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Cancer–nerve interplay in cancer progression and cancer-induced bone pain

  • Invited Review
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Introduction

Cancer-induced bone pain (CIBP) is one of the most common and debilitating complications associated with bone metastasis. Although our understanding of the precise mechanism is limited, it has been known that bone is densely innervated, and that CIBP is elicited as a consequence of increased neurogenesis, reprogramming, and axonogenesis in conjunction with sensitization and excitation of sensory nerves (SNs) in response to the noxious stimuli that are derived from the tumor microenvironment developed in bone. Recent studies have shown that the sensitized and excited nerves innervating the tumor establish intimate communications with cancer cells by releasing various tumor-stimulating factors for tumor progression.

Approaches

In this review, the role of the interactions of cancer cells and SNs in bone in the pathophysiology of CIBP will be discussed with a special focus on the role of the noxious acidic tumor microenvironment, considering that bone is in nature hypoxic, which facilitates the generation of acidic conditions by cancer. Subsequently, the role of SNs in the regulation of cancer progression in the bone will be discussed together with our recent experimental findings.

Conclusion

It is suggested that SNs may be a newly-recognized important component of the bone microenvironment that contribute to not only in the pathophysiology of CIBP but also cancer progression in bone and dissemination from bone. Suppression of the activity of bone-innervating SNs, thus, may provide unique opportunities in the treatment of cancer progression and dissemination, as well as CIBP.

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Data availability statement

All the data presented in this article are available upon request to the corresponding author.

Abbreviations

a3V-H + -ATPase:

A3 isoform V-H + -ATPase

AN:

Autonomic nerve

ASIC:

Acid-sensing ion channel

CGRP:

Calcitonin gene-related protein

CIBP:

Cancer-induced bone pain

CNS:

Central nervous system

CRPC:

Castration-resistant prostate cancer

DRG:

Dorsal root ganglion

GPR81:

G-protein-coupled receptor 81

HIF-1α:

Hypoxia-inducible factor-1α

HMGB1:

High mobility group box 1

HRPC:

Hormone-refractory prostate cancer

IGF-1:

Insulin-like growth factor 1

MCT1:

Monocarboxylate transporter 1

MCT4:

Monocarboxylate transporter 4

NGF:

Nerve growth factor

NMDA:

N-methyl-D-aspartate

pCREB:

Phosphorylated cyclic AMP-responsive element-binding protein

pERK1/2:

Phosphorylated extracellular receptor kinase 1/2

PNI:

Perineural invasion

PTH-rP:

Parathyroid hormone-related protein

RAGE:

Receptor for advanced glycation end products

SN:

Sensory nerve

SRE:

Skeletal-related events

TGFβ1:

Transforming growth factor β1

TLR:

Toll-like receptors

TRPV1:

Transient receptor potential channel, vanilloid subfamily member 1

WT:

Wild-type

References

  1. Goldberg DS, McGee SJ (2011) Pain as a global public health priority. BMC Public Health 11:770. https://doi.org/10.1186/1471-2458-11-770

    Article  PubMed  PubMed Central  Google Scholar 

  2. Swieboda P, Filip R, Prystupa A, Drozd M (2013) Assessment of pain: types, mechanism and treatment. Ann Agric Environ Med Spec 1:2–7

    Google Scholar 

  3. Falk S, Dickenson AH (2014) Pain and nociception: mechanisms of cancer-induced bone pain. J Clin Oncol 32:1647–1654. https://doi.org/10.1200/jco.2013.51.7219

    Article  CAS  PubMed  Google Scholar 

  4. Zylla D, Steele G, Gupta P (2017) A systematic review of the impact of pain on overall survival in patients with cancer. Support Care Cancer 25:1687–1698. https://doi.org/10.1007/s00520-017-3614-y

    Article  PubMed  Google Scholar 

  5. Coleman RE, Croucher PI, Padhani AR, Clézardin P, Chow E, Fallon M, Guise T, Colangeli S, Capanna R, Costa L (2020) Bone metastases. Nat Rev Dis Primers 6:83. https://doi.org/10.1038/s41572-020-00216-3

