{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T23:10:59Z","timestamp":1782861059473,"version":"3.54.5"},"reference-count":140,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,10]],"date-time":"2018-05-10T00:00:00Z","timestamp":1525910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-17-1-0541"],"award-info":[{"award-number":["W81XWH-17-1-0541"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-14-1-0403"],"award-info":[{"award-number":["W81XWH-14-1-0403"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UL1TR001420"],"award-info":[{"award-number":["UL1TR001420"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA012197"],"award-info":[{"award-number":["P30CA012197"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Cancer-induced bone pain (CIBP) is the most common and painful complication in patients with bone metastases. It causes a significant reduction in patient quality of life. Available analgesic treatments for CIBP, such as opioids that target the central nervous system, come with severe side effects as well as the risk of abuse and addiction. Therefore, alternative treatments for CIBP are desperately needed. Although the exact mechanisms of CIBP have not been fully elucidated, recent studies using preclinical models have demonstrated the role of the bone marrow microenvironment (e.g., osteoclasts, osteoblasts, macrophages, mast cells, mesenchymal stem cells, and fibroblasts) in CIBP development. Several clinical trials have been performed based on these findings. CIBP is a complex and challenging condition that currently has no standard effective treatments other than opioids. Further studies are clearly warranted to better understand this painful condition and develop more effective and safer targeted therapies.<\/jats:p>","DOI":"10.3390\/cancers10050141","type":"journal-article","created":{"date-parts":[[2018,5,10]],"date-time":"2018-05-10T03:48:27Z","timestamp":1525924107000},"page":"141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Role of the Bone Microenvironment in the Development of Painful Complications of Skeletal Metastases"],"prefix":"10.3390","volume":"10","author":[{"given":"Sun H.","family":"Park","sequence":"first","affiliation":[{"name":"Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Eber","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Brooke","family":"Widner","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9814-9230","authenticated-orcid":false,"given":"Yusuke","family":"Shiozawa","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1111\/iju.13170","article-title":"Skeletal complications in cancer patients with bone metastases","volume":"23","author":"Tsuzuki","year":"2016","journal-title":"Int. J. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0304-3959(01)00324-4","article-title":"Symptoms during cancer pain treatment following who-guidelines: A longitudinal follow-up study of symptom prevalence, severity and etiology","volume":"93","author":"Meuser","year":"2001","journal-title":"Pain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/S0022-5347(05)67149-2","article-title":"Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: Predictive role of bone resorption and formation markers evaluated at baseline","volume":"164","author":"Berruti","year":"2000","journal-title":"J. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1007\/s00520-010-0961-3","article-title":"Characterization of cancer-induced bone pain: An exploratory study","volume":"19","author":"Laird","year":"2011","journal-title":"Support Care Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S105","DOI":"10.36076\/ppj.2008\/11\/S105","article-title":"Opioid complications and side effects","volume":"11","author":"Benyamin","year":"2008","journal-title":"Pain Phys."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1533-2500.2008.00204.x","article-title":"Opioids and the management of chronic severe pain in the elderly: Consensus statement of an international expert panel with focus on the six clinically most often used world health organization step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone)","volume":"8","author":"Pergolizzi","year":"2008","journal-title":"Pain Pract."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1053\/ctrv.2000.0192","article-title":"The use of anti-inflammatory drugs in cancer pain","volume":"27","author":"Mercadante","year":"2001","journal-title":"Cancer Treat. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"25691","DOI":"10.18632\/oncotarget.14823","article-title":"The role of radiation therapy in bone metastases management","volume":"8","author":"Piccioli","year":"2017","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5132","DOI":"10.1200\/JCO.2010.29.7101","article-title":"Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: A randomized, double-blind study","volume":"28","author":"Stopeck","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S0140-6736(10)62344-6","article-title":"Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study","volume":"377","author":"Fizazi","year":"2011","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1159\/000448219","article-title":"Enzalutamide as a fourth- or fifth-line treatment option for metastatic castration-resistant prostate cancer","volume":"91","author":"Badrising","year":"2016","journal-title":"Oncology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ctrv.2016.02.002","article-title":"Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer","volume":"44","author":"Vignani","year":"2016","journal-title":"Cancer Treat. