1. Introduction
Cancer-induced bone pain (CIBP) is the most common complication of bone metastases, and it significantly reduces the patient’s quality of life (QOL) [ 1 ]. CIBP poses a tremendous challenge to patients and their caregivers, in both managing it and identifying its underlying cause. In the quest for effective cancer therapy, maintaining QOL can be as crucial as treating the disease itself. Seventy-five percent of cancer patients experience pain throughout their disease [ 2 ]. Once cancer metastasizes to the bone, the first symptom is often acute bone pain. A full 80% of patients with bone metastases have CIBP [ 3 ].
CIBP remains a therapeutically challenging condition. It includes both spontaneous (ongoing) pain and breakthrough (movement-related) pain, which can present individually or in combination [ 4 ]. Unless each component of CIBP is appropriately treated, it cannot be managed. Analgesics for CIBP that target the central nervous system (e.g., opioids, nonsteroidal anti-inflammatory drugs or NSAIDs) are somewhat effective to reduce pain, but have severe side effects and are often extremely addictive [ 5 , 6 , 7 ]. External beam radiation, used for patients with bone metastases, is primarily palliative and only half of the patients receiving this therapy achieve partial or complete pain relief [ 4 , 8 ]. Alternatively, bisphosphonate and anti-receptor activator of nuclear factor κB ligand (RANKL) antibody treatments that decrease bone resorption in cancer patients with bone metastases [ 9 , 10 ], and radium-223 which forms complexes with hydroxylapatite in bone [ 11 , 12 , 13 ] can also reduce the onset of pain. However, even with these well-accepted clinical treatment modalities, 50% of patients with CIBP do not achieve controlled pain status [ 14 ].
CIBP is a very complex phenomenon that is uniquely distinct from other forms of chronic pain, such as inflammatory or neuropathic pain [ 15 ]. Bone is a richly innervated organ, and it has been suggested that bone metastatic cancer cells interact with sensory nerves in the bone microenvironment, resulting in CIBP development [ 15 ]. Mechanical stresses or mass effects from bone metastatic progression can directly induce CIBP, since sensory nerves that express mechanoreceptors reside throughout the interosseous membrane of long bones [ 16 ]. However, it has also been suggested that CIBP is not correlated with tumor type, location, number, or size of the metastases [ 17 , 18 ]. This may indicate that CIBP is developed not only during physical contact between bone metastatic cancer cells and sensory nerves, but also from signaling events initiated by cancer-derived factors [ 15 , 19 , 20 , 21 ]. Indeed, the acidic environment surrounding the tumor or cancer secreted growth factors, cytokines, or chemokines can all stimulate receptors on sensory nerves to induce CIBP [ 15 , 19 , 22 , 23 ].
The bone marrow provides a unique environment for both hematopoiesis and bone metastatic progression [ 24 , 25 , 26 ]. This microenvironment consists of several types of cells, including those that regulate bone remodeling, immune cells, stromal cells, and endothelial cells. It has been appreciated that the crosstalk between the bone microenvironment and bone metastatic cancer cells is crucial for bone metastatic progression [ 26 , 27 , 28 ]. However, little is known about how the molecular interactions between metastatic cancer and the bone marrow microenvironment affect CIBP.
Therefore, in this review, we provide a concise overview of the known roles of the bone marrow microenvironment in the development of CIBP and discuss the future directions of research on this topic.
2. The Roles of the Bone Marrow Microenvironment in the Development of Cancer-Induced Bone Pain
2.1. Osteoclasts
During bone metastatic progression, osteolytic cancer cells—originating from primary tumors from breast cancer, lung cancer, renal cancer, sarcomas, and multiple myeloma, etc.—stimulate osteoblasts to release RANKL. The osteoblast-derived RANKL binds to its receptor RANK expressed on osteoclasts. This interaction induces osteoclast maturation and increases osteolytic activity, resulting in enhanced bone resorption. Resorption of the bone matrix then causes the release of growth factors such as transforming growth factor beta (TGF-β) and insulin-like growth factor 1 (IGF-1), leading to further bone metastatic progression. The process whereby bone metastatic cancer cells establish osteolytic lesions to enhance bone metastatic progression is called the “vicious cycle” [ 27 , 29 , 30 , 31 , 32 , 33 , 34 ]. It has been suggested that enhanced osteoclast activity can also lead to CIBP. Consistent with this notion, increased mechanical and thermal hyperalgesia are observed in rodents inoculated with osteolytic osteosarcoma into the bone, compared to animals without tumors [ 35 , 36 , 37 ]. Administration of the decoy RANKL receptor osteoprotegerin (OPG) to osteosarcoma-bearing animals significantly decreased spontaneous pain behaviors [ 35 , 36 ]. However, OPG treatments did not affect tumor size.
During the bone resorption process, osteoclasts acidify (pH 4.0–4.5) the extracellular space by releasing protons and chloride ions through membrane transport (V-type H + ATPase) [ 38 ]. The low pH condition sensitizes sensory nerves to mechanical, thermal, and chemical stimuli by activating acid sensing receptors such as the acid-sensing ion channels (ASICs) and transient receptor potential cation channel subfamily V member 1 (TRPV1) expressed on sensory nerves [ 39 , 40 ]. In addition, osteoclast activity indirectly causes TRPV1 upregulation in sensory nerves through the release of TGF-β and IGF-1 derived from the resorbed bone matrix. These factors increase the expression of their receptors (TGF-βRI and IGF-1R) on sensory nerves. In a rat CIBP model using mammary gland carcinoma, the upregulation of these growth factor receptors correlates with the upregulation and sensitization of TRPV1 in sensory nerves. The tumor-bearing animals in these studies had significantly increased mechanical and thermal sensitivity, and observed pain behaviors were reversed with treatments of TGF-βRI and IGF-1R antagonists [ 41 , 42 ].
Osteoclasts mediate bone resorption not only through the creation of acidic conditions, but also through adenosine triphosphate (ATP) production by mitochondrial cytochrome c oxidative activity [ 43 ]. Osteoclasts release accumulated intracellular ATP into the extracellular space, which can activate purinergic receptors such as P2X receptors, known as the ATP-gated ion channels [ 44 , 45 ]. It has been demonstrated that: (1) approximately 90% of the peripheral and central sensory neurons express P2X receptors; and (2) the subtypes of P2X receptors including P2X4, P2X3, and P2X7 regulate the development of neuropathic and inflammatory pain [ 46 , 47 ]. Specifically, P2X3 and P2X2/3 expressed on the terminal end of primary afferent neurons innervating bone have been shown to be involved in CIBP development [ 48 , 49 , 50 , 51 , 52 ]. For instance, in C3H/HeJ mice receiving intratibial inoculations of osteolytic fibrosarcoma, increased expression of P2X3 receptor in the peripheral nociceptive fibers is observed, and peri-tumoral injections of receptor antagonist naloxone-methiodide (A-317491) inhibited cancer-mediated thermal hyperalgesia [ 52 ]. Moreover, growing tumor cells also generate ATP [ 53 , 54 ], and ATP itself stimulates osteoclast activities through the P2X3 receptor [ 55 , 56 ]. Therefore, ATP can induce CIBP by directly interacting with P2X receptors on sensory nerves or indirectly through enhanced osteoclastic activity. Although further studies are warranted, pharmacologically targeting the ATP/P2X receptors axis may prove to be a potential therapeutic strategy for CIBP.