    Article  PubMed  Google Scholar 

  6. Coleman RE (2006) Clinical features of metastatic bone disease and risk of skeletalmorbidity. Clin Cancer Res 12:6243s-s6249. https://doi.org/10.1158/1078-0432.Ccr-06-0931

    Article  PubMed  Google Scholar 

  7. Cleeland CS, Body JJ, Stopeck A, von Moos R, Fallowfield L, Mathias SD, Patrick DL, Clemons M, Tonkin K, Masuda N, Lipton A, de Boer R, Salvagni S, Oliveira CT, Qian Y, Jiang Q, Dansey R, Braun A, Chung K (2013) Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, double-blind study of denosumab and zoledronic acid. Cancer 119:832–838. https://doi.org/10.1002/cncr.27789

    Article  CAS  PubMed  Google Scholar 

  8. Clézardin P, Coleman R, Puppo M, Ottewell P, Bonnelye E, Paycha F, Confavreux CB, Holen I (2021) Bone metastasis: mechanisms, therapies, and biomarkers. Physiol Rev 101:797–855. https://doi.org/10.1152/physrev.00012.2019

    Article  CAS  PubMed  Google Scholar 

  9. von Moos R, Costa L, Ripamonti CI, Niepel D, Santini D (2017) Improving quality of life in patients with advanced cancer: targeting metastatic bone pain. Eur J Cancer 71:80–94. https://doi.org/10.1016/j.ejca.2016.10.021

    Article  Google Scholar 

  10. Halabi S, Vogelzang NJ, Kornblith AB, Ou SS, Kantoff PW, Dawson NA, Small EJ (2008) Pain predicts overall survival in men with metastatic castration-refractory prostate cancer. J Clin Oncol 26:2544–2549. https://doi.org/10.1200/jco.2007.15.0367

    Article  PubMed  Google Scholar 

  11. Coveler AL, Mizrahi J, Eastman B, Apisarnthanarax SJ, Dalal S, McNearney T, Pant S (2021) Pancreas cancer-associated pain management. Oncologist 26:e971–e982. https://doi.org/10.1002/onco.13796

    Article  PubMed  PubMed Central  Google Scholar 

  12. Patrick DL, Ferketich SL, Frame PS, Harris JJ, Hendricks CB, Levin B, Link MP, Lustig C, McLaughlin J, Ried LD, Turrisi AT 3rd, Unützer J, Vernon SW (2003) National institutes of health state-of-the-science conference statement: symptom management in cancer: pain, depression, and fatigue, July 15–17, 2002. J Natl Cancer Inst 95:1110–1117. https://doi.org/10.1093/jnci/djg014

    Article  PubMed  Google Scholar 

  13. Staats PS, Hekmat H, Sauter P, Lillemoe K (2001) The effects of alcohol celiac plexus block, pain, and mood on longevity in patients with unresectable pancreatic cancer: a double-blind, randomized, placebo-controlled study. Pain Med 2:28–34. https://doi.org/10.1046/j.1526-4637.2001.002001028.x

    Article  CAS  PubMed  Google Scholar 

  14. Mantyh PW (2014) Bone cancer pain: from mechanism to therapy. Curr Opin Support Palliat Care 8:83–90. https://doi.org/10.1097/spc.0000000000000048

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ivanusic JJ (2017) Molecular mechanisms that contribute to bone marrow pain. Front Neurol 8:458. https://doi.org/10.3389/fneur.2017.00458

    Article  PubMed  PubMed Central  Google Scholar 

  16. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D (2009) Perineural invasion in cancer: a review of the literature. Cancer 115:3379–3391. https://doi.org/10.1002/cncr.24396

    Article  CAS  PubMed  Google Scholar 

  17. Bapat AA, Hostetter G, Von Hoff DD, Han H (2011) Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer 11:695–707. https://doi.org/10.1038/nrc3131

    Article  CAS  PubMed  Google Scholar 

  18. Ivanusic JJ (2009) Size, neurochemistry, and segmental distribution of sensory neurons innervating the rat tibia. J Comp Neurol 517:276–283. https://doi.org/10.1002/cne.22160

