Vai trò của vi môi trường xương trong sự phát triển các biến chứng đau đớn của di căn vào xương

Cancers - Tập 10 Số 5 - Trang 141
Jeong Park1, Matthew R. Eber1, D. Brooke Widner1, Yusuke Shiozawa1
1Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

Tóm tắt

Đau xương do ung thư (CIBP) là biến chứng đau đớn và phổ biến nhất ở bệnh nhân có di căn vào xương. Nó gây ra sự giảm sút đáng kể về chất lượng cuộc sống của bệnh nhân. Các phương pháp điều trị giảm đau hiện có cho CIBP, chẳng hạn như opioid nhắm vào hệ thần kinh trung ương, đi kèm với những tác dụng phụ nghiêm trọng cũng như nguy cơ lạm dụng và nghiện. Do đó, rất cần các phương pháp điều trị thay thế cho CIBP. Mặc dù các cơ chế chính xác của CIBP vẫn chưa được làm sáng tỏ hoàn toàn, các nghiên cứu gần đây sử dụng các mô hình tiền lâm sàng đã chỉ ra vai trò của vi môi trường tủy xương (ví dụ: tế bào hủy xương, tế bào tạo xương, đại thực bào, tế bào mast, tế bào gốc trung mô và nguyên bào sợi) trong sự phát triển của CIBP. Một số thử nghiệm lâm sàng đã được thực hiện dựa trên những phát hiện này. CIBP là một tình trạng phức tạp và khó khăn hiện chưa có các phương pháp điều trị hiệu quả tiêu chuẩn ngoài opioid. Rõ ràng cần có thêm các nghiên cứu để hiểu sâu hơn về tình trạng đau đớn này và phát triển các liệu pháp nhắm mục tiêu hiệu quả và an toàn hơn.

Từ khóa


Tài liệu tham khảo

Tsuzuki, 2016, Skeletal complications in cancer patients with bone metastases, Int. J. Urol., 23, 825, 10.1111/iju.13170

Meuser, 2001, Symptoms during cancer pain treatment following who-guidelines: A longitudinal follow-up study of symptom prevalence, severity and etiology, Pain, 93, 247, 10.1016/S0304-3959(01)00324-4

Berruti, 2000, 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, J. Urol., 164, 1248, 10.1016/S0022-5347(05)67149-2

Laird, 2011, Characterization of cancer-induced bone pain: An exploratory study, Support Care Cancer, 19, 1393, 10.1007/s00520-010-0961-3

Benyamin, 2008, Opioid complications and side effects, Pain Phys., 11, S105, 10.36076/ppj.2008/11/S105

Pergolizzi, 2008, 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), Pain Pract., 8, 287, 10.1111/j.1533-2500.2008.00204.x

Mercadante, 2001, The use of anti-inflammatory drugs in cancer pain, Cancer Treat. Rev., 27, 51, 10.1053/ctrv.2000.0192

Piccioli, 2017, The role of radiation therapy in bone metastases management, Oncotarget, 8, 25691, 10.18632/oncotarget.14823

Stopeck, 2010, Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: A randomized, double-blind study, J. Clin. Oncol., 28, 5132, 10.1200/JCO.2010.29.7101

Fizazi, 2011, Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study, Lancet, 377, 813, 10.1016/S0140-6736(10)62344-6

Badrising, 2016, Enzalutamide as a fourth- or fifth-line treatment option for metastatic castration-resistant prostate cancer, Oncology, 91, 267, 10.1159/000448219

Vignani, 2016, Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer, Cancer Treat. Rev., 44, 61, 10.1016/j.ctrv.2016.02.002

Abou, 2016, Whole-body and microenvironmental localization of radium-223 in naive and mouse models of prostate cancer metastasis, J. Natl. Cancer Inst., 108, djv380, 10.1093/jnci/djv380

Delaney, 2008, Translational medicine: Cancer pain mechanisms and management, Br. J. Anaesth., 101, 87, 10.1093/bja/aen100

Vanderah, 2013, Cancer-induced bone pain: Mechanisms and models, Neurosci. Lett., 557, 52, 10.1016/j.neulet.2013.08.003