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"djv380","DOI":"10.1093\/jnci\/djv380","article-title":"Whole-body and microenvironmental localization of radium-223 in naive and mouse models of prostate cancer metastasis","volume":"108","author":"Abou","year":"2016","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/bja\/aen100","article-title":"Translational medicine: Cancer pain mechanisms and management","volume":"101","author":"Delaney","year":"2008","journal-title":"Br. J. Anaesth."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neulet.2013.08.003","article-title":"Cancer-induced bone pain: Mechanisms and models","volume":"557","author":"Vanderah","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/j.1440-1681.2005.04136.x","article-title":"Mechanosensory perception: Are there contributions from bone-associated receptors?","volume":"32","author":"Rowe","year":"2005","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1748-717X-8-85","article-title":"Continuous controversy about radiation oncologists\u2019 choice of treatment regimens for bone metastases: Should we blame doctors, cancer-related features, or design of previous clinical studies?","volume":"8","author":"Nieder","year":"2013","journal-title":"Radiat. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.ijsu.2008.12.035","article-title":"Ablation of painful metastatic bone tumors: A systematic review","volume":"6","author":"Carrafiello","year":"2008","journal-title":"Int. J. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nrc747","article-title":"Molecular mechanisms of cancer pain","volume":"2","author":"Mantyh","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.neuroscience.2004.04.027","article-title":"Endothelin and the tumorigenic component of bone cancer pain","volume":"126","author":"Peters","year":"2004","journal-title":"Neuroscience"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.pain.2005.02.022","article-title":"Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization","volume":"115","author":"Sevcik","year":"2005","journal-title":"Pain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1523\/JNEUROSCI.3815-04.2005","article-title":"Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain","volume":"25","author":"Ghilardi","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.bone.2010.07.009","article-title":"Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain","volume":"48","author":"Yoneda","year":"2011","journal-title":"Bone"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nri1779","article-title":"Bone-marrow haematopoietic-stem-cell niches","volume":"6","author":"Wilson","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1172\/JCI28568","article-title":"The stem cell niches in bone","volume":"116","author":"Yin","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/bonekey.2015.57","article-title":"Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors","volume":"4","author":"Shiozawa","year":"2015","journal-title":"Bonekey Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.jbo.2012.11.002","article-title":"The role of the bone microenvironment in skeletal metastasis","volume":"2","author":"Zheng","year":"2013","journal-title":"J. Bone Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"875305","DOI":"10.1155\/2014\/875305","article-title":"Dissecting the role of bone marrow stromal cells on bone metastases","volume":"2014","author":"Buenrostro","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1615\/CritRevEukarGeneExpr.v10.i2.50","article-title":"Molecular mechanisms of tumor-bone interactions in osteolytic metastases","volume":"10","author":"Chirgwin","year":"2000","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.3816\/CBC.2005.s.004","article-title":"Molecular mechanisms of breast cancer metastases to bone","volume":"5","author":"Guise","year":"2005","journal-title":"Clin. Breast Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6213s","DOI":"10.1158\/1078-0432.CCR-06-1007","article-title":"Basic mechanisms responsible for osteolytic and osteoblastic bone metastases","volume":"12","author":"Guise","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1002\/cncr.11132","article-title":"Mechanisms of osteolytic bone metastases in breast carcinoma","volume":"97","author":"Kakonen","year":"2003","journal-title":"Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1158\/1535-7163.MCT-07-0234","article-title":"Molecular biology of bone metastasis","volume":"6","author":"Kingsley","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I","article-title":"Mechanisms of bone metastasis","volume":"80","author":"Mundy","year":"1997","journal-title":"Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/74999","article-title":"Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord","volume":"6","author":"Honore","year":"2000","journal-title":"Nat. Med."