    Article  PubMed  Google Scholar 

  19. Jung WC, Levesque JP, Ruitenberg MJ (2017) It takes nerve to fight back: the significance of neural innervation of the bone marrow and spleen for immune function. Semin Cell Dev Biol 61:60–70. https://doi.org/10.1016/j.semcdb.2016.08.010

    Article  CAS  PubMed  Google Scholar 

  20. Brazill JM, Beeve AT, Craft CS, Ivanusic JJ, Scheller EL (2019) Nerves in bone: evolving concepts in pain and anabolism. J Bone Miner Res 34:1393–1406. https://doi.org/10.1002/jbmr.3822

    Article  PubMed  Google Scholar 

  21. Wan QQ, Qin WP, Ma YX, Shen MJ, Li J, Zhang ZB, Chen JH, Tay FR, Niu LN, Jiao K (2021) Crosstalk between Bone and Nerves within Bone. Adv Sci (Weinh) 8:2003390. https://doi.org/10.1002/advs.202003390

    Article  CAS  PubMed  Google Scholar 

  22. Cooper RR (1968) Nerves in cortical bone. Science 160:327–328. https://doi.org/10.1126/science.160.3825.327

    Article  CAS  PubMed  Google Scholar 

  23. Serre CM, Farlay D, Delmas PD, Chenu C (1999) Evidence for a dense and intimate innervation of the bone tissue, including glutamate-containing fibers. Bone 25:623–629. https://doi.org/10.1016/s8756-3282(99)00215-x

    Article  CAS  PubMed  Google Scholar 

  24. Irie K, Hara-Irie F, Ozawa H, Yajima T (2002) Calcitonin gene-related peptide (CGRP)-containing nerve fibers in bone tissue and their involvement in bone remodeling. Microsc Res Tech 58:85–90. https://doi.org/10.1002/jemt.10122

    Article  CAS  PubMed  Google Scholar 

  25. Mach DB, Rogers SD, Sabino MC, Luger NM, Schwei MJ, Pomonis JD, Keyser CP, Clohisy DR, Adams DJ, O’Leary P, Mantyh PW (2002) Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience 113:155–166. https://doi.org/10.1016/s0306-4522(02)00165-3

    Article  CAS  PubMed  Google Scholar 

  26. Fukuda T, Takeda S, Xu R, Ochi H, Sunamura S et al (2013) Sema3A regulates bone-mass accrual through sensory innervations. Nature 497:490–493. https://doi.org/10.1038/nature12115

    Article  CAS  PubMed  Google Scholar 

  27. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210. https://doi.org/10.1038/35093019

    Article  CAS  PubMed  Google Scholar 

  28. Chartier SR, Mitchell SAT, Majuta LA, Mantyh PW (2018) The changing sensory and sympathetic innervation of the young, adult and aging mouse femur. Neuroscience 387:178–190. https://doi.org/10.1016/j.neuroscience.2018.01.047

    Article  CAS  PubMed  Google Scholar 

  29. Hiasa M, Okui T, Allette YM, Ripsch MS, Sun-Wada GH, Wakabayashi H, Roodman GD, White FA, Yoneda T (2017) Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3. Cancer Res 77:1283–1295. https://doi.org/10.1158/0008-5472.Can-15-3545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wakabayashi H, Wakisaka S, Hiraga T, Hata K, Nishimura R, Tominaga M, Yoneda T (2018) Decreased sensory nerve excitation and bone pain associated with mouse Lewis lung cancer in TRPV1-deficient mice. J Bone Miner Metab 36:274–285. https://doi.org/10.1007/s00774-017-0842-7

    Article  CAS  PubMed  Google Scholar 

  31. Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS (2013) Autonomic nerve development contributes to prostate cancer progression. Science 341:1236361. https://doi.org/10.1126/science.1236361

    Article  PubMed  Google Scholar 

  32. Jobling P, Pundavela J, Oliveira SM, Roselli S, Walker MM, Hondermarck H (2015) Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res 75:1777–1781. https://doi.org/10.1158/0008-5472.Can-14-3180