Rowe, 2005, Mechanosensory perception: Are there contributions from bone-associated receptors?, Clin. Exp. Pharmacol. Physiol., 32, 100, 10.1111/j.1440-1681.2005.04136.x

Nieder, 2013, Continuous controversy about radiation oncologists’ choice of treatment regimens for bone metastases: Should we blame doctors, cancer-related features, or design of previous clinical studies?, Radiat. Oncol., 8, 85, 10.1186/1748-717X-8-85

Carrafiello, 2008, Ablation of painful metastatic bone tumors: A systematic review, Int. J. Surg., 6, S47, 10.1016/j.ijsu.2008.12.035

Mantyh, 2002, Molecular mechanisms of cancer pain, Nat. Rev. Cancer, 2, 201, 10.1038/nrc747

Peters, 2004, Endothelin and the tumorigenic component of bone cancer pain, Neuroscience, 126, 1043, 10.1016/j.neuroscience.2004.04.027

Sevcik, 2005, Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization, Pain, 115, 128, 10.1016/j.pain.2005.02.022

Ghilardi, 2005, Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain, J. Neurosci., 25, 3126, 10.1523/JNEUROSCI.3815-04.2005

Yoneda, 2011, Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain, Bone, 48, 100, 10.1016/j.bone.2010.07.009

Wilson, 2006, Bone-marrow haematopoietic-stem-cell niches, Nat. Rev. Immunol., 6, 93, 10.1038/nri1779

Yin, 2006, The stem cell niches in bone, J. Clin. Investig., 116, 1195, 10.1172/JCI28568

Shiozawa, 2015, Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors, Bonekey Rep., 4, 689, 10.1038/bonekey.2015.57

Zheng, 2013, The role of the bone microenvironment in skeletal metastasis, J. Bone Oncol., 2, 47, 10.1016/j.jbo.2012.11.002

Buenrostro, 2014, Dissecting the role of bone marrow stromal cells on bone metastases, BioMed Res. Int., 2014, 875305, 10.1155/2014/875305

Chirgwin, 2000, Molecular mechanisms of tumor-bone interactions in osteolytic metastases, Crit. Rev. Eukaryot. Gene Expr., 10, 159, 10.1615/CritRevEukarGeneExpr.v10.i2.50

Guise, 2005, Molecular mechanisms of breast cancer metastases to bone, Clin. Breast Cancer, 5, S46, 10.3816/CBC.2005.s.004

Guise, 2006, Basic mechanisms responsible for osteolytic and osteoblastic bone metastases, Clin. Cancer Res., 12, 6213s, 10.1158/1078-0432.CCR-06-1007

Kakonen, 2003, Mechanisms of osteolytic bone metastases in breast carcinoma, Cancer, 97, 834, 10.1002/cncr.11132

Kingsley, 2007, Molecular biology of bone metastasis, Mol. Cancer Ther., 6, 2609, 10.1158/1535-7163.MCT-07-0234

Mundy, 1997, Mechanisms of bone metastasis, Cancer, 80, 1546, 10.1002/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I

Honore, 2000, Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord, Nat. Med., 6, 521, 10.1038/74999

Luger, 2001, Osteoprotegerin diminishes advanced bone cancer pain, Cancer Res., 61, 4038

Schwei, 1999, Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain, J. Neurosci., 19, 10886, 10.1523/JNEUROSCI.19-24-10886.1999

Qin, 2012, V-atpases in osteoclasts: Structure, function and potential inhibitors of bone resorption, Int. J. Biochem. Cell Biol., 44, 1422, 10.1016/j.biocel.2012.05.014

Lingueglia, 2007, Acid-sensing ion channels in sensory perception, J. Biol. Chem., 282, 17325, 10.1074/jbc.R700011200

Holzer, P. (2009). Acid-sensitive ion channels and receptors. Handb. Exp. Pharmacol., 283–332.