2.2. Osteoblasts
Unlike osteolytic bone metastatic progression, the mechanisms driving osteoblastic bone metastatic progression are largely unknown. Prostate cancer is one of the primary cancer types that gives rise to developing osteoblastic lesions. It has been demonstrated that prostate cancer cells facilitate new bone formation by secreting parathyroid hormone-related protein (PTHrP) [ 57 ], urokinase-type plasminogen activator (uPA) [ 58 ], or prostate-specific antigen (PSA) [ 59 ]. Endothelin-1 (ET-1), a vasoconstrictor, is also known as an osteoblast inducing factor. It stimulates mitogenesis of osteoblasts when it binds to endothelin A receptor (ETAR) and endothelin B receptor (ETBR) expressed by osteoblasts [ 60 , 61 ]. When the osteolytic human breast cancer cell line ZR-75-1 was made to overexpress ET-1, osteoblastic metastases along with new bone formation were detected after inoculation into murine bone, and treatments with the ETAR selective antagonist (ABT-627) attenuated these osteoblastic lesions [ 62 ]. The ET-1/ETAR interaction also plays important roles in CIBP development [ 20 , 63 ]. In fact, the administration of ABT-627 into ET-1 expressing osteosarcoma-bearing mice attenuates CIBP behaviors, but the ETBR selective antagonist, A-192621, does not reduce CIBP behavior [ 20 ]. Consistently, phase II and III clinical trials in patients with hormone refractory prostate cancer showed that ABT-627 delayed the time to bone alkaline phosphatase progression and reduced bone pain, compared to those with placebo [ 64 , 65 ]. Additionally, local injection of ET-1 into the peri-tumoral area of a fibrosarcoma bone cancer murine model increased pain behaviors, and the ETAR antagonist BQ-123 inhibited these behaviors [ 66 ]. A meta-analysis of 9 clinical studies examining the effects of ETAR antagonists on castration-resistant prostate cancer patients, consistently showed that the ETAR antagonist Atrasentan reduces the relative risk of bone pain [ 67 ].
Newly formed bone or woven bone that is mediated by bone metastatic cancer cells is weaker than normal bone. While normal bone has a regular parallel alignment of collagen sheets and is mechanically strong, newly formed immature bone is made of a smaller number of randomly oriented collagen fibers and is mechanically weak, although it forms quickly [ 68 , 69 ]. Therefore, the weakening and instability of new tumor-bearing bone, easily leads to bone damage and CIBP. A canine prostate cancer cell line ACE-1 establishes osteoblastic bone metastatic lesions and develops spontaneous and mechanical pain behaviors in vivo [ 70 ]. Since the studies to reveal the impact of tumor-bearing newly formed bone on CIBP are underdeveloped, the use of this model can be helpful to further determine the detailed molecular mechanisms.
2.3. Immune Cells
Inflammation is also involved in the pathobiology of CIBP via several immune cell types (e.g., macrophages and mast cells) [ 71 ]. Macrophages are known to contribute to the tumor microenvironment, and they release inflammatory factors upon interacting with tumor cells. These inflammatory factors can induce both disease progression and cancer-related pain [ 72 , 73 , 74 ]. Some types of cancer cells that metastasize to the bone (e.g., breast cancer, prostate cancer) highly express and secrete the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) [ 75 , 76 ]. Macrophages express the functional receptors for NGF [p75 neurotrophin receptor (p75NTR), tropomyosin receptor kinase A (TrkA)] and BDNF [tropomyosin receptor kinase B (TrkB)] [ 77 ]. NGF and BDNF derived from bone metastatic cancer cells activate macrophages to release pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1β] and inflammatory regulators [NGF, Prostaglandin E 2 (PGE 2 )] that sensitize nociceptors [ 78 , 79 ]. In addition, as their names indicate, NGF and BDNF also directly regulate the survival, development, and function of neurons [ 80 ].
IL-1β can stimulate expression of cyclooxygenase 2 (Cox-2), and Cox-2 facilitates synthesis of prostaglandins in macrophages [ 81 ]. Prostaglandins can sensitize or activate the sensory nerves by binding to prostanoid receptors, resulting in CIBP [ 82 ]. The administration of a Cox-2 inhibitor into an osteosarcoma CIBP model inhibits pain behaviors as well as bone destruction without affecting tumor burden [ 82 , 83 , 84 , 85 , 86 ]. Since most NSAIDs inhibit both Cox-1 and Cox-2, which are required for PGE 2 synthesis [ 87 ], and the major adverse events mediated by NSAIDs are thought to be Cox-1 dependent [ 88 , 89 ], blocking Cox-2 release from macrophages may be a better option for CIBP treatment than NSAIDs. However, a randomized, Phase III trial between a selective Cox-2 inhibitor (rofecoxib) and a non-selective NSAID (naproxen) in patients with rheumatoid arthritis revealed that chronic administration of rofecoxib causes more myocardial infarction than naproxen, while there is no significant difference in treatment efficacy between the two [ 90 ]. A more recent pre-clinical study using a lung carcinoma CIBP mouse model demonstrated that when microsomal PGE synthase-1 (mPGES-1), another prostaglandin synthesizing enzyme, is deleted, the onset of pain behaviors mediated by the growth of lung carcinoma in the tibia is delayed [ 91 ]. These findings suggest that targeting Cox-2 expression and PGE 2 synthesis in macrophages can be potential therapeutic strategies for CIBP. However, further studies are needed to elucidate the pathophysiology of adverse events before moving into the clinic.
Pre-clinical murine CIBP studies of osteosarcoma, breast cancer, and prostate cancer have demonstrated that blockage of NGF significantly attenuates pain behaviors and bone destruction mediated by bone tumors [ 92 , 93 , 94 ]. Additionally, an anti-NGF monoclonal antibody tanezumab was clinically tested in patients with osteoarthritis and diabetic peripheral neuropathy, and overall significant pain relief is observed in patients treated with tanezumab compared to those treated with placebo [ 95 , 96 , 97 , 98 ]. Although larger clinical trials will be needed, a recent clinical study in patients with bone metastatic prostate cancer, breast cancer, renal cell carcinoma, or multiple myeloma (placebo n = 30, tanezumab n = 29) demonstrated greater efficacy in pain relief in patients treated with tanezumab than placebo treated patients [ 99 ].
Protease-activated receptors (PAR-2), a sub-family of G protein-coupled receptors that are highly expressed on sensory nerves, are known to be involved in the development of inflammatory and neuropathic pain in rodent models [ 100 , 101 , 102 ]. PAR-2 is mainly activated by mast cell tryptase and trypsin [ 103 , 104 , 105 ]. Mast cells are located near sensory neurons; contain cytoplasmic granules that store inflammatory mediators; and their release of pain transmitters causes pain [ 106 , 107 , 108 ]. When the conditioned medium obtained from human squamous cell carcinoma is injected into the mouse hind paw, the skin mast cells are activated and increased pain behaviors are observed [ 109 ]. However, this cancer-associated mechanical allodynia is reversed with treatments of the tryptase inhibitor APC-366 or soybean trypsin inhibitor (SBTI) [ 109 ]. Activation of PAR-2 has been shown to increase levels of neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP). Sensory nerve sprouting from CGRP expressing neurons is known to be associated with skeletal pain behaviors [ 110 , 111 , 112 , 113 ], and levels of plasma CGRP directly correlate with the pain intensity experienced in several pain related conditions [ 114 , 115 ]. It has been demonstrated that bone tumor enhances the PAR-2 expression in sensory nerves [ 116 ]. In addition, recent studies have revealed that tumor-infiltrating mast cells in bone metastatic tumors of gastric cancer promote bone metastatic growth, osteolytic lesions, and CIBP by stimulating angiogenesis [ 117 , 118 ].