    Article  CAS  PubMed  Google Scholar 

  33. Elefteriou F (2018) Impact of the autonomic nervous system on the skeleton. Physiol Rev 98:1083–1112. https://doi.org/10.1152/physrev.00014.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zahalka AH, Frenette PS (2020) Nerves in cancer. Nat Rev Cancer 20:143–157. https://doi.org/10.1038/s41568-019-0237-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lorenz MR, Brazill JM, Beeve AT, Shen I, Scheller EL (2021) A neuroskeletal atlas: spatial mapping and contextualization of axon subtypes innervating the long bones of C3H and B6 mice. J Bone Miner Res 36:1012–1025. https://doi.org/10.1002/jbmr.4273

    Article  PubMed  Google Scholar 

  36. Mercadante S (1997) Malignant bone pain: pathophysiology and treatment. Pain 69:1–18. https://doi.org/10.1016/s0304-3959(96)03267-8

    Article  CAS  PubMed  Google Scholar 

  37. Zajączkowska R, Kocot-Kępska M, Leppert W, Wordliczek J (2019) Bone pain in cancer patients: mechanisms and current treatment. Int J Mol Sci. https://doi.org/10.3390/ijms20236047

    Article  PubMed  PubMed Central  Google Scholar 

  38. Silverman DA, Martinez VK, Dougherty PM, Myers JN, Calin GA, Amit M (2021) Cancer-associated neurogenesis and nerve-cancer cross-talk. Cancer Res 81:1431–1440. https://doi.org/10.1158/0008-5472.Can-20-2793

    Article  CAS  PubMed  Google Scholar 

  39. Okui T, Hiasa M, Ryumon S, Ono K, Kunisada Y, Ibaragi S, Sasaki A, Roodman GD, White FA, Yoneda T (2021) The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone. J Bone Oncol 26:100330. https://doi.org/10.1016/j.jbo.2020.100330

    Article  PubMed  Google Scholar 

  40. Jimenez-Andrade JM, Bloom AP, Stake JI, Mantyh WG, Taylor RN, Freeman KT, Ghilardi JR, Kuskowski MA, Mantyh PW (2010) Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. J Neurosci 30:14649–14656. https://doi.org/10.1523/jneurosci.3300-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. March B, Faulkner S, Jobling P, Steigler A, Blatt A, Denham J, Hondermarck H (2020) Tumour innervation and neurosignalling in prostate cancer. Nat Rev Urol 17:119–130. https://doi.org/10.1038/s41585-019-0274-3

    Article  PubMed  Google Scholar 

  42. Maes C, Carmeliet G, Schipani E (2012) Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol 8:358–366. https://doi.org/10.1038/nrrheum.2012.36

    Article  CAS  PubMed  Google Scholar 

  43. Simon MC, Keith B (2008) The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9:285–296. https://doi.org/10.1038/nrm2354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liberti MV, Locasale JW (2016) The Warburg Effect: how does it benefit cancer cells? Trends Biochem Sci 41:211–218. https://doi.org/10.1016/j.tibs.2015.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Parks SK, Mueller-Klieser W, Pouysségur J (2020) Lactate and Acidity in the cancer microenvironment. Ann Rev Cancer Biol 4:141–158. https://doi.org/10.1146/annurev-cancerbio-030419-033556

    Article  Google Scholar 

  46. Nakanishi-Matsui M, Matsumoto N (2022) V-ATPase a3 subunit in secretory lysosome trafficking in osteoclasts. Biol Pharm Bull 45:1426–1431. https://doi.org/10.1248/bpb.b22-00371

    Article  CAS  PubMed  Google Scholar 

  47. Maeda H, Kowada T, Kikuta J, Furuya M, Shirazaki M, Mizukami S, Ishii M, Kikuchi K (2016) Real-time intravital imaging of pH variation associated with osteoclast activity. Nat Chem Biol 12:579–585. https://doi.org/10.1038/nchembio.2096

    Article  CAS  PubMed  Google Scholar 

  48. Mantyh PW (2006) Cancer pain and its impact on diagnosis, survival and quality of life. Nat Rev Neurosci 7:797–809. https://doi.org/10.1038/nrn1914