},{"key":"ref_36","first-page":"4038","article-title":"Osteoprotegerin diminishes advanced bone cancer pain","volume":"61","author":"Luger","year":"2001","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10886","DOI":"10.1523\/JNEUROSCI.19-24-10886.1999","article-title":"Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain","volume":"19","author":"Schwei","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1016\/j.biocel.2012.05.014","article-title":"V-atpases in osteoclasts: Structure, function and potential inhibitors of bone resorption","volume":"44","author":"Qin","year":"2012","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17325","DOI":"10.1074\/jbc.R700011200","article-title":"Acid-sensing ion channels in sensory perception","volume":"282","author":"Lingueglia","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Holzer, P. (2009). Acid-sensitive ion channels and receptors. Handb. Exp. Pharmacol., 283\u2013332.","DOI":"10.1007\/978-3-540-79090-7_9"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1002\/j.1532-2149.2013.00420.x","article-title":"Enhanced function of TRPV1 via up-regulation by insulin-like growth factor-1 in a rat model of bone cancer pain","volume":"18","author":"Li","year":"2014","journal-title":"Eur. J. Pain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"19099","DOI":"10.1523\/JNEUROSCI.4852-12.2013","article-title":"Peripheral TGF-beta1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents","volume":"33","author":"Xu","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0891-5849(00)00305-1","article-title":"Mitochondrial energy metabolism is regulated via nuclear-coded subunits of cytochrome C oxidase","volume":"29","author":"Kadenbach","year":"2000","journal-title":"Free Radic. Biol. Med."},{"key":"ref_44","first-page":"41","article-title":"The P2X7 receptor is an important regulator of extracellular ATP levels","volume":"3","author":"Key","year":"2012","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.2741\/214","article-title":"P2 receptor expression, signaling and function in osteoclasts","volume":"3","author":"Reyes","year":"2011","journal-title":"Front. Biosci. (Schol. Ed.)"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1113\/jphysiol.2003.048587","article-title":"P2X3 receptors and peripheral pain mechanisms","volume":"554","author":"North","year":"2004","journal-title":"J. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s12035-007-0033-y","article-title":"P2X3 receptor involvement in pain states","volume":"36","author":"Wirkner","year":"2007","journal-title":"Mol. Neurobiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1093\/brain\/awq194","article-title":"Systemic blockade of P2X3 and P2X2\/3 receptors attenuates bone cancer pain behaviour in rats","volume":"133","author":"Kaan","year":"2010","journal-title":"Brain"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1093\/oxfordjournals.bja.a013473","article-title":"P2X receptors in sensory neurones","volume":"84","author":"Burnstock","year":"2000","journal-title":"Br. J. Anaesth."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ejphar.2012.05.008","article-title":"Chronic administration of the selective P2X3, P2X2\/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice","volume":"688","author":"Hansen","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1002\/j.1532-2149.2012.00149.x","article-title":"Functional up-regulation of p2X3 receptors in dorsal root ganglion in a rat model of bone cancer pain","volume":"16","author":"Wu","year":"2012","journal-title":"Eur. J. Pain"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.neulet.2009.09.015","article-title":"Involvement of enkephalins in the inhibition of osteosarcoma-induced thermal hyperalgesia evoked by the blockade of peripheral P2X3 receptors","volume":"465","author":"Pevida","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Epstein, T., Gatenby, R.A., and Brown, J.S. (2017). The warburg effect as an adaptation of cancer cells to rapid fluctuations in energy demand. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185085"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1113\/jphysiol.2012.244145","article-title":"Imaging and characterization of stretch-induced ATP release from alveolar a549 cells","volume":"591","author":"Grygorczyk","year":"2013","journal-title":"J. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/S8756-3282(00)00351-3","article-title":"Expression of P2 receptors in bone and cultured bone cells","volume":"27","author":"Hoebertz","year":"2000","journal-title":"Bone"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/j.1469-7793.1998.495bh.x","article-title":"ATP is a potent stimulator of the activation and formation of rodent osteoclasts","volume":"511","author":"Morrison","year":"1998","journal-title":"J. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1002\/ijc.23602","article-title":"Tumor expressed PTHRP facilitates prostate cancer-induced osteoblastic lesions","volume":"123","author":"Liao","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_58","first-page":"2372","article-title":"Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo","volume":"54","author":"Achbarou","year":"1994","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1006\/bbrc.1993.1506","article-title":"Mitogenic response of osteoblast cells to prostate-specific antigen suggests an activation of latent TGF-beta and a proteolytic modulation of cell adhesion receptors","volume":"192","author":"Killian","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1359\/jbmr.1998.13.2.237","article-title":"Gene expression of bone matrix proteins and endothelin receptors in endothelin-1-deficient mice revealed by in situ hybridization","volume":"13","author":"Kitano","year":"1998","journal-title":"J. Bone Miner. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1007\/s002239900245","article-title":"Endothelin-1 is a potent regulator of human bone cell metabolism in vitro","volume":"60","author":"Kasperk","year":"1997","journal-title":"Calcif. Tissue Int."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"10954","DOI":"10.1073\/pnas.1830978100","article-title":"A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases","volume":"100","author":"Yin","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1523\/JNEUROSCI.21-03-00999.2001","article-title":"Expression and localization of endothelin receptors: Implications for the involvement of peripheral GLIA in nociception","volume":"21","author":"Pomonis","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1097\/01.ju.0000042162.08938.27","article-title":"Suppression of prostate cancer induced bone remodeling by the endothelin receptor a antagonist atrasentan","volume":"169","author":"Nelson","year":"2003","journal-title":"J. Urol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1002\/cncr.22996","article-title":"A phase 3 randomized controlled trial of the efficacy and safety of Atrasentan in men with metastatic hormone-refractory prostate cancer","volume":"110","author":"Carducci","year":"2007","journal-title":"Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"9355","DOI":"10.1523\/JNEUROSCI.21-23-09355.2001","article-title":"Functional interactions between tumor and peripheral nerve: Morphology, algogen identification, and behavioral characterization of a new murine model of cancer pain","volume":"21","author":"Wacnik","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_67","first-page":"3465","article-title":"Endothelin-A receptor antagonists in prostate cancer treatment-a meta-analysis","volume":"8","author":"Qiao","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1146\/annurev.matsci.28.1.271","article-title":"The material bone: Structure-mechanical function relations","volume":"28","author":"Weiner","year":"1998","journal-title":"Annu. Rev. Mater. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1111\/bij.12323","article-title":"Development-based revision of bone tissue classification: The importance of semantics for science","volume":"112","author":"Prondvai","year":"2014","journal-title":"Biol. J. Linn. Soc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1097\/01.ajp.0000210902.67849.e6","article-title":"Similarities and differences in tumor growth, skeletal remodeling and pain in an osteolytic and osteoblastic model of bone cancer","volume":"22","author":"Halvorson","year":"2006","journal-title":"Clin. J. Pain"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1093\/rheumatology\/kex308","article-title":"Divergent roles of immune cells and their mediators in pain","volume":"57","author":"Raoof","year":"2018","journal-title":"Rheumatology (Oxford)"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1111\/j.1349-7006.2008.00880.x","article-title":"Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes\/macrophages","volume":"99","author":"Hiraoka","year":"2008","journal-title":"Cancer Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00005-017-0480-8","article-title":"Tumor-associated macrophages as target for antitumor therapy","volume":"66","year":"2018","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.pain.2005.04.018","article-title":"Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain","volume":"116","author":"Zelenka","year":"2005","journal-title":"Pain"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1158\/0008-5472.CAN-07-1183","article-title":"Nerve growth factor is a potential therapeutic target in breast cancer","volume":"68","author":"Adriaenssens","year":"2008","journal-title":"Cancer Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.cytogfr.2012.06.004","article-title":"Neurotrophins and their receptors in breast cancer","volume":"23","author":"Hondermarck","year":"2012","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.jneuroim.2015.05.016","article-title":"Differential regulation of macrophage phenotype by mature and pro-nerve growth factor","volume":"285","author":"Williams","year":"2015","journal-title":"J. Neuroimmunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.pain.2010.10.002","article-title":"Tumor