2.4. Stromal Cells
Bone is a hypoxic tissue (pO2: 8.1–26.7 mmHg) [ 119 , 120 ], and this hypoxic environment is crucial for controlling angiogenesis [ 121 ], bone repair [ 122 ], osteoblastogenesis [ 123 ], osteoclastogenesis [ 124 ], and hematopoiesis [ 125 ]. Moreover, under hypoxia, tumor cells generate large amounts of lactate through elevated levels of aerobic glycolysis, leading to a lowering of intracellular pH (pH 6.8). This is known as the Warburg effect [ 53 , 126 ]. To prevent cell death mediated by this intracellular acidification, tumor cells actively pump out the protons and lactate to the extracellular space. This extracellular acidic environment surrounding tumor cells can stimulate the cells of stromal origin in the marrow, such as mesenchymal stem cells (MSCs) and fibroblasts [ 127 ]. Bone marrow MSCs and fibroblasts are known to express high levels of acid sensing receptors [acid-sensing ion channel 3 (ASIC3), ASIC4, G protein-coupled receptor 4 (GPR4), and GPR65] [ 128 ], and become activated by the acidic environment created by bone metastatic tumor cells. This interaction leads to expression and secretion of inflammatory cytokines [IL-6, IL-8, IL-15, chemokine (C-C motif) ligand 5 (CCL5), IL-1ß] as well as nociceptive mediators such as NGF and BDNF [ 128 ]. Therefore, it has been suggested that bone metastatic tumor cells induce CIBP by interacting with bone marrow stromal cells.
3. Discussion
Despite the improvement of current cytotoxic treatments, these treatments may not provide survival benefits to all advanced cancer patients. However, most of these patients suffer from symptoms that negatively impact their QOL, such as CIBP. CIBP is a very complex symptom since bone metastatic cancer, sensory nerves, and the bone microenvironment interact together to cause such a painful condition. Therefore, revealing the detailed mechanisms whereby the components that are responsible for bone metastatic progression are involved in the CIBP development will be very important in furthering understanding of this painful symptom and possibly for the development of effective therapies. In this review, we discussed the roles of the cells controlling bone remodeling, immune cells, and stromal cells in the development of CIBP ( Figure 1 ). However, these findings are based on limited evidence. Further studies are therefore clearly needed in this area.
It has been suggested that higher patient QOL may indicate a survival benefit [ 129 ]. Along with this notion, recent research suggests that CIBP may be both a reason for decreased QOL and an indicator of survival [ 130 , 131 , 132 , 133 ]. For instance, the ALSYMPCA trial [ 134 ], which investigated the role of radium-223 in patients with prostate cancer and bone metastases, demonstrated that decreased pain levels correlated with increased overall survival. Additionally, the importance of nerves for cancer development has been appreciated [ 135 ]. Recent studies revealed that the sympathetic nervous system regulates the metastatic process of prostate cancer to bone [ 136 ], and that denervation can suppress tumorigenesis and metastasis [ 136 , 137 , 138 , 139 ]. However, it remains unclear whether sensory nerves that innervate bone, which are responsible for bone pain, also promote metastatic progression to bone. Therefore, revealing the mechanisms of CIBP may provide a strong foundation for much-needed treatments for bone metastases. Stopping pain signals may be useful to improve both morbidity and mortality.
4. Conclusions
The current first-line treatment for CIBP is still opioids. Opioids are somewhat effective, but can have serious side effects, and abuse and addiction of these analgesics are a growing concern. Therefore, more effective and safer alternative treatment options for CIBP are urgently needed. Unfortunately, there is currently no better treatment for CIBP than opioids, when administered alone. However, several lines of evidence suggest that the combination of non-opioid analgesics with opioids provides synergistic or additive analgesic effects that can lead to decreased opioid dose. In the case of CIBP, the combination treatment of PAR-2 antagonists with morphine can allow the use of significantly lower doses of morphine (1 mg/kg) while maintaining the same levels of analgesia as single high doses of morphine (3 or 10 mg/kg) in a CIBP rat model [ 140 ]. Although it might be difficult to immediately replace opioids with other treatment modalities, we still need to continue efforts to reduce opioid use by discovering potential therapeutic targets for CIBP within the bone marrow microenvironment.
Acknowledgments
Y.S. is supported as the Translational Research Academy which is supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR001420.
Funding
This research was funded by Department of Defense (W81XWH-14-1-0403, Y.S.; W81XWH-17-1-0541, Y.S.), the Wake Forest Baptist Comprehensive Cancer Center Internal Pilot Funding (Y.S.), and the Wake Forest School of Medicine Internal Pilot Funding (Y.S.). This work is also supported by the National Cancer Institute’s Cancer Center Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.
Conflicts of Interest
The authors declare that they have no competing financial interest.