    Article  CAS  PubMed  Google Scholar 

  49. Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284. https://doi.org/10.1016/j.cell.2009.09.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sun WH, Dai SP (2018) Tackling pain associated with rheumatoid arthritis: proton-sensing receptors. Adv Exp Med Biol 1099:49–64. https://doi.org/10.1007/978-981-13-1756-9_5

    Article  CAS  PubMed  Google Scholar 

  51. Louca Jounger S, Eriksson N, Lindskog H, Oscarsson A, Simonsson V, Ernberg M, Christidis N (2019) Repeated buffered acidic saline infusion in the human masseter muscle as a putative experimental pain model. Sci Rep 9:15474. https://doi.org/10.1038/s41598-019-51670-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Esposito MF, Malayil R, Hanes M, Deer T (2019) Unique characteristics of the dorsal root ganglion as a target for neuromodulation. Pain Med 20:S23-s30. https://doi.org/10.1093/pm/pnz012

    Article  PubMed  PubMed Central  Google Scholar 

  53. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824. https://doi.org/10.1038/39807

    Article  CAS  PubMed  Google Scholar 

  54. Bujak JK, Kosmala D, Szopa IM, Majchrzak K, Bednarczyk P (2019) Inflammation, cancer and immunity-implication of TRPV1 channel. Front Oncol 9:1087. https://doi.org/10.3389/fonc.2019.01087

    Article  PubMed  PubMed Central  Google Scholar 

  55. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313. https://doi.org/10.1126/science.288.5464.306

    Article  CAS  PubMed  Google Scholar 

  56. Bourinet E, Altier C, Hildebrand ME, Trang T, Salter MW, Zamponi GW (2014) Calcium-permeable ion channels in pain signaling. Physiol Rev 94:81–140. https://doi.org/10.1152/physrev.00023.2013

    Article  CAS  PubMed  Google Scholar 

  57. Lieben L, Carmeliet G (2012) The involvement of TRP channels in Bone homeostasis. Front Endocrinol (Lausanne) 3:99. https://doi.org/10.3389/fendo.2012.00099

    Article  PubMed  Google Scholar 

  58. Li L, Chen C, Chiang C, Xiao T, Chen Y, Zhao Y, Zheng D (2021) The impact of TRPV1 on cancer pathogenesis and therapy: a systematic review. Int J Biol Sci 17:2034–2049. https://doi.org/10.7150/ijbs.59918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ghilardi JR, Röhrich H, Lindsay TH, Sevcik MA, Schwei MJ, Kubota K, Halvorson KG, Poblete J, Chaplan SR, Dubin AE, Carruthers NI, Swanson D, Kuskowski M, Flores CM, Julius D, Mantyh PW (2005) Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J Neurosci 25:3126–3131. https://doi.org/10.1523/jneurosci.3815-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Niiyama Y, Kawamata T, Yamamoto J, Omote K, Namiki A (2007) Bone cancer increases transient receptor potential vanilloid subfamily 1 expression within distinct subpopulations of dorsal root ganglion neurons. Neuroscience 148:560–572. https://doi.org/10.1016/j.neuroscience.2007.05.049

    Article  CAS  PubMed  Google Scholar 

  61. Niiyama Y, Kawamata T, Yamamoto J, Furuse S, Namiki A (2009) SB366791, a TRPV1 antagonist, potentiates analgesic effects of systemic morphine in a murine model of bone cancer pain. Br J Anaesth 102:251–258. https://doi.org/10.1093/bja/aen347

    Article  CAS  PubMed  Google Scholar 

  62. Xu Q, Zhang XM, Duan KZ, Gu XY, Han M, Liu BL, Zhao ZQ, Zhang YQ (2013) Peripheral TGF-β1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents. J Neurosci 33:19099–19111. https://doi.org/10.1523/jneurosci.4852-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Li Y, Cai J, Han Y, Xiao X, Meng XL, Su L, Liu FY, Xing GG, Wan Y (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 18:774–784. https://doi.org/10.1002/j.1532-2149.2013.00420.x