necrosis factor-alpha induces sensitization of meningeal nociceptors mediated via local COX and P38 map kinase actions","volume":"152","author":"Zhang","year":"2011","journal-title":"Pain"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"14062","DOI":"10.1523\/JNEUROSCI.3795-08.2008","article-title":"Nociceptors are interleukin-1beta sensors","volume":"28","author":"Binshtok","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1146\/annurev.neuro.24.1.677","article-title":"Neurotrophins: Roles in neuronal development and function","volume":"24","author":"Huang","year":"2001","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.4049\/jimmunol.161.5.2441","article-title":"Novel regulation of cyclooxygenase-2 expression and prostaglandin e2 production by IFN-gamma in human macrophages","volume":"161","author":"Chadee","year":"1998","journal-title":"J. Immunol."},{"key":"ref_82","first-page":"561","article-title":"The involvement of prostaglandins in tumorigenesis, tumor-induced osteolysis and bone cancer pain","volume":"2","author":"Sabino","year":"2002","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.pain.2003.09.003","article-title":"Anti-hyperalgesic activity of the COX-2 inhibitor lumiracoxib in a model of bone cancer pain in the rat","volume":"107","author":"Fox","year":"2004","journal-title":"Pain"},{"key":"ref_84","first-page":"7343","article-title":"Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2","volume":"62","author":"Sabino","year":"2002","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Bottner, F., Roedl, R., Wortler, K., Grethen, C., Winkelmann, W., and Lindner, N. (2001). Cyclooxygenase-2 inhibitor for pain management in osteoid osteoma. Clin. Orthop. Relat. Res., 258\u2013263.","DOI":"10.1097\/00003086-200112000-00029"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.3928\/0147-7447-20041101-17","article-title":"Effect of rofecoxib on pain caused by osteoid osteoma","volume":"27","author":"Aguirre","year":"2004","journal-title":"Orthopedics"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/rheumatology\/35.suppl_1.1","article-title":"Introduction: Mechanism of action of NSAIDs","volume":"35","author":"Vane","year":"1996","journal-title":"Br. J. Rheumatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S0022-3565(25)23861-7","article-title":"Differential inhibition of human prostaglandin endoperoxide h synthases-1 and -2 by nonsteroidal anti-inflammatory drugs","volume":"271","author":"Laneuville","year":"1994","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_89","first-page":"1634","article-title":"Use of nonsteroidal antiinflammatory drugs","volume":"115","author":"Antman","year":"2007","journal-title":"Update Clin. Sci. Statement Am. Heart Assoc."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1056\/NEJM200011233432103","article-title":"Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. Vigor study group","volume":"343","author":"Bombardier","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.lfs.2011.02.008","article-title":"Microsomal prostaglandin e synthase-1 enhances bone cancer growth and bone cancer-related pain behaviors in mice","volume":"88","author":"Isono","year":"2011","journal-title":"Life Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"7014","DOI":"10.1158\/0008-5472.CAN-14-1220","article-title":"Ngf blockade at early times during bone cancer development attenuates bone destruction and increases limb use","volume":"74","author":"McCaffrey","year":"2014","journal-title":"Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"9426","DOI":"10.1158\/0008-5472.CAN-05-0826","article-title":"A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone","volume":"65","author":"Halvorson","year":"2005","journal-title":"Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.jpain.2010.12.016","article-title":"Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers","volume":"12","author":"Bloom","year":"2011","journal-title":"J. Pain"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1056\/NEJMoa0901510","article-title":"Tanezumab for the treatment of pain from osteoarthritis of the knee","volume":"363","author":"Lane","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1136\/annrheumdis-2013-204905","article-title":"Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain","volume":"74","author":"Schnitzer","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1016\/j.pain.2011.05.003","article-title":"Efficacy and safety of tanezumab in the treatment of chronic low back pain","volume":"152","author":"Katz","year":"2011","journal-title":"Pain"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1111\/pme.12677","article-title":"Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain","volume":"16","author":"Bramson","year":"2015","journal-title":"Pain Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1097\/j.pain.0000000000000211","article-title":"Efficacy and safety of tanezumab in the treatment of pain from bone metastases","volume":"156","author":"Sopata","year":"2015","journal-title":"Pain"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1055\/s-2006-939553","article-title":"Protease-activated receptors: How proteases signal to cells to cause inflammation and pain","volume":"32","author":"Bunnett","year":"2006","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/89945","article-title":"Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway","volume":"7","author":"Vergnolle","year":"2001","journal-title":"Nat. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"357","DOI":"10.33549\/physiolres.933269","article-title":"The role of protease-activated receptor type 2 in nociceptive signaling and pain","volume":"65","author":"Mrozkova","year":"2016","journal-title":"Physiol. Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1113\/jphysiol.2002.032011","article-title":"Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons","volume":"547","author":"Reed","year":"2003","journal-title":"J. Physiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4043","DOI":"10.1074\/jbc.272.7.4043","article-title":"Interactions of mast cell tryptase with thrombin receptors and par-2","volume":"272","author":"Molino","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"9208","DOI":"10.1073\/pnas.91.20.9208","article-title":"Molecular cloning of a potential proteinase activated receptor","volume":"91","author":"Nystedt","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","first-page":"65","article-title":"Significance of conversation between mast cells and nerves","volume":"1","author":"Kleij","year":"2005","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1053\/j.gastro.2003.11.055","article-title":"Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome","volume":"126","author":"Barbara","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Demir, I.E., Schorn, S., Schremmer-Danninger, E., Wang, K., Kehl, T., Giese, N.A., Algul, H., Friess, H., and Ceyhan, G.O. (2013). Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain in pancreatic cancer and chronic pancreatitis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060529"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.pain.2010.02.010","article-title":"Serine proteases and protease-activated receptor 2-dependent allodynia: A novel cancer pain pathway","volume":"149","author":"Lam","year":"2010","journal-title":"Pain"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/ejn.12462","article-title":"The neurobiology of skeletal pain","volume":"39","author":"Mantyh","year":"2014","journal-title":"Eur. J. Neurosci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0304-3959(93)90146-G","article-title":"Dexamethasone treatment reduces sensory neuropeptides and nerve sprouting reactions in injured teeth","volume":"55","author":"Hong","year":"1993","journal-title":"Pain"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1002\/art.34385","article-title":"Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint","volume":"64","author":"Ghilardi","year":"2012","journal-title":"Arthritis Rheum"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1016\/j.pain.2014.08.026","article-title":"Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain","volume":"155","author":"Chartier","year":"2014","journal-title":"Pain"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s11916-017-0618-8","article-title":"Neuropeptides as a marker for chronic headache","volume":"21","author":"Riesco","year":"2017","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s10194-017-0741-2","article-title":"Calcitonin gene-related peptide and pain: A systematic review","volume":"18","author":"Schou","year":"2017","journal-title":"J. Headache Pain"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1002\/j.1532-2149.2013.00372.x","article-title":"Protease-activated receptor 2 in dorsal root ganglion contributes to peripheral sensitization of bone cancer pain","volume":"18","author":"Liu","year":"2014","journal-title":"Eur. J. Pain"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"10493","DOI":"10.3748\/wjg.v21.i37.10493","article-title":"Targeting mast cells in gastric cancer with special reference to bone metastases","volume":"21","author":"Leporini","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"3237","DOI":"10.3390\/ijms16023237","article-title":"Infiltrating mast cells correlate with angiogenesis in bone metastases from gastric cancer patients","volume":"16","author":"Ammendola","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"527","DOI":"10.3109\/17453677908989799","article-title":"Observations on long bone medullary pressure in relation to mean arterial blood pressure in the anaesthetized dog","volume":"50","author":"Tondevold","year":"1979","journal-title":"Acta Orthop. Scand."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1242\/dmm.008961","article-title":"Understanding the hypoxic niche of multiple myeloma: Therapeutic implications and contributions of mouse models","volume":"5","author":"Hu","year":"2012","journal-title":"Dis. Models Mech."