008","unstructured":"Swanson, K. R., Rostomily, R. C. & Alvord, E. C., Jr. A mathematical modelling tool for predicting survival of individual patients following resection of glioblastoma: a proof of principle. British Journal of Cancer 98, 113\u2013119, doi: 10.1038\/sj.bjc.6604125 (2008).","journal-title":"British Journal of Cancer"},{"key":"BFsrep29384_CR15","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1002\/wsbm.102","volume":"3","author":"KA Rejniak","year":"2011","unstructured":"Rejniak, K. A. & Anderson, A. R. Hybrid models of tumor growth. Wiley interdisciplinary reviews . Systems biology and medicine 3, 115\u2013125, doi: 10.1002\/wsbm.102 (2011).","journal-title":"Systems biology and medicine"},{"key":"BFsrep29384_CR16","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/j.cell.2006.09.042","volume":"127","author":"AR Anderson","year":"2006","unstructured":"Anderson, A. R., Weaver, A. M., Cummings, P. T. & Quaranta, V. Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell 127, 905\u2013915, doi: 10.1016\/j.cell.2006.09.042 (2006).","journal-title":"Cell"},{"key":"BFsrep29384_CR17","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1158\/0008-5472.CAN-14-1428","volume":"75","author":"M Robertson-Tessi","year":"2015","unstructured":"Robertson-Tessi, M., Gillies, R. J., Gatenby, R. A. & Anderson, A. R. Impact of metabolic heterogeneity on tumor growth, invasion, and treatment outcomes. Cancer Res 75, 1567\u20131579, doi: 10.1158\/0008-5472.CAN-14-1428 (2015).","journal-title":"Cancer Res"},{"key":"BFsrep29384_CR18","doi-asserted-by":"publisher","first-page":"2391","DOI":"10.1158\/0008-5472.CAN-13-2652","volume":"74","author":"A Araujo","year":"2014","unstructured":"Araujo, A., Cook, L. M., Lynch, C. C. & Basanta, D. An integrated computational model of the bone microenvironment in bone-metastatic prostate cancer. Cancer Res 74, 2391\u20132401, doi: 10.1158\/0008-5472.CAN-13-2652 (2014).","journal-title":"Cancer Res"},{"key":"BFsrep29384_CR19","doi-asserted-by":"crossref","unstructured":"Gallaher, J. et al. Improving Treatment Strategies for Patients with Metastatic Castrate Resistan Prostate Cancer through Personalized Computational Modeling. Clin Exp Metastasis In Press (2014).","DOI":"10.1007\/s10585-014-9674-1"},{"key":"BFsrep29384_CR20","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1158\/2159-8290.CD-13-0465","volume":"4","author":"B Zhao","year":"2014","unstructured":"Zhao, B., Pritchard, J. R., Lauffenburger, D. A. & Hemann, M. T. Addressing Genetic Tumor Heterogeneity through Computationally Predictive Combination Therapy. Cancer Discov 4, 166\u2013174, doi: 10.1158\/2159-8290.CD-13-0465 (2014).","journal-title":"Cancer Discov"},{"key":"BFsrep29384_CR21","first-page":"473","volume":"1","author":"RR Berges","year":"1995","unstructured":"Berges, R. R. et al. Implication of cell kinetic changes during the progression of human prostatic cancer. Clin Cancer Res 1, 473\u2013480 (1995).","journal-title":"Clin Cancer Res"},{"key":"BFsrep29384_CR22","doi-asserted-by":"publisher","first-page":"e90353","DOI":"10.1371\/journal.pone.0090353","volume":"9","author":"JC Morris","year":"2014","unstructured":"Morris, J. C. et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One 9, e90353, doi: 10.1371\/journal.pone.0090353 (2014).","journal-title":"PLoS One"},{"key":"BFsrep29384_CR23","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1038\/nm.1943","volume":"15","author":"M Korpal","year":"2009","unstructured":"Korpal, M. et al. Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med 15, 960\u2013966, doi: 10.1038\/nm.1943 (2009).","journal-title":"Nat Med"},{"key":"BFsrep29384_CR24","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1016\/j.ejca.2010.02.040","volume":"46","author":"M Korpal","year":"2010","unstructured":"Korpal, M. & Kang, Y. Targeting the transforming growth factor-beta signalling pathway in metastatic cancer. Eur J Cancer 46, 1232\u20131240, doi: 10.1016\/j.ejca.2010.02.040 (2010).","journal-title":"Eur J Cancer"},{"key":"BFsrep29384_CR25","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1038\/nrc1926","volume":"6","author":"B Bierie","year":"2006","unstructured":"Bierie, B. & Moses, H. L. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 6, 506\u2013520 (2006).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep29384_CR26","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1002\/jbmr.5650050805","volume":"5","author":"J Pfeilschifter","year":"1990","unstructured":"Pfeilschifter, J. et al. Chemotactic response of osteoblastlike cells to transforming growth factor beta. J Bone Miner Res 5, 825\u2013830, doi: 10.1002\/jbmr.5650050805 (1990).","journal-title":"J Bone Miner Res"},{"key":"BFsrep29384_CR27","doi-asserted-by":"crossref","first-page":"4267","DOI":"10.1242\/dev.126.19.4267","volume":"126","author":"E Filvaroff","year":"1999","unstructured":"Filvaroff, E. et al. Inhibition of TGF-beta receptor signaling in osteoblasts leads to decreased bone remodeling and increased trabecular bone mass. Development 126, 4267\u20134279 (1999).","journal-title":"Development"},{"key":"BFsrep29384_CR28","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1210\/er.2004-0001","volume":"26","author":"K Janssens","year":"2005","unstructured":"Janssens, K., Ten Dijke, P., Janssens, S. & Van Hul, W. Transforming growth factor-beta1 to the bone. Endocr.Rev. 26, 743\u2013774 (2005).","journal-title":"Endocr.Rev."},{"key":"BFsrep29384_CR29","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.1002\/jbmr.139","volume":"25","author":"JR Edwards","year":"2010","unstructured":"Edwards, J. R. et al. Inhibition of TGF-beta signaling by 1D11 antibody treatment increases bone mass and quality in vivo . J Bone Miner Res 25, 2419\u20132426, doi: 10.1002\/jbmr.139 (2010).","journal-title":"J Bone Miner Res"},{"key":"BFsrep29384_CR30","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/1476-4598-9-122","volume":"9","author":"V Ganapathy","year":"2010","unstructured":"Ganapathy, V. et al. Targeting the Transforming Growth Factor-beta pathway inhibits human basal-like breast cancer metastasis. Mol Cancer 9, 122, doi: 1476-4598-9-122 (2010).","journal-title":"Mol Cancer"},{"key":"BFsrep29384_CR31","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1002\/jcb.21255","volume":"101","author":"KA Brown","year":"2007","unstructured":"Brown, K. A., Pietenpol, J. A. & Moses, H. L. A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem 101, 9\u201333, doi: 10.1002\/jcb.21255 (2007).","journal-title":"J Cell Biochem"},{"key":"BFsrep29384_CR32","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1242\/jcs.113.13.2445","volume":"113","author":"K Fuller","year":"2000","unstructured":"Fuller, K., Lean, J. M., Bayley, K. E., Wani, M. R. & Chambers, T. J. A role for TGFbeta(1) in osteoclast differentiation and survival. J Cell Sci 113 (Pt 13), 2445\u20132453 (2000).","journal-title":"J Cell Sci"},{"key":"BFsrep29384_CR33","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1038\/nm1096-1132","volume":"2","author":"DE Hughes","year":"1996","unstructured":"Hughes, D. E. et al. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 2, 1132\u20131136 (1996).","journal-title":"Nat Med"},{"key":"BFsrep29384_CR34","doi-asserted-by":"crossref","unstructured":"Cook, L. M., Shay, G., Aruajo, A. & Lynch, C. C. Integrating new discoveries into the \u201cvicious cycle\u201d paradigm of prostate to bone metastases. Cancer Metastasis Rev, doi: 10.1007\/s10555-014-9494-4 (2014).","DOI":"10.1007\/s10555-014-9507-3"},{"key":"BFsrep29384_CR35","doi-asserted-by":"publisher","first-page":"20130020","DOI":"10.1098\/rsfs.2013.0020","volume":"3","author":"D Basanta","year":"2013","unstructured":"Basanta, D. & Anderson, A. R. Exploiting ecological principles to better understand cancer progression and treatment. Interface focus 3, 20130020, doi: 10.1098\/rsfs.2013.0020 (2013).","journal-title":"Interface focus"},{"key":"BFsrep29384_CR36","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1038\/nrc4029","volume":"15","author":"PM Altrock","year":"2015","unstructured":"Altrock, P. M., Liu, L. L. & Michor, F. The mathematics of cancer: integrating quantitative models. Nat Rev Cancer 15, 730\u2013745, doi: 10.1038\/nrc4029 (2015).