    Article  CAS  PubMed  Google Scholar 

  64. Fang D, Kong LY, Cai J, Li S, Liu XD, Han JS, Xing GG (2015) Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway: roles in the development of bone cancer pain in a rat model. Pain 156:1124–1144. https://doi.org/10.1097/j.pain.0000000000000158

    Article  CAS  PubMed  Google Scholar 

  65. Nagae M, Hiraga T, Wakabayashi H, Wang L, Iwata K, Yoneda T (2006) Osteoclasts play a part in pain due to the inflammation adjacent to bone. Bone 39:1107–1115. https://doi.org/10.1016/j.bone.2006.04.033

    Article  CAS  PubMed  Google Scholar 

  66. Shepherd AJ, Mickle AD, Kadunganattil S, Hu H, Mohapatra DP (2018) Parathyroid hormone-related peptide elicits peripheral TRPV1-dependent mechanical hypersensitivity. Front Cell Neurosci 12:38. https://doi.org/10.3389/fncel.2018.00038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Riera CE, Huising MO, Follett P, Leblanc M, Halloran J, Van Andel R, de Magalhaes Filho CD, Merkwirth C, Dillin A (2014) TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell 157:1023–1036. https://doi.org/10.1016/j.cell.2014.03.051

    Article  CAS  PubMed  Google Scholar 

  68. Lee CH, Chen CC (2018) Roles of ASICs in nociception and proprioception. Adv Exp Med Biol 1099:37–47. https://doi.org/10.1007/978-981-13-1756-9_4

    Article  CAS  PubMed  Google Scholar 

  69. Olson TH, Riedl MS, Vulchanova L, Ortiz-Gonzalez XR, Elde R (1998) An acid sensing ion channel (ASIC) localizes to small primary afferent neurons in rats. NeuroReport 9:1109–1113. https://doi.org/10.1097/00001756-199804200-00028

    Article  CAS  PubMed  Google Scholar 

  70. Jahr H, van Driel M, van Osch GJ, Weinans H, van Leeuwen JP (2005) Identification of acid-sensing ion channels in bone. Biochem Biophys Res Commun 337:349–354. https://doi.org/10.1016/j.bbrc.2005.09.054

    Article  CAS  PubMed  Google Scholar 

  71. Wemmie JA, Taugher RJ, Kreple CJ (2013) Acid-sensing ion channels in pain and disease. Nat Rev Neurosci 14:461–471. https://doi.org/10.1038/nrn3529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sluka KA, Price MP, Breese NM, Stucky CL, Wemmie JA, Welsh MJ (2003) Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain 106:229–239. https://doi.org/10.1016/s0304-3959(03)00269-0

    Article  CAS  PubMed  Google Scholar 

  73. Wu WL, Cheng CF, Sun WH, Wong CW, Chen CC (2012) Targeting ASIC3 for pain, anxiety, and insulin resistance. Pharmacol Ther 134:127–138. https://doi.org/10.1016/j.pharmthera.2011.12.009

    Article  CAS  PubMed  Google Scholar 

  74. Karczewski J, Spencer RH, Garsky VM, Liang A, Leitl MD, Cato MJ, Cook SP, Kane S, Urban MO (2010) Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2. Br J Pharmacol 161:950–960. https://doi.org/10.1111/j.1476-5381.2010.00918.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yu Y, Chen Z, Li WG, Cao H, Feng EG, Yu F, Liu H, Jiang H, Xu TL (2010) A nonproton ligand sensor in the acid-sensing ion channel. Neuron 68:61–72. https://doi.org/10.1016/j.neuron.2010.09.001

    Article  CAS  PubMed  Google Scholar 

  76. Hsieh WS, Kung CC, Huang SL, Lin SC, Sun WH (2017) TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis. Sci Rep 7:8870. https://doi.org/10.1038/s41598-017-09200-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nagae M, Hiraga T, Yoneda T (2007) Acidic microenvironment created by osteoclasts causes bone pain associated with tumor colonization. J Bone Miner Metab 25:99–104. https://doi.org/10.1007/s00774-006-0734-8