References
1. Tsuzuki S. Park S.H. Eber M.R. Peters C.M. Shiozawa Y. Skeletal complications in cancer patients with bone metastases Int. J. Urol. 2016 23 825 832 10.1111/iju.13170 27488133 PMC5718365
2. Meuser T. Pietruck C. Radbruch L. Stute P. Lehmann K.A. Grond S. Symptoms during cancer pain treatment following who-guidelines: A longitudinal follow-up study of symptom prevalence, severity and etiology Pain 2001 93 247 257 10.1016/S0304-3959(01)00324-4 11514084
3. Berruti A. Dogliotti L. Bitossi R. Fasolis G. Gorzegno G. Bellina M. Torta M. Porpiglia F. Fontana D. Angeli A. 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. 2000 164 1248 1253 10.1016/S0022-5347(05)67149-2 10992374
4. Laird B.J. Walley J. Murray G.D. Clausen E. Colvin L.A. Fallon M.T. Characterization of cancer-induced bone pain: An exploratory study Support Care Cancer 2011 19 1393 1401 10.1007/s00520-010-0961-3 20680354
5. Benyamin R. Trescot A.M. Datta S. Buenaventura R. Adlaka R. Sehgal N. Glaser S.E. Vallejo R. Opioid complications and side effects Pain Phys. 2008 11 S105 S120 18443635
6. Pergolizzi J. Boger R.H. Budd K. Dahan A. Erdine S. Hans G. Kress H.G. Langford R. Likar R. Raffa R.B. 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. 2008 8 287 313 18503626 10.1111/j.1533-2500.2008.00204.x
7. Mercadante S. The use of anti-inflammatory drugs in cancer pain Cancer Treat. Rev. 2001 27 51 61 10.1053/ctrv.2000.0192 11237777
8. De Felice F. Piccioli A. Musio D. Tombolini V. The role of radiation therapy in bone metastases management Oncotarget 2017 8 25691 25699 10.18632/oncotarget.14823 28148890 PMC5421962
9. Stopeck A.T. Lipton A. Body J.J. Steger G.G. Tonkin K. de Boer R.H. Lichinitser M. Fujiwara Y. Yardley D.A. Viniegra M. 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. 2010 28 5132 5139 10.1200/JCO.2010.29.7101 21060033
10. Fizazi K. Carducci M. Smith M. Damiao R. Brown J. Karsh L. Milecki P. Shore N. Rader M. Wang H. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study Lancet 2011 377 813 822 10.1016/S0140-6736(10)62344-6 21353695 PMC3090685
11. Badrising S.K. van der Noort V. Hamberg P. Coenen J.L. Aarts M.J. van Oort I.M. van den Eertwegh A.J. Los M. van den Berg H.P. Gelderblom H. Enzalutamide as a fourth- or fifth-line treatment option for metastatic castration-resistant prostate cancer Oncology 2016 91 267 273 10.1159/000448219 27544669
12. Vignani F. Bertaglia V. Buttigliero C. Tucci M. Scagliotti G.V. Di Maio M. Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer Cancer Treat. Rev. 2016 44 61 73 10.1016/j.ctrv.2016.02.002 26907461
13. Abou D.S. Ulmert D. Doucet M. Hobbs R.F. Riddle R.C. Thorek D.L. Whole-body and microenvironmental localization of radium-223 in naive and mouse models of prostate cancer metastasis J. Natl. Cancer Inst. 2016 108 djv380 10.1093/jnci/djv380 26683407 PMC4849807
14. Delaney A. Fleetwood-Walker S.M. Colvin L.A. Fallon M. Translational medicine: Cancer pain mechanisms and management Br. J. Anaesth. 2008 101 87 94 10.1093/bja/aen100 18492671
15. Lozano-Ondoua A.N. Symons-Liguori A.M. Vanderah T.W. Cancer-induced bone pain: Mechanisms and models Neurosci. Lett. 2013 557 Pt A 52 59 10.1016/j.neulet.2013.08.003 24076008 PMC4542064
16. Rowe M.J. Tracey D.J. Mahns D.A. Sahai V. Ivanusic J.J. Mechanosensory perception: Are there contributions from bone-associated receptors? Clin. Exp. Pharmacol. Physiol. 2005 32 100 108 10.1111/j.1440-1681.2005.04136.x 15730443
17. Nieder C. Pawinski A. Dalhaug A. 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. 2013 8 85 10.1186/1748-717X-8-85 23574944 PMC3643865
18. Carrafiello G. Lagana D. Pellegrino C. Mangini M. Fontana F. Piacentino F. Recaldini C. Rovera F. Dionigi G. Boni L. Ablation of painful metastatic bone tumors: A systematic review Int. J. Surg. 2008 6 Suppl. 1 S47 S52 10.1016/j.ijsu.2008.12.035 19196558
19. Mantyh P.W. Clohisy D.R. Koltzenburg M. Hunt S.P. Molecular mechanisms of cancer pain Nat. Rev. Cancer 2002 2 201 209 10.1038/nrc747 11990856
20. Peters C.M. Lindsay T.H. Pomonis J.D. Luger N.M. Ghilardi J.R. Sevcik M.A. Mantyh P.W. Endothelin and the tumorigenic component of bone cancer pain Neuroscience 2004 126 1043 1052 10.1016/j.neuroscience.2004.04.027 15207337
21. Sevcik M.A. Ghilardi J.R. Peters C.M. Lindsay T.H. Halvorson K.G. Jonas B.M. Kubota K. Kuskowski M.A. Boustany L. Shelton D.L. Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization Pain 2005 115 128 141 10.1016/j.pain.2005.02.022 15836976
22. Ghilardi J.R. Rohrich H. Lindsay T.H. Sevcik M.A. Schwei M.J. Kubota K. Halvorson K.G. Poblete J. Chaplan S.R. Dubin A.E. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain J. Neurosci. 2005 25 3126 3131 10.1523/JNEUROSCI.3815-04.2005 15788769 PMC6725088
23. Yoneda T. Hata K. Nakanishi M. Nagae M. Nagayama T. Wakabayashi H. Nishisho T. Sakurai T. Hiraga T. Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain Bone 2011 48 100 105 10.1016/j.bone.2010.07.009 20637323
24. Wilson A. Trumpp A. Bone-marrow haematopoietic-stem-cell niches Nat. Rev. Immunol. 2006 6 93 106 10.1038/nri1779 16491134
25. Yin T. Li L. The stem cell niches in bone J. Clin. Investig. 2006 116 1195 1201 10.1172/JCI28568 16670760 PMC1451221
26. Shiozawa Y. Eber M.R. Berry J.E. Taichman R.S. Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors Bonekey Rep. 2015 4 689 10.1038/bonekey.2015.57 26029360 PMC4440229
27. Zheng Y. Zhou H. Dunstan C.R. Sutherland R.L. Seibel M.J. The role of the bone microenvironment in skeletal metastasis J. Bone Oncol. 2013 2 47 57 10.1016/j.jbo.2012.11.002 26909265 PMC4723345
28. Buenrostro D. Park S.I. Sterling J.A. Dissecting the role of bone marrow stromal cells on bone metastases BioMed Res. Int. 2014 2014 875305 10.1155/2014/875305 25054153 PMC4099112
29. Chirgwin J.M. Guise T.A. Molecular mechanisms of tumor-bone interactions in osteolytic metastases Crit. Rev. Eukaryot. Gene Expr. 2000 10 159 178 10.1615/CritRevEukarGeneExpr.v10.i2.50 11186331
30. Guise T.A. Kozlow W.M. Heras-Herzig A. Padalecki S.S. Yin J.J. Chirgwin J.M. Molecular mechanisms of breast cancer metastases to bone Clin. Breast Cancer 2005 5 Suppl. 2 S46 S53 10.3816/CBC.2005.s.004 15807924