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1172\/JCI31581","article-title":"The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development","volume":"117","author":"Wang","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1073\/pnas.0708474105","article-title":"Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration","volume":"105","author":"Wan","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/jcb.22396","article-title":"Hypoxia-inducible factors 1alpha and 2alpha exert both distinct and overlapping functions in long bone development","volume":"109","author":"Shomento","year":"2010","journal-title":"J. Cell. Biochem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/path.2534","article-title":"Acute hypoxia and osteoclast activity: A balance between enhanced resorption and increased apoptosis","volume":"218","author":"Knowles","year":"2009","journal-title":"J. Pathol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s11914-011-0047-2","article-title":"A central role for hypoxic signaling in cartilage, bone, and hematopoiesis","volume":"9","author":"Rankin","year":"2011","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the warburg effect: The metabolic requirements of cell proliferation","volume":"324","author":"Cantley","year":"2009","journal-title":"Science"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.1080\/15384101.2015.1078032","article-title":"Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression","volume":"14","author":"Peppicelli","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"54478","DOI":"10.18632\/oncotarget.17091","article-title":"Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma","volume":"8","author":"Lemma","year":"2017","journal-title":"Oncotarget"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/1477-7525-7-102","article-title":"Quality of life data as prognostic indicators of survival in cancer patients: An overview of the literature from 1982 to 2008","volume":"7","author":"Montazeri","year":"2009","journal-title":"Health Qual. Life Outcomes"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1200\/JCO.2007.15.0367","article-title":"Pain predicts overall survival in men with metastatic castration-refractory prostate cancer","volume":"26","author":"Halabi","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Koizumi, M., Yoshimoto, M., Kasumi, F., Iwase, T., and Ogata, E. (2010). Post-operative breast cancer patients diagnosed with skeletal metastasis without bone pain had fewer skeletal-related events and deaths than those with bone pain. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-423"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.eururo.2014.10.001","article-title":"Bone-related parameters are the main prognostic factors for overall survival in men with bone metastases from castration-resistant prostate cancer","volume":"68","author":"Fizazi","year":"2015","journal-title":"Eur. Urol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1634\/theoncologist.2010-0350","article-title":"Treatment outcome and prognostic factors for patients with bone-only metastases of breast cancer: A single-institution retrospective analysis","volume":"16","author":"Niikura","year":"2011","journal-title":"Oncologist"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1056\/NEJMoa1213755","article-title":"Alpha emitter radium-223 and survival in metastatic prostate cancer","volume":"369","author":"Parker","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.ccell.2017.02.005","article-title":"Nerve dependence: From regeneration to cancer","volume":"31","author":"Boilly","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1236361","DOI":"10.1126\/science.1236361","article-title":"Autonomic nerve development contributes to prostate cancer progression","volume":"341","author":"Magnon","year":"2013","journal-title":"Science"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ccell.2016.11.005","article-title":"Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling","volume":"31","author":"Hayakawa","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"250ra115","DOI":"10.1126\/scitranslmed.3009569","article-title":"Denervation suppresses gastric tumorigenesis","volume":"6","author":"Zhao","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"3078","DOI":"10.1073\/pnas.1512603113","article-title":"Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer","volume":"113","author":"Saloman","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1097\/AAP.0000000000000211","article-title":"Protease-activated receptor 2 antagonist potentiates analgesic effects of systemic morphine in a rat model of bone cancer pain","volume":"40","author":"Bao","year":"2015","journal-title":"Reg. Anesth. Pain Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/10\/5\/141\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:04:01Z","timestamp":1760195041000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/10\/5\/141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,10]]},"references-count":140,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["cancers10050141"],"URL":"https:\/\/doi.org\/10.3390\/cancers10050141","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,10]]}}}