    Article  PubMed  Google Scholar 

  78. Qiu F, Wei X, Zhang S, Yuan W, Mi W (2014) Increased expression of acid-sensing ion channel 3 within dorsal root ganglia in a rat model of bone cancer pain. NeuroReport 25:887–893. https://doi.org/10.1097/wnr.0000000000000182

    Article  CAS  PubMed  Google Scholar 

  79. Qian HY, Zhou F, Wu R, Cao XJ, Zhu T, Yuan HD, Chen YN, Zhang PA (2021) Metformin attenuates bone cancer pain by reducing TRPV1 and ASIC3 expression. Front Pharmacol 12:713944. https://doi.org/10.3389/fphar.2021.713944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Terpos E, Zamagni E, Lentzsch S, Drake MT, García-Sanz R, Abildgaard N, Ntanasis-Stathopoulos I, Schjesvold F, de la Rubia J, Kyriakou C, Hillengass J, Zweegman S, Cavo M, Moreau P, San-Miguel J, Dimopoulos MA, Munshi N, Durie BGM, Raje N (2021) Treatment of multiple myeloma-related bone disease: recommendations from the bone working group of the international myeloma working group. Lancet Oncol 22:e119–e130. https://doi.org/10.1016/s1470-2045(20)30559-3

    Article  CAS  PubMed  Google Scholar 

  81. Mamet J, Baron A, Lazdunski M, Voilley N (2002) Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci 22:10662–10670. https://doi.org/10.1523/jneurosci.22-24-10662.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Marra S, Ferru-Clément R, Breuil V, Delaunay A, Christin M, Friend V, Sebille S, Cognard C, Ferreira T, Roux C, Euller-Ziegler L, Noel J, Lingueglia E, Deval E (2016) Non-acidic activation of pain-related acid-sensing ion channel 3 by lipids. Embo J 35:414–428. https://doi.org/10.15252/embj.201592335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kang R, Zhang Q, Zeh HJ 3rd, Lotze MT, Tang D (2013) HMGB1 in cancer: good, bad, or both? Clin Cancer Res 19:4046–4057. https://doi.org/10.1158/1078-0432.Ccr-13-0495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Das N, Dewan V, Grace PM, Gunn RJ, Tamura R, Tzarum N, Watkins LR, Wilson IA, Yin H (2016) HMGB1 activates proinflammatory signaling via TLR5 leading to allodynia. Cell Rep 17:1128–1140. https://doi.org/10.1016/j.celrep.2016.09.076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sun S, Li H, Chen J, Qian Q (2017) Lactic acid: no longer an inert and end-product of glycolysis. Physiology (Bethesda) 32:453–463. https://doi.org/10.1152/physiol.00016.2017

    Article  CAS  PubMed  Google Scholar 

  86. Doherty JR, Cleveland JL (2013) Targeting lactate metabolism for cancer therapeutics. J Clin Invest 123:3685–3692. https://doi.org/10.1172/jci69741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Brooks GA (2018) The science and translation of lactate shuttle theory. Cell Metab 27:757–785. https://doi.org/10.1016/j.cmet.2018.03.008

    Article  CAS  PubMed  Google Scholar 

  88. Magistretti PJ, Allaman I (2018) Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 19:235–249. https://doi.org/10.1038/nrn.2018.19

    Article  CAS  PubMed  Google Scholar 

  89. Brown TP, Ganapathy V (2020) Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther 206:107451. https://doi.org/10.1016/j.pharmthera.2019.107451

    Article  CAS  PubMed  Google Scholar 

  90. Ishihara S, Hata K, Hirose K, Okui T, Toyosawa S, Uzawa N, Nishimura R, Yoneda T (2022) The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer. Sci Rep 12:6261. https://doi.org/10.1038/s41598-022-10143-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Simatou A, Simatos G, Goulielmaki M, Spandidos DA, Baliou S, Zoumpourlis V (2020) Historical retrospective of the SRC oncogene and new perspectives (review). Mol Clin Oncol 13:21. https://doi.org/10.3892/mco.2020.2091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Li Y, Bao Y, Zheng H, Qin Y, Hua B (2021) The nonreceptor protein tyrosine kinase Src participates in every step of cancer-induced bone pain. Biomed Pharmacother 141:111822. https://doi.org/10.1016/j.biopha.2021.111822