31. Guise T.A. Mohammad K.S. Clines G. Stebbins E.G. Wong D.H. Higgins L.S. Vessella R. Corey E. Padalecki S. Suva L. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases Clin. Cancer Res. 2006 12 6213s 6216s 10.1158/1078-0432.CCR-06-1007 17062703
32. Kakonen S.M. Mundy G.R. Mechanisms of osteolytic bone metastases in breast carcinoma Cancer 2003 97 834 839 10.1002/cncr.11132 12548583
33. Kingsley L.A. Fournier P.G. Chirgwin J.M. Guise T.A. Molecular biology of bone metastasis Mol. Cancer Ther. 2007 6 2609 2617 10.1158/1535-7163.MCT-07-0234 17938257
34. Mundy G.R. Mechanisms of bone metastasis Cancer 1997 80 1546 1556 10.1002/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I 9362421
35. Honore P. Luger N.M. Sabino M.A. Schwei M.J. Rogers S.D. Mach D.B. O’Keefe P F. Ramnaraine M.L. Clohisy D.R. Mantyh P.W. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord Nat. Med. 2000 6 521 528 10802707 10.1038/74999
36. Luger N.M. Honore P. Sabino M.A. Schwei M.J. Rogers S.D. Mach D.B. Clohisy D.R. Mantyh P.W. Osteoprotegerin diminishes advanced bone cancer pain Cancer Res. 2001 61 4038 4047 11358823
37. Schwei M.J. Honore P. Rogers S.D. Salak-Johnson J.L. Finke M.P. Ramnaraine M.L. Clohisy D.R. Mantyh P.W. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain J. Neurosci. 1999 19 10886 10897 10.1523/JNEUROSCI.19-24-10886.1999 10594070 PMC6784931
38. Qin A. Cheng T.S. Pavlos N.J. Lin Z. Dai K.R. Zheng M.H. V-atpases in osteoclasts: Structure, function and potential inhibitors of bone resorption Int. J. Biochem. Cell Biol. 2012 44 1422 1435 10.1016/j.biocel.2012.05.014 22652318
39. Lingueglia E. Acid-sensing ion channels in sensory perception J. Biol. Chem. 2007 282 17325 17329 10.1074/jbc.R700011200 17430882
40. Holzer P. Acid-sensitive ion channels and receptors Handb. Exp. Pharmacol. 2009 283 332 19655111 10.1007/978-3-540-79090-7_9 PMC4359897
41. Li Y. Cai J. Han Y. Xiao X. Meng X.L. Su L. Liu F.Y. Xing G.G. Wan Y. Enhanced function of TRPV1 via up-regulation by insulin-like growth factor-1 in a rat model of bone cancer pain Eur. J. Pain 2014 18 774 784 10.1002/j.1532-2149.2013.00420.x 24827675
42. Xu Q. Zhang X.M. Duan K.Z. Gu X.Y. Han M. Liu B.L. Zhao Z.Q. Zhang Y.Q. Peripheral TGF-beta1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents J. Neurosci. 2013 33 19099 19111 10.1523/JNEUROSCI.4852-12.2013 24305807 PMC6618781
43. Kadenbach B. Huttemann M. Arnold S. Lee I. Bender E. Mitochondrial energy metabolism is regulated via nuclear-coded subunits of cytochrome C oxidase Free Radic. Biol. Med. 2000 29 211 221 10.1016/S0891-5849(00)00305-1 11035249
44. Brandao-Burch A. Key M.L. Patel J.J. Arnett T.R. Orriss I.R. The P2X7 receptor is an important regulator of extracellular ATP levels Front. Endocrinol. (Lausanne) 2012 3 41 10.3389/fendo.2012.00041 22654865 PMC3355863
45. Reyes J.P. Sims S.M. Dixon S.J. P2 receptor expression, signaling and function in osteoclasts Front. Biosci. (Schol. Ed.) 2011 3 1101 1118 10.2741/214 21622259
46. North R.A. P2X3 receptors and peripheral pain mechanisms J. Physiol. 2004 554 301 308 10.1113/jphysiol.2003.048587 12832496 PMC1664762
47. Wirkner K. Sperlagh B. Illes P. P2X3 receptor involvement in pain states Mol. Neurobiol. 2007 36 165 183 10.1007/s12035-007-0033-y 17952660
48. Kaan T.K. Yip P.K. Patel S. Davies M. Marchand F. Cockayne D.A. Nunn P.A. Dickenson A.H. Ford A.P. Zhong Y. Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats Brain 2010 133 2549 2564 10.1093/brain/awq194 20802203
49. Burnstock G. P2X receptors in sensory neurones Br. J. Anaesth. 2000 84 476 488 10.1093/oxfordjournals.bja.a013473 10823099
50. Hansen R.R. Nasser A. Falk S. Baldvinsson S.B. Ohlsson P.H. Bahl J.M. Jarvis M.F. Ding M. Heegaard A.M. Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice Eur. J. Pharmacol. 2012 688 27 34 10.1016/j.ejphar.2012.05.008 22634164
51. Wu J.X. Xu M.Y. Miao X.R. Lu Z.J. Yuan X.M. Li X.Q. Yu W.F. Functional up-regulation of p2X3 receptors in dorsal root ganglion in a rat model of bone cancer pain Eur. J. Pain 2012 16 1378 1388 10.1002/j.1532-2149.2012.00149.x 22528605
52. Gonzalez-Rodriguez S. Pevida M. Roques B.P. Fournie-Zaluski M.C. Hidalgo A. Menendez L. Baamonde A. Involvement of enkephalins in the inhibition of osteosarcoma-induced thermal hyperalgesia evoked by the blockade of peripheral P2X3 receptors Neurosci. Lett. 2009 465 285 289 10.1016/j.neulet.2009.09.015 19765404
53. Epstein T. Gatenby R.A. Brown J.S. The warburg effect as an adaptation of cancer cells to rapid fluctuations in energy demand PLoS ONE 2017 12 e0185085 10.1371/journal.pone.0185085 28922380 PMC5602667
54. Grygorczyk R. Furuya K. Sokabe M. Imaging and characterization of stretch-induced ATP release from alveolar a549 cells J. Physiol. 2013 591 1195 1215 10.1113/jphysiol.2012.244145 23247110 PMC3607866
55. Hoebertz A. Townsend-Nicholson A. Glass R. Burnstock G. Arnett T.R. Expression of P2 receptors in bone and cultured bone cells Bone 2000 27 503 510 10.1016/S8756-3282(00)00351-3 11033445
56. Morrison M.S. Turin L. King B.F. Burnstock G. Arnett T.R. ATP is a potent stimulator of the activation and formation of rodent osteoclasts J. Physiol. 1998 511 Pt 2 495 500 10.1111/j.1469-7793.1998.495bh.x 9706025 PMC2231120
57. Liao J. Li X. Koh A.J. Berry J.E. Thudi N. Rosol T.J. Pienta K.J. McCauley L.K. Tumor expressed PTHRP facilitates prostate cancer-induced osteoblastic lesions Int. J. Cancer 2008 123 2267 2278 10.1002/ijc.23602 18729185 PMC3979464
58. Achbarou A. Kaiser S. Tremblay G. Ste-Marie L.G. Brodt P. Goltzman D. Rabbani S.A. Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo Cancer Res. 1994 54 2372 2377 8162583
59. Killian C.S. Corral D.A. Kawinski E. Constantine R.I. 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. 1993 192 940 947 10.1006/bbrc.1993.1506 7683467
60. Kitano Y. Kurihara H. Kurihara Y. Maemura K. Ryo Y. Yazaki Y. Harii K. Gene expression of bone matrix proteins and endothelin receptors in endothelin-1-deficient mice revealed by in situ hybridization J. Bone Miner. Res. 1998 13 237 244 10.1359/jbmr.1998.13.2.237 9495516