Li, 2014, Enhanced function of TRPV1 via up-regulation by insulin-like growth factor-1 in a rat model of bone cancer pain, Eur. J. Pain, 18, 774, 10.1002/j.1532-2149.2013.00420.x

Xu, 2013, Peripheral TGF-beta1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents, J. Neurosci., 33, 19099, 10.1523/JNEUROSCI.4852-12.2013

Kadenbach, 2000, Mitochondrial energy metabolism is regulated via nuclear-coded subunits of cytochrome C oxidase, Free Radic. Biol. Med., 29, 211, 10.1016/S0891-5849(00)00305-1

Key, 2012, The P2X7 receptor is an important regulator of extracellular ATP levels, Front. Endocrinol. (Lausanne), 3, 41

Reyes, 2011, P2 receptor expression, signaling and function in osteoclasts, Front. Biosci. (Schol. Ed.), 3, 1101, 10.2741/214

North, 2004, P2X3 receptors and peripheral pain mechanisms, J. Physiol., 554, 301, 10.1113/jphysiol.2003.048587

Wirkner, 2007, P2X3 receptor involvement in pain states, Mol. Neurobiol., 36, 165, 10.1007/s12035-007-0033-y

Kaan, 2010, Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats, Brain, 133, 2549, 10.1093/brain/awq194

Burnstock, 2000, P2X receptors in sensory neurones, Br. J. Anaesth., 84, 476, 10.1093/oxfordjournals.bja.a013473

Hansen, 2012, Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice, Eur. J. Pharmacol., 688, 27, 10.1016/j.ejphar.2012.05.008

Wu, 2012, Functional up-regulation of p2X3 receptors in dorsal root ganglion in a rat model of bone cancer pain, Eur. J. Pain, 16, 1378, 10.1002/j.1532-2149.2012.00149.x

Pevida, 2009, Involvement of enkephalins in the inhibition of osteosarcoma-induced thermal hyperalgesia evoked by the blockade of peripheral P2X3 receptors, Neurosci. Lett., 465, 285, 10.1016/j.neulet.2009.09.015

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.

Grygorczyk, 2013, Imaging and characterization of stretch-induced ATP release from alveolar a549 cells, J. Physiol., 591, 1195, 10.1113/jphysiol.2012.244145

Hoebertz, 2000, Expression of P2 receptors in bone and cultured bone cells, Bone, 27, 503, 10.1016/S8756-3282(00)00351-3

Morrison, 1998, ATP is a potent stimulator of the activation and formation of rodent osteoclasts, J. Physiol., 511, 495, 10.1111/j.1469-7793.1998.495bh.x

Liao, 2008, Tumor expressed PTHRP facilitates prostate cancer-induced osteoblastic lesions, Int. J. Cancer, 123, 2267, 10.1002/ijc.23602

Achbarou, 1994, Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo, Cancer Res., 54, 2372

Killian, 1993, Mitogenic response of osteoblast cells to prostate-specific antigen suggests an activation of latent TGF-beta and a proteolytic modulation of cell adhesion receptors, Biochem. Biophys. Res. Commun., 192, 940, 10.1006/bbrc.1993.1506

Kitano, 1998, Gene expression of bone matrix proteins and endothelin receptors in endothelin-1-deficient mice revealed by in situ hybridization, J. Bone Miner. Res., 13, 237, 10.1359/jbmr.1998.13.2.237

Kasperk, 1997, Endothelin-1 is a potent regulator of human bone cell metabolism in vitro, Calcif. Tissue Int., 60, 368, 10.1007/s002239900245

Yin, 2003, A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases, Proc. Natl. Acad. Sci. USA, 100, 10954, 10.1073/pnas.1830978100

Pomonis, 2001, Expression and localization of endothelin receptors: Implications for the involvement of peripheral GLIA in nociception, J. Neurosci., 21, 999, 10.1523/JNEUROSCI.21-03-00999.2001

Nelson, 2003, Suppression of prostate cancer induced bone remodeling by the endothelin receptor a antagonist atrasentan, J. Urol., 169, 1143, 10.1097/01.ju.0000042162.08938.27