    Article  CAS  PubMed  Google Scholar 

  93. De Felice M, Lambert D, Holen I, Escott KJ, Andrew D (2016) Effects of Src-kinase inhibition in cancer-induced bone pain. Mol Pain. https://doi.org/10.1177/1744806916643725

    Article  PubMed  PubMed Central  Google Scholar 

  94. Appel CK, Gallego-Pedersen S, Andersen L, Blancheflor Kristensen S, Ding M, Falk S, Sayilekshmy M, Gabel-Jensen C, Heegaard AM (2017) The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain. Sci Rep 7:4792. https://doi.org/10.1038/s41598-017-05029-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Danson S, Mulvey MR, Turner L, Horsman J, Escott K, Coleman RE, Ahmedzai SH, Bennett MI, Andrew D (2019) An exploratory randomized-controlled trial of the efficacy of the Src-kinase inhibitor saracatinib as a novel analgesic for cancer-induced bone pain. J Bone Oncol 19:100261. https://doi.org/10.1016/j.jbo.2019.100261

    Article  PubMed  PubMed Central  Google Scholar 

  96. Oudard S, Banu E, Medioni J, Scotte F, Banu A, Levy E, Wasserman J, Kacso G, Andrieu JM (2009) What is the real impact of bone pain on survival in patients with metastatic hormone-refractory prostate cancer treated with docetaxel? BJU Int 103:1641–1646. https://doi.org/10.1111/j.1464-410X.2008.08283.x

    Article  CAS  PubMed  Google Scholar 

  97. Inoue T, Segawa T, Kamba T, Yoshimura K, Nakamura E, Nishiyama H, Ito N, Kamoto T, Habuchi T, Ogawa O (2009) Prevalence of skeletal complications and their impact on survival of hormone refractory prostate cancer patients in Japan. Urology 73:1104–1109. https://doi.org/10.1016/j.urology.2008.07.062

    Article  PubMed  Google Scholar 

  98. Saad F, Carles J, Gillessen S, Heidenreich A, Heinrich D, Gratt J, Lévy J, Miller K, Nilsson S, Petrenciuc O, Tucci M, Wirth M, Federhofer J, O’Sullivan JM (2016) Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. Lancet Oncol 17:1306–1316. https://doi.org/10.1016/s1470-2045(16)30173-5

    Article  CAS  PubMed  Google Scholar 

  99. Koizumi M, Yoshimoto M, Kasumi F, Iwase T, 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 10:423. https://doi.org/10.1186/1471-2407-10-423

    Article  PubMed  PubMed Central  Google Scholar 

  100. Chen SH, Zhang BY, Zhou B, Zhu CZ, Sun LQ, Feng YJ (2019) Perineural invasion of cancer: a complex crosstalk between cells and molecules in the perineural niche. Am J Cancer Res 9:1–21

    PubMed  PubMed Central  Google Scholar 

  101. Delahunt B, Murray JD, Steigler A, Atkinson C, Christie D, Duchesne G, Egevad L, Joseph D, Matthews J, Oldmeadow C, Samaratunga H, Spry NA, Srigley JR, Hondermarck H, Denham JW (2020) Perineural invasion by prostate adenocarcinoma in needle biopsies predicts bone metastasis: Ten year data from the TROG 03.04 RADAR Trial. Histopathology 77:284–292. https://doi.org/10.1111/his.14107

    Article  PubMed  Google Scholar 

  102. Duraker N, Caynak ZC, Türköz K (2006) Perineural invasion has no prognostic value in patients with invasive breast carcinoma. Breast 15:629–634. https://doi.org/10.1016/j.breast.2005.12.003

    Article  CAS  PubMed  Google Scholar 

  103. Karak SG, Quatrano N, Buckley J, Ricci A Jr (2010