61. Kasperk C.H. Borcsok I. Schairer H.U. Schneider U. Nawroth P.P. Niethard F.U. Ziegler R. Endothelin-1 is a potent regulator of human bone cell metabolism in vitro Calcif. Tissue Int. 1997 60 368 374 10.1007/s002239900245 9075635
62. Yin J.J. Mohammad K.S. Kakonen S.M. Harris S. Wu-Wong J.R. Wessale J.L. Padley R.J. Garrett I.R. Chirgwin J.M. Guise T.A. A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases Proc. Natl. Acad. Sci. USA 2003 100 10954 10959 10.1073/pnas.1830978100 12941866 PMC196909
63. Pomonis J.D. Rogers S.D. Peters C.M. Ghilardi J.R. Mantyh P.W. Expression and localization of endothelin receptors: Implications for the involvement of peripheral GLIA in nociception J. Neurosci. 2001 21 999 1006 10.1523/JNEUROSCI.21-03-00999.2001 11157085 PMC6762331
64. Nelson J.B. Nabulsi A.A. Vogelzang N.J. Breul J. Zonnenberg B.A. Daliani D.D. Schulman C.C. Carducci M.A. Suppression of prostate cancer induced bone remodeling by the endothelin receptor a antagonist atrasentan J. Urol. 2003 169 1143 1149 10.1097/01.ju.0000042162.08938.27 12576870
65. Carducci M.A. Saad F. Abrahamsson P.A. Dearnaley D.P. Schulman C.C. North S.A. Sleep D.J. Isaacson J.D. Nelson J.B. Atrasentan Phase I.I.I.S.G.I. A phase 3 randomized controlled trial of the efficacy and safety of Atrasentan in men with metastatic hormone-refractory prostate cancer Cancer 2007 110 1959 1966 10.1002/cncr.22996 17886253
66. Wacnik P.W. Eikmeier L.J. Ruggles T.R. Ramnaraine M.L. Walcheck B.K. Beitz A.J. Wilcox G.L. Functional interactions between tumor and peripheral nerve: Morphology, algogen identification, and behavioral characterization of a new murine model of cancer pain J. Neurosci. 2001 21 9355 9366 10.1523/JNEUROSCI.21-23-09355.2001 11717369 PMC6763897
67. Qiao L. Liang Y. Li N. Hu X. Luo D. Gu J. Lu Y. Zheng Q. Endothelin-A receptor antagonists in prostate cancer treatment-a meta-analysis Int. J. Clin. Exp. Med. 2015 8 3465 3473 26064237 PMC4443071
68. Weiner S. Wagner H.D. The material bone: Structure-mechanical function relations Annu. Rev. Mater. Sci. 1998 28 271 298
69. Prondvai E. Stein K.H.W. de Ricqlès A. Cubo J. Development-based revision of bone tissue classification: The importance of semantics for science Biol. J. Linn. Soc. 2014 112 799 816 10.1111/bij.12323
70. Halvorson K.G. Sevcik M.A. Ghilardi J.R. Rosol T.J. Mantyh P.W. Similarities and differences in tumor growth, skeletal remodeling and pain in an osteolytic and osteoblastic model of bone cancer Clin. J. Pain 2006 22 587 600 10.1097/01.ajp.0000210902.67849.e6 16926574
71. Raoof R. Willemen H. Eijkelkamp N. Divergent roles of immune cells and their mediators in pain Rheumatology (Oxford) 2018 57 429 440 10.1093/rheumatology/kex308 28968842 PMC5850827
72. Hiraoka K. Zenmyo M. Watari K. Iguchi H. Fotovati A. Kimura Y.N. Hosoi F. Shoda T. Nagata K. Osada H. Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages Cancer Sci. 2008 99 1595 1602 10.1111/j.1349-7006.2008.00880.x 18754872 PMC11158597
73. Sawa-Wejksza K. Kandefer-Szerszen M. Tumor-associated macrophages as target for antitumor therapy Arch. Immunol. Ther. Exp. 2018 66 97 111 10.1007/s00005-017-0480-8 28660349 PMC5851686
74. Zelenka M. Schafers M. Sommer C. Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain Pain 2005 116 257 263 10.1016/j.pain.2005.04.018 15964142
75. Adriaenssens E. Vanhecke E. Saule P. Mougel A. Page A. Romon R. Nurcombe V. Le Bourhis X. Hondermarck H. Nerve growth factor is a potential therapeutic target in breast cancer Cancer Res. 2008 68 346 351 10.1158/0008-5472.CAN-07-1183 18199526
76. Hondermarck H. Neurotrophins and their receptors in breast cancer Cytokine Growth Factor Rev. 2012 23 357 365 10.1016/j.cytogfr.2012.06.004 22749855
77. Williams K.S. Killebrew D.A. Clary G.P. Seawell J.A. Meeker R.B. Differential regulation of macrophage phenotype by mature and pro-nerve growth factor J. Neuroimmunol. 2015 285 76 93 10.1016/j.jneuroim.2015.05.016 26198923 PMC4528983
78. Zhang X.C. Kainz V. Burstein R. Levy D. Tumor necrosis factor-alpha induces sensitization of meningeal nociceptors mediated via local COX and P38 map kinase actions Pain 2011 152 140 149 10.1016/j.pain.2010.10.002 21036476 PMC3391748
79. Binshtok A.M. Wang H. Zimmermann K. Amaya F. Vardeh D. Shi L. Brenner G.J. Ji R.R. Bean B.P. Woolf C.J. Nociceptors are interleukin-1beta sensors J. Neurosci. 2008 28 14062 14073 10.1523/JNEUROSCI.3795-08.2008 19109489 PMC2690713
80. Huang E.J. Reichardt L.F. Neurotrophins: Roles in neuronal development and function Annu. Rev. Neurosci. 2001 24 677 736 10.1146/annurev.neuro.24.1.677 11520916 PMC2758233
81. Barrios-Rodiles M. Chadee K. Novel regulation of cyclooxygenase-2 expression and prostaglandin e2 production by IFN-gamma in human macrophages J. Immunol. 1998 161 2441 2448 9725242
82. Sabino M.C. Ghilardi J.R. Feia K.J. Jongen J.L. Keyser C.P. Luger N.M. Mach D.B. Peters C.M. Rogers S.D. Schwei M.J. The involvement of prostaglandins in tumorigenesis, tumor-induced osteolysis and bone cancer pain J. Musculoskelet. Neuronal Interact. 2002 2 561 562 15758394
83. Fox A. Medhurst S. Courade J.P. Glatt M. Dawson J. Urban L. Bevan S. Gonzalez I. Anti-hyperalgesic activity of the COX-2 inhibitor lumiracoxib in a model of bone cancer pain in the rat Pain 2004 107 33 40 10.1016/j.pain.2003.09.003 14715386
84. Sabino M.A. Ghilardi J.R. Jongen J.L. Keyser C.P. Luger N.M. Mach D.B. Peters C.M. Rogers S.D. Schwei M.J. de Felipe C. Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2 Cancer Res. 2002 62 7343 7349 12499278
85. Bottner F. Roedl R. Wortler K. Grethen C. Winkelmann W. Lindner N. Cyclooxygenase-2 inhibitor for pain management in osteoid osteoma Clin. Orthop. Relat. Res. 2001 258 263 10.1097/00003086-200112000-00029 11764357
86. Carpintero-Benitez P. Aguirre M.A. Serrano J.A. Lluch M. Effect of rofecoxib on pain caused by osteoid osteoma Orthopedics 2004 27 1188 1191 15566132 10.3928/0147-7447-20041101-17
87. Vane J.R. Introduction: Mechanism of action of NSAIDs Br. J. Rheumatol. 1996 35 Suppl. 1 1 3 10.1093/rheumatology/35.suppl_1.1 8630629