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep29384_CR37","doi-asserted-by":"publisher","first-page":"e1003800","DOI":"10.1371\/journal.pcbi.1003800","volume":"10","author":"S Benzekry","year":"2014","unstructured":"Benzekry, S. et al. Classical mathematical models for description and prediction of experimental tumor growth. PLoS Comput Biol 10, e1003800, doi: 10.1371\/journal.pcbi.1003800 (2014).","journal-title":"PLoS Comput Biol"},{"key":"BFsrep29384_CR38","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.bpj.2012.12.044","volume":"104","author":"JA Ditlev","year":"2013","unstructured":"Ditlev, J. A., Mayer, B. J. & Loew, L. M. There is more than one way to model an elephant. Experiment-driven modeling of the actin cytoskeleton. Biophysical journal 104, 520\u2013532, doi: 10.1016\/j.bpj.2012.12.044 (2013).","journal-title":"Biophysical journal"},{"key":"BFsrep29384_CR39","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.jtbi.2012.04.019","volume":"307","author":"PR Buenzli","year":"2012","unstructured":"Buenzli, P. R., Pivonka, P., Gardiner, B. S. & Smith, D. W. Modelling the anabolic response of bone using a cell population model. J Theor Biol 307, 42\u201352, doi: 10.1016\/j.jtbi.2012.04.019 (2012).","journal-title":"J Theor Biol"},{"key":"BFsrep29384_CR40","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1002\/psp4.12013","volume":"4","author":"RJ Eudy","year":"2015","unstructured":"Eudy, R. J., Gastonguay, M. R., Baron, K. T. & Riggs, M. M. Connecting the Dots: Linking Osteocyte Activity and Therapeutic Modulation of Sclerostin by Extending a Multiscale Systems Model. CPT: pharmacometrics & systems pharmacology 4, 527\u2013536, doi: 10.1002\/psp4.12013 (2015).","journal-title":"CPT: pharmacometrics & systems pharmacology"},{"key":"BFsrep29384_CR41","doi-asserted-by":"publisher","first-page":"e63884","DOI":"10.1371\/journal.pone.0063884","volume":"8","author":"JM Graham","year":"2013","unstructured":"Graham, J. M., Ayati, B. P., Holstein, S. A. & Martin, J. A. The role of osteocytes in targeted bone remodeling: a mathematical model. PLoS One 8, e63884, doi: 10.1371\/journal.pone.0063884 (2013).","journal-title":"PLoS One"},{"key":"BFsrep29384_CR42","doi-asserted-by":"publisher","first-page":"51","DOI":"10.3389\/fcell.2015.00051","volume":"3","author":"SV Komarova","year":"2015","unstructured":"Komarova, S. V. et al. Mathematical model for bone mineralization. Frontiers in cell and developmental biology 3, 51, doi: 10.3389\/fcell.2015.00051 (2015).","journal-title":"Frontiers in cell and developmental biology"},{"key":"BFsrep29384_CR43","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1359\/jbmr.081229","volume":"24","author":"MD Ryser","year":"2009","unstructured":"Ryser, M. D., Nigam, N. & Komarova, S. V. Mathematical modeling of spatio-temporal dynamics of a single bone multicellular unit. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 24, 860\u2013870, doi: 10.1359\/jbmr.081229 (2009).","journal-title":"Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research"},{"key":"BFsrep29384_CR44","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1002\/cnm.2645","volume":"30","author":"B Ji","year":"2014","unstructured":"Ji, B., Genever, P. G., Patton, R. J. & Fagan, M. J. Mathematical modelling of the pathogenesis of multiple myeloma-induced bone disease. International journal for numerical methods in biomedical engineering 30, 1085\u20131102, doi: 10.1002\/cnm.2645 (2014).","journal-title":"International journal for numerical methods in biomedical engineering"},{"key":"BFsrep29384_CR45","doi-asserted-by":"publisher","first-page":"e1002703","DOI":"10.1371\/journal.pcbi.1002703","volume":"8","author":"MD Ryser","year":"2012","unstructured":"Ryser, M. D., Qu, Y. & Komarova, S. V. Osteoprotegerin in bone metastases: mathematical solution to the puzzle. PLoS Comput Biol 8, e1002703, doi: 10.1371\/journal.pcbi.1002703 (2012).","journal-title":"PLoS Comput Biol"},{"key":"BFsrep29384_CR46","doi-asserted-by":"publisher","first-page":"8797","DOI":"10.1158\/0008-5472.CAN-09-0437","volume":"69","author":"ARA Anderson","year":"2009","unstructured":"Anderson, A. R. A. et al. Microenvironmental independence associated with tumor progression. Cancer Res 69, 8797\u20138806, doi: 10.1158\/0008-5472.CAN-09-0437 (2009).","journal-title":"Cancer Res"},{"key":"BFsrep29384_CR47","doi-asserted-by":"publisher","first-page":"7111","DOI":"10.1158\/0008-5472.CAN-08-3957","volume":"69","author":"D Basanta","year":"2009","unstructured":"Basanta, D. et al. The role of transforming growth factor-beta-mediated tumor-stroma interactions in prostate cancer progression: an integrative approach. Cancer Res 69, 7111\u20137120, doi: 0008-5472.CAN-08-3957 (2009).","journal-title":"Cancer Res"},{"key":"BFsrep29384_CR48","doi-asserted-by":"crossref","unstructured":"Bonewald, L. F. & Mundy, G. R. Role of transforming growth factor-beta in bone remodeling. Clinical orthopaedics and related research 261\u2013276 (1990).","DOI":"10.1097\/00003086-199001000-00036"},{"key":"BFsrep29384_CR49","doi-asserted-by":"crossref","first-page":"329","DOI":"10.18388\/abp.2005_3446","volume":"52","author":"B Kaminska","year":"2005","unstructured":"Kaminska, B., Wesolowska, A. & Danilkiewicz, M. TGF beta signalling and its role in tumour pathogenesis. Acta Biochim Pol 52, 329\u2013337 (2005).","journal-title":"Acta Biochim Pol"},{"key":"BFsrep29384_CR50","doi-asserted-by":"crossref","unstructured":"Fournier, P. G. et al. The TGF-beta Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone. Cancer Cell doi: 10.1016\/j.ccell.2015.04.009 (2015).","DOI":"10.1016\/j.ccell.2015.04.009"},{"key":"BFsrep29384_CR51","doi-asserted-by":"publisher","first-page":"6247","DOI":"10.1158\/0008-5472.CAN-12-1444","volume":"72","author":"P Juarez","year":"2012","unstructured":"Juarez, P. et al. Halofuginone inhibits the establishment and progression of melanoma bone metastases. Cancer Res 72, 6247\u20136256, doi: 10.1158\/0008-5472.CAN-12-1444 (2012).","journal-title":"Cancer Res"},{"key":"BFsrep29384_CR52","doi-asserted-by":"publisher","first-page":"e27090","DOI":"10.1371\/journal.pone.0027090","volume":"6","author":"S Biswas","year":"2011","unstructured":"Biswas, S. et al. Anti-transforming growth factor ss antibody treatment rescues bone loss and prevents breast cancer metastasis to bone. PLoS One 6, e27090, doi: 10.1371\/journal.pone.0027090 (2011).","journal-title":"PLoS One"},{"key":"BFsrep29384_CR53","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1158\/0008-5472.CAN-13-2397","volume":"74","author":"ZP Khin","year":"2014","unstructured":"Khin, Z. P. et al. A preclinical assay for chemosensitivity in multiple myeloma. Cancer Res 74, 56\u201367, doi: 10.1158\/0008-5472.CAN-13-2397 (2014).","journal-title":"Cancer Res"},{"key":"BFsrep29384_CR54","doi-asserted-by":"publisher","first-page":"7419","DOI":"10.1038\/ncomms8419","volume":"6","author":"TA Ince","year":"2015","unstructured":"Ince, T. A. et al. Characterization of twenty-five ovarian tumour cell lines that phenocopy primary tumours. Nat Commun 6, 7419, doi: 10.1038\/ncomms8419 (2015).","journal-title":"Nat Commun"},{"key":"BFsrep29384_CR55","doi-asserted-by":"publisher","first-page":"327ra324","DOI":"10.1126\/scitranslmed.aad7842","volume":"8","author":"PM Enriquez-Navas","year":"2016","unstructured":"Enriquez-Navas, P. M. et al. Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer. Sci Transl Med 8, 327ra324, doi: 10.1126\/scitranslmed.aad7842 (2016).","journal-title":"Sci Transl Med"},{"key":"BFsrep29384_CR56","doi-asserted-by":"publisher","first-page":"3153","DOI":"10.1210\/endo-126-6-3153","volume":"126","author":"DM Shinar","year":"1990","unstructured":"Shinar, D. M. & Rodan, G. A. Biphasic effects of transforming growth factor-beta on the production of osteoclast-like cells in mouse bone marrow cultures: the role of prostaglandins in the generation of these cells. Endocrinology 126, 3153\u20133158, doi: 10.1210\/endo-126-6-3153 (1990).","journal-title":"Endocrinology"},{"key":"BFsrep29384_CR57","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1002\/jcp.20036","volume":"200","author":"M Karst","year":"2004","unstructured":"Karst, M., Gorny, G., Galvin, R. J. & Oursler, M. J. Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-beta regulation of osteoclast differentiation. J Cell Physiol 200, 99\u2013106, doi: 10.1002\/jcp.20036 (2004).","journal-title":"J Cell Physiol"},{"key":"BFsrep29384_CR58","doi-asserted-by":"crossref","unstructured":"Hodde, J. P., Suckow, M. A., Wolter, W. R. & Hiles, M. C. Small intestinal submucosa does not promote PAIII tumor growth in Lobund-Wistar rats. J Surg Res 120, 189\u2013194, doi: 10.1016\/j.jss.2003.10.022 (2004).","DOI":"10.1016\/j.jss.2003.10.022"},{"key":"BFsrep29384_CR59","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1002\/pros.1065","volume":"47","author":"DL Lin","year":"2001","unstructured":"Lin, D. L. et al. Bone metastatic LNCaP-derivative C4-2B prostate cancer cell line mineralizes in vitro . Prostate 47, 212\u2013221, doi: 10.1002\/pros.1065 (2001).","journal-title":"Prostate"},{"key":"BFsrep29384_CR60","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1158\/1541-7786.MCR-11-0404","volume":"10","author":"J Joseph","year":"2012","unstructured":"Joseph, J. et al. Disseminated prostate cancer cells can instruct hematopoietic stem and progenitor cells to regulate bone phenotype. Mol Cancer Res 10, 282\u2013292, doi: 10.1158\/1541-7786.MCR-11-0404 (2012).","journal-title":"Mol Cancer Res"},{"key":"BFsrep29384_CR61","doi-asserted-by":"publisher","first-page":"e29862","DOI":"10.1371\/journal.pone.0029862","volume":"7","author":"S Thiolloy","year":"2012","unstructured":"Thiolloy, S. et al. An osteoblast-derived proteinase controls tumor cell survival via TGF-beta activation in the bone microenvironment. PLoS One 7, e29862, doi: 10.1371\/journal.pone.0029862 (2012).","journal-title":"PLoS One"},{"key":"BFsrep29384_CR62","doi-asserted-by":"crossref","unstructured":"Thiolloy, S. et al. Osteoclast-derived matrix metalloproteinase-7, but not matrix metalloproteinase-9, contributes to tumor-induced osteolysis. Cancer Res 69, 6747\u20136755, doi: 69\/16\/6747(2009).","DOI":"10.1158\/0008-5472.CAN-08-3949"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep29384.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep29384","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep29384.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T06:52:58Z","timestamp":1672901578000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep29384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,14]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,7,29]]}},"alternative-id":["BFsrep29384"],"URL":"https:\/\/doi.org\/10.1038\/srep29384","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,14]]},"assertion":[{"value":"19 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 July 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"29384"}}