Carducci, 2007, A phase 3 randomized controlled trial of the efficacy and safety of Atrasentan in men with metastatic hormone-refractory prostate cancer, Cancer, 110, 1959, 10.1002/cncr.22996

Wacnik, 2001, Functional interactions between tumor and peripheral nerve: Morphology, algogen identification, and behavioral characterization of a new murine model of cancer pain, J. Neurosci., 21, 9355, 10.1523/JNEUROSCI.21-23-09355.2001

Qiao, 2015, Endothelin-A receptor antagonists in prostate cancer treatment-a meta-analysis, Int. J. Clin. Exp. Med., 8, 3465

Weiner, 1998, The material bone: Structure-mechanical function relations, Annu. Rev. Mater. Sci., 28, 271, 10.1146/annurev.matsci.28.1.271

Prondvai, 2014, Development-based revision of bone tissue classification: The importance of semantics for science, Biol. J. Linn. Soc., 112, 799, 10.1111/bij.12323

Halvorson, 2006, Similarities and differences in tumor growth, skeletal remodeling and pain in an osteolytic and osteoblastic model of bone cancer, Clin. J. Pain, 22, 587, 10.1097/01.ajp.0000210902.67849.e6

Raoof, 2018, Divergent roles of immune cells and their mediators in pain, Rheumatology (Oxford), 57, 429, 10.1093/rheumatology/kex308

Hiraoka, 2008, Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages, Cancer Sci., 99, 1595, 10.1111/j.1349-7006.2008.00880.x

2018, Tumor-associated macrophages as target for antitumor therapy, Arch. Immunol. Ther. Exp., 66, 97, 10.1007/s00005-017-0480-8

Zelenka, 2005, Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain, Pain, 116, 257, 10.1016/j.pain.2005.04.018

Adriaenssens, 2008, Nerve growth factor is a potential therapeutic target in breast cancer, Cancer Res., 68, 346, 10.1158/0008-5472.CAN-07-1183

Hondermarck, 2012, Neurotrophins and their receptors in breast cancer, Cytokine Growth Factor Rev., 23, 357, 10.1016/j.cytogfr.2012.06.004

Williams, 2015, Differential regulation of macrophage phenotype by mature and pro-nerve growth factor, J. Neuroimmunol., 285, 76, 10.1016/j.jneuroim.2015.05.016

Zhang, 2011, Tumor necrosis factor-alpha induces sensitization of meningeal nociceptors mediated via local COX and P38 map kinase actions, Pain, 152, 140, 10.1016/j.pain.2010.10.002

Binshtok, 2008, Nociceptors are interleukin-1beta sensors, J. Neurosci., 28, 14062, 10.1523/JNEUROSCI.3795-08.2008

Huang, 2001, Neurotrophins: Roles in neuronal development and function, Annu. Rev. Neurosci., 24, 677, 10.1146/annurev.neuro.24.1.677

Chadee, 1998, Novel regulation of cyclooxygenase-2 expression and prostaglandin e2 production by IFN-gamma in human macrophages, J. Immunol., 161, 2441, 10.4049/jimmunol.161.5.2441

Sabino, 2002, The involvement of prostaglandins in tumorigenesis, tumor-induced osteolysis and bone cancer pain, J. Musculoskelet. Neuronal Interact., 2, 561

Fox, 2004, Anti-hyperalgesic activity of the COX-2 inhibitor lumiracoxib in a model of bone cancer pain in the rat, Pain, 107, 33, 10.1016/j.pain.2003.09.003

Sabino, 2002, Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2, Cancer Res., 62, 7343

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., 258–263.