88. Laneuville O. Breuer D.K. Dewitt D.L. Hla T. Funk C.D. Smith W.L. Differential inhibition of human prostaglandin endoperoxide h synthases-1 and -2 by nonsteroidal anti-inflammatory drugs J. Pharmacol. Exp. Ther. 1994 271 927 934 7965814
89. Antman E.M. Bennett J.S. Daugherty A. Furberg C. Roberts H. Taubert K.A. Use of nonsteroidal antiinflammatory drugs Update Clin. Sci. Statement Am. Heart Assoc. 2007 115 1634 1642 10.1161/CIRCULATIONAHA.106.181424 17325246
90. Bombardier C. Laine L. Reicin A. Shapiro D. Burgos-Vargas R. Davis B. Day R. Ferraz M.B. Hawkey C.J. Hochberg M.C. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. Vigor study group N. Engl. J. Med. 2000 343 1520 1528 10.1056/NEJM200011233432103 11087881
91. Isono M. Suzuki T. Hosono K. Hayashi I. Sakagami H. Uematsu S. Akira S. DeClerck Y.A. Okamoto H. Majima M. Microsomal prostaglandin e synthase-1 enhances bone cancer growth and bone cancer-related pain behaviors in mice Life Sci. 2011 88 693 700 10.1016/j.lfs.2011.02.008 21324324
92. McCaffrey G. Thompson M.L. Majuta L. Fealk M.N. Chartier S. Longo G. Mantyh P.W. Ngf blockade at early times during bone cancer development attenuates bone destruction and increases limb use Cancer Res. 2014 74 7014 7023 10.1158/0008-5472.CAN-14-1220 25287160 PMC4253026
93. Halvorson K.G. Kubota K. Sevcik M.A. Lindsay T.H. Sotillo J.E. Ghilardi J.R. Rosol T.J. Boustany L. Shelton D.L. Mantyh P.W. A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone Cancer Res. 2005 65 9426 9435 10.1158/0008-5472.CAN-05-0826 16230406
94. Bloom A.P. Jimenez-Andrade J.M. Taylor R.N. Castaneda-Corral G. Kaczmarska M.J. Freeman K.T. Coughlin K.A. Ghilardi J.R. Kuskowski M.A. Mantyh P.W. Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers J. Pain 2011 12 698 711 10.1016/j.jpain.2010.12.016 21497141 PMC3111843
95. Lane N.E. Schnitzer T.J. Birbara C.A. Mokhtarani M. Shelton D.L. Smith M.D. Brown M.T. Tanezumab for the treatment of pain from osteoarthritis of the knee N. Engl. J. Med. 2010 363 1521 1531 10.1056/NEJMoa0901510 20942668 PMC6896791
96. Schnitzer T.J. Ekman E.F. Spierings E.L. Greenberg H.S. Smith M.D. Brown M.T. West C.R. Verburg K.M. 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. 2015 74 1202 1211 10.1136/annrheumdis-2013-204905 24625625
97. Katz N. Borenstein D.G. Birbara C. Bramson C. Nemeth M.A. Smith M.D. Brown M.T. Efficacy and safety of tanezumab in the treatment of chronic low back pain Pain 2011 152 2248 2258 10.1016/j.pain.2011.05.003 21696889
98. Bramson C. Herrmann D.N. Carey W. Keller D. Brown M.T. West C.R. Verburg K.M. Dyck P.J. Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain Pain Med. 2015 16 1163 1176 10.1111/pme.12677 25594611
99. Sopata M. Katz N. Carey W. Smith M.D. Keller D. Verburg K.M. West C.R. Wolfram G. Brown M.T. Efficacy and safety of tanezumab in the treatment of pain from bone metastases Pain 2015 156 1703 1713 10.1097/j.pain.0000000000000211 25919474
100. Bunnett N.W. Protease-activated receptors: How proteases signal to cells to cause inflammation and pain Semin. Thromb. Hemost. 2006 32 Suppl. 1 39 48 10.1055/s-2006-939553 16673265
101. Vergnolle N. Bunnett N.W. Sharkey K.A. Brussee V. Compton S.J. Grady E.F. Cirino G. Gerard N. Basbaum A.I. Andrade-Gordon P. Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway Nat. Med. 2001 7 821 826 10.1038/89945 11433347
102. Mrozkova P. Palecek J. Spicarova D. The role of protease-activated receptor type 2 in nociceptive signaling and pain Physiol. Res. 2016 65 357 367 27070742 10.33549/physiolres.933269
103. Reed D.E. Barajas-Lopez C. Cottrell G. Velazquez-Rocha S. Dery O. Grady E.F. Bunnett N.W. Vanner S.J. Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons J. Physiol. 2003 547 531 542 10.1113/jphysiol.2002.032011 12562962 PMC2342663
104. Molino M. Barnathan E.S. Numerof R. Clark J. Dreyer M. Cumashi A. Hoxie J.A. Schechter N. Woolkalis M. Brass L.F. Interactions of mast cell tryptase with thrombin receptors and par-2 J. Biol. Chem. 1997 272 4043 4049 10.1074/jbc.272.7.4043 9020112
105. Nystedt S. Emilsson K. Wahlestedt C. Sundelin J. Molecular cloning of a potential proteinase activated receptor Proc. Natl. Acad. Sci. USA 1994 91 9208 9212 10.1073/pnas.91.20.9208 7937743 PMC44781
106. Kleij H.P. Bienenstock J. Significance of conversation between mast cells and nerves Allergy Asthma Clin. Immunol. 2005 1 65 80 10.1186/1710-1492-1-2-65 20529227 PMC2877069
107. Barbara G. Stanghellini V. De Giorgio R. Cremon C. Cottrell G.S. Santini D. Pasquinelli G. Morselli-Labate A.M. Grady E.F. Bunnett N.W. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome Gastroenterology 2004 126 693 702 10.1053/j.gastro.2003.11.055 14988823
108. Demir I.E. Schorn S. Schremmer-Danninger E. Wang K. Kehl T. Giese N.A. Algul H. Friess H. Ceyhan G.O. Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain in pancreatic cancer and chronic pancreatitis PLoS ONE 2013 8 e60529 10.1371/journal.pone.0060529 23555989 PMC3610867
109. Lam D.K. Schmidt B.L. Serine proteases and protease-activated receptor 2-dependent allodynia: A novel cancer pain pathway Pain 2010 149 263 272 10.1016/j.pain.2010.02.010 20189717 PMC2861734
110. Mantyh P.W. The neurobiology of skeletal pain Eur. J. Neurosci. 2014 39 508 519 10.1111/ejn.12462 24494689 PMC4453827
111. Hong D. Byers M.R. Oswald R.J. Dexamethasone treatment reduces sensory neuropeptides and nerve sprouting reactions in injured teeth Pain 1993 55 171 181 10.1016/0304-3959(93)90146-G 7906026
112. Ghilardi J.R. Freeman K.T. Jimenez-Andrade J.M. Coughlin K.A. Kaczmarska M.J. Castaneda-Corral G. Bloom A.P. Kuskowski M.A. Mantyh P.W. Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint Arthritis Rheum 2012 64 2223 2232 10.1002/art.34385 22246649 PMC3386465
113. Chartier S.R. Thompson M.L. Longo G. Fealk M.N. Majuta L.A. Mantyh P.W. Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain Pain 2014 155 2323 2336 10.1016/j.pain.2014.08.026 25196264 PMC4254205
114. Riesco N. Cernuda-Morollon E. Pascual J. Neuropeptides as a marker for chronic headache Curr. Pain Headache Rep. 2017 21 18 10.1007/s11916-017-0618-8 28281109