Aguirre, 2004, Effect of rofecoxib on pain caused by osteoid osteoma, Orthopedics, 27, 1188, 10.3928/0147-7447-20041101-17

Vane, 1996, Introduction: Mechanism of action of NSAIDs, Br. J. Rheumatol., 35, 1, 10.1093/rheumatology/35.suppl_1.1

Laneuville, 1994, Differential inhibition of human prostaglandin endoperoxide h synthases-1 and -2 by nonsteroidal anti-inflammatory drugs, J. Pharmacol. Exp. Ther., 271, 927

Antman, 2007, Use of nonsteroidal antiinflammatory drugs, Update Clin. Sci. Statement Am. Heart Assoc., 115, 1634

Bombardier, 2000, Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. Vigor study group, N. Engl. J. Med., 343, 1520, 10.1056/NEJM200011233432103

Isono, 2011, Microsomal prostaglandin e synthase-1 enhances bone cancer growth and bone cancer-related pain behaviors in mice, Life Sci., 88, 693, 10.1016/j.lfs.2011.02.008

McCaffrey, 2014, Ngf blockade at early times during bone cancer development attenuates bone destruction and increases limb use, Cancer Res., 74, 7014, 10.1158/0008-5472.CAN-14-1220

Halvorson, 2005, A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone, Cancer Res., 65, 9426, 10.1158/0008-5472.CAN-05-0826

Bloom, 2011, Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers, J. Pain, 12, 698, 10.1016/j.jpain.2010.12.016

Lane, 2010, Tanezumab for the treatment of pain from osteoarthritis of the knee, N. Engl. J. Med., 363, 1521, 10.1056/NEJMoa0901510

Schnitzer, 2015, Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain, Ann. Rheum. Dis., 74, 1202, 10.1136/annrheumdis-2013-204905

Katz, 2011, Efficacy and safety of tanezumab in the treatment of chronic low back pain, Pain, 152, 2248, 10.1016/j.pain.2011.05.003

Bramson, 2015, Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain, Pain Med., 16, 1163, 10.1111/pme.12677

Sopata, 2015, Efficacy and safety of tanezumab in the treatment of pain from bone metastases, Pain, 156, 1703, 10.1097/j.pain.0000000000000211

Bunnett, 2006, Protease-activated receptors: How proteases signal to cells to cause inflammation and pain, Semin. Thromb. Hemost., 32, 39, 10.1055/s-2006-939553

Vergnolle, 2001, Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway, Nat. Med., 7, 821, 10.1038/89945

Mrozkova, 2016, The role of protease-activated receptor type 2 in nociceptive signaling and pain, Physiol. Res., 65, 357, 10.33549/physiolres.933269

Reed, 2003, Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons, J. Physiol., 547, 531, 10.1113/jphysiol.2002.032011

Molino, 1997, Interactions of mast cell tryptase with thrombin receptors and par-2, J. Biol. Chem., 272, 4043, 10.1074/jbc.272.7.4043

Nystedt, 1994, Molecular cloning of a potential proteinase activated receptor, Proc. Natl. Acad. Sci. USA, 91, 9208, 10.1073/pnas.91.20.9208

Kleij, 2005, Significance of conversation between mast cells and nerves, Allergy Asthma Clin. Immunol., 1, 65

Barbara, 2004, Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome, Gastroenterology, 126, 693, 10.1053/j.gastro.2003.11.055

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.

Lam, 2010, Serine proteases and protease-activated receptor 2-dependent allodynia: A novel cancer pain pathway, Pain, 149, 263, 10.1016/j.pain.2010.02.010

Mantyh, 2014, The neurobiology of skeletal pain, Eur. J. Neurosci., 39, 508, 10.1111/ejn.12462

Hong, 1993, Dexamethasone treatment reduces sensory neuropeptides and nerve sprouting reactions in injured teeth, Pain, 55, 171, 10.1016/0304-3959(93)90146-G

Ghilardi, 2012, Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint, Arthritis Rheum, 64, 2223, 10.1002/art.34385

Chartier, 2014, Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain, Pain, 155, 2323, 10.1016/j.pain.2014.08.026

Riesco, 2017, Neuropeptides as a marker for chronic headache, Curr. Pain Headache Rep., 21, 18, 10.1007/s11916-017-0618-8

Schou, 2017, Calcitonin gene-related peptide and pain: A systematic review, J. Headache Pain, 18, 34, 10.1186/s10194-017-0741-2

Liu, 2014, Protease-activated receptor 2 in dorsal root ganglion contributes to peripheral sensitization of bone cancer pain, Eur. J. Pain, 18, 326, 10.1002/j.1532-2149.2013.00372.x

Leporini, 2015, Targeting mast cells in gastric cancer with special reference to bone metastases, World J. Gastroenterol., 21, 10493, 10.3748/wjg.v21.i37.10493

Ammendola, 2015, Infiltrating mast cells correlate with angiogenesis in bone metastases from gastric cancer patients, Int. J. Mol. Sci., 16, 3237, 10.3390/ijms16023237

Tondevold, 1979, Observations on long bone medullary pressure in relation to mean arterial blood pressure in the anaesthetized dog, Acta Orthop. Scand., 50, 527, 10.3109/17453677908989799

Hu, 2012, Understanding the hypoxic niche of multiple myeloma: Therapeutic implications and contributions of mouse models, Dis. Models Mech., 5, 763, 10.1242/dmm.008961

Wang, 2007, The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development, J. Clin. Investig., 117, 1616, 10.1172/JCI31581

Wan, 2008, Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration, Proc. Natl. Acad. Sci. USA, 105, 686, 10.1073/pnas.0708474105

Shomento, 2010, Hypoxia-inducible factors 1alpha and 2alpha exert both distinct and overlapping functions in long bone development, J. Cell. Biochem., 109, 196, 10.1002/jcb.22396

Knowles, 2009, Acute hypoxia and osteoclast activity: A balance between enhanced resorption and increased apoptosis, J. Pathol., 218, 256, 10.1002/path.2534

Rankin, 2011, A central role for hypoxic signaling in cartilage, bone, and hematopoiesis, Curr. Osteoporos. Rep., 9, 46, 10.1007/s11914-011-0047-2

Cantley, 2009, Understanding the warburg effect: The metabolic requirements of cell proliferation, Science, 324, 1029, 10.1126/science.1160809

Peppicelli, 2015, Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression, Cell Cycle, 14, 3088, 10.1080/15384101.2015.1078032

Lemma, 2017, Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma, Oncotarget, 8, 54478, 10.18632/oncotarget.17091

Montazeri, 2009, Quality of life data as prognostic indicators of survival in cancer patients: An overview of the literature from 1982 to 2008, Health Qual. Life Outcomes, 7, 102, 10.1186/1477-7525-7-102

Halabi, 2008, Pain predicts overall survival in men with metastatic castration-refractory prostate cancer, J. Clin. Oncol., 26, 2544, 10.1200/JCO.2007.15.0367

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.

Fizazi, 2015, Bone-related parameters are the main prognostic factors for overall survival in men with bone metastases from castration-resistant prostate cancer, Eur. Urol., 68, 42, 10.1016/j.eururo.2014.10.001

Niikura, 2011, Treatment outcome and prognostic factors for patients with bone-only metastases of breast cancer: A single-institution retrospective analysis, Oncologist, 16, 155, 10.1634/theoncologist.2010-0350

Parker, 2013, Alpha emitter radium-223 and survival in metastatic prostate cancer, N. Engl. J. Med., 369, 213, 10.1056/NEJMoa1213755

Boilly, 2017, Nerve dependence: From regeneration to cancer, Cancer Cell, 31, 342, 10.1016/j.ccell.2017.02.005

Magnon, 2013, Autonomic nerve development contributes to prostate cancer progression, Science, 341, 1236361, 10.1126/science.1236361

Hayakawa, 2017, Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling, Cancer Cell, 31, 21, 10.1016/j.ccell.2016.11.005

Zhao, 2014, Denervation suppresses gastric tumorigenesis, Sci. Transl. Med., 6, 250ra115, 10.1126/scitranslmed.3009569

Saloman, 2016, Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer, Proc. Natl. Acad. Sci. USA, 113, 3078, 10.1073/pnas.1512603113

Bao, 2015, Protease-activated receptor 2 antagonist potentiates analgesic effects of systemic morphine in a rat model of bone cancer pain, Reg. Anesth. Pain Med., 40, 158, 10.1097/AAP.0000000000000211