115. Schou W.S. Ashina S. Amin F.M. Goadsby P.J. Ashina M. Calcitonin gene-related peptide and pain: A systematic review J. Headache Pain 2017 18 34 10.1186/s10194-017-0741-2 28303458 PMC5355411
116. Liu S. Liu Y.P. Yue D.M. Liu G.J. Protease-activated receptor 2 in dorsal root ganglion contributes to peripheral sensitization of bone cancer pain Eur. J. Pain 2014 18 326 337 10.1002/j.1532-2149.2013.00372.x 23893658
117. Leporini C. Ammendola M. Marech I. Sammarco G. Sacco R. Gadaleta C.D. Oakley C. Russo E. De Sarro G. Ranieri G. Targeting mast cells in gastric cancer with special reference to bone metastases World J. Gastroenterol. 2015 21 10493 10501 10.3748/wjg.v21.i37.10493 26457010 PMC4588072
118. Ammendola M. Marech I. Sammarco G. Zuccala V. Luposella M. Zizzo N. Patruno R. Crovace A. Ruggieri E. Zito A.F. Infiltrating mast cells correlate with angiogenesis in bone metastases from gastric cancer patients Int. J. Mol. Sci. 2015 16 3237 3250 10.3390/ijms16023237 25648323 PMC4346892
119. Tondevold E. Eriksen J. Jansen E. Observations on long bone medullary pressure in relation to mean arterial blood pressure in the anaesthetized dog Acta Orthop. Scand. 1979 50 527 531 10.3109/17453677908989799 525317
120. Hu J. Van Valckenborgh E. Menu E. De Bruyne E. Vanderkerken K. Understanding the hypoxic niche of multiple myeloma: Therapeutic implications and contributions of mouse models Dis. Models Mech. 2012 5 763 771 10.1242/dmm.008961 23115205 PMC3484859
121. Wang Y. Wan C. Deng L. Liu X. Cao X. Gilbert S.R. Bouxsein M.L. Faugere M.C. Guldberg R.E. Gerstenfeld L.C. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development J. Clin. Investig. 2007 117 1616 1626 10.1172/JCI31581 17549257 PMC1878533
122. Wan C. Gilbert S.R. Wang Y. Cao X. Shen X. Ramaswamy G. Jacobsen K.A. Alaql Z.S. Eberhardt A.W. Gerstenfeld L.C. Activation of the hypoxia-inducible factor-1alpha pathway accelerates bone regeneration Proc. Natl. Acad. Sci. USA 2008 105 686 691 10.1073/pnas.0708474105 18184809 PMC2206597
123. Shomento S.H. Wan C. Cao X. Faugere M.C. Bouxsein M.L. Clemens T.L. Riddle R.C. Hypoxia-inducible factors 1alpha and 2alpha exert both distinct and overlapping functions in long bone development J. Cell. Biochem. 2010 109 196 204 10.1002/jcb.22396 19899108
124. Knowles H.J. Athanasou N.A. Acute hypoxia and osteoclast activity: A balance between enhanced resorption and increased apoptosis J. Pathol. 2009 218 256 264 10.1002/path.2534 19291710
125. Rankin E.B. Giaccia A.J. Schipani E. A central role for hypoxic signaling in cartilage, bone, and hematopoiesis Curr. Osteoporos. Rep. 2011 9 46 52 10.1007/s11914-011-0047-2 21360287 PMC4012534
126. Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the warburg effect: The metabolic requirements of cell proliferation Science 2009 324 1029 1033 10.1126/science.1160809 19460998 PMC2849637
127. Peppicelli S. Bianchini F. Toti A. Laurenzana A. Fibbi G. Calorini L. Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression Cell Cycle 2015 14 3088 3100 10.1080/15384101.2015.1078032 26496168 PMC4825622
128. Di Pompo G. Lemma S. Canti L. Rucci N. Ponzetti M. Errani C. Donati D.M. Russell S. Gillies R. Chano T. Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma Oncotarget 2017 8 54478 54496 10.18632/oncotarget.17091 28903357 PMC5589596
129. Montazeri A. 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 2009 7 102 10.1186/1477-7525-7-102 20030832 PMC2805623
130. Halabi S. Vogelzang N.J. Kornblith A.B. Ou S.S. Kantoff P.W. Dawson N.A. Small E.J. Pain predicts overall survival in men with metastatic castration-refractory prostate cancer J. Clin. Oncol. 2008 26 2544 2549 10.1200/JCO.2007.15.0367 18487572
131. Koizumi M. Yoshimoto M. Kasumi F. Iwase T. Ogata E. 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 2010 10 423 10.1186/1471-2407-10-423 20704752 PMC3161388
132. Fizazi K. Massard C. Smith M. Rader M. Brown J. Milecki P. Shore N. Oudard S. Karsh L. Carducci M. Bone-related parameters are the main prognostic factors for overall survival in men with bone metastases from castration-resistant prostate cancer Eur. Urol. 2015 68 42 50 10.1016/j.eururo.2014.10.001 25449207
133. Niikura N. Liu J. Hayashi N. Palla S.L. Tokuda Y. Hortobagyi G.N. Ueno N.T. Theriault R.L. Treatment outcome and prognostic factors for patients with bone-only metastases of breast cancer: A single-institution retrospective analysis Oncologist 2011 16 155 164 10.1634/theoncologist.2010-0350 21266401 PMC3228079
134. Parker C. Nilsson S. Heinrich D. Helle S.I. O’Sullivan J.M. Fossa S.D. Chodacki A. Wiechno P. Logue J. Seke M. Alpha emitter radium-223 and survival in metastatic prostate cancer N. Engl. J. Med. 2013 369 213 223 10.1056/NEJMoa1213755 23863050
135. Boilly B. Faulkner S. Jobling P. Hondermarck H. Nerve dependence: From regeneration to cancer Cancer Cell 2017 31 342 354 10.1016/j.ccell.2017.02.005 28292437
136. Magnon C. Hall S.J. Lin J. Xue X. Gerber L. Freedland S.J. Frenette P.S. Autonomic nerve development contributes to prostate cancer progression Science 2013 341 1236361 10.1126/science.1236361 23846904
137. Hayakawa Y. Sakitani K. Konishi M. Asfaha S. Niikura R. Tomita H. Renz B.W. Tailor Y. Macchini M. Middelhoff M. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling Cancer Cell 2017 31 21 34 10.1016/j.ccell.2016.11.005 27989802 PMC5225031
138. Zhao C.M. Hayakawa Y. Kodama Y. Muthupalani S. Westphalen C.B. Andersen G.T. Flatberg A. Johannessen H. Friedman R.A. Renz B.W. Denervation suppresses gastric tumorigenesis Sci. Transl. Med. 2014 6 250ra115 10.1126/scitranslmed.3009569 25143365 PMC4374618
139. Saloman J.L. Albers K.M. Li D. Hartman D.J. Crawford H.C. Muha E.A. Rhim A.D. Davis B.M. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer Proc. Natl. Acad. Sci. USA 2016 113 3078 3083 10.1073/pnas.1512603113 26929329 PMC4801275
140. Bao Y. Hou W. Yang L. Kong X. Du M. Zheng H. Gao Y. Hua B. Protease-activated receptor 2 antagonist potentiates analgesic effects of systemic morphine in a rat model of bone cancer pain Reg. Anesth. Pain Med. 2015 40 158 165 10.1097/AAP.0000000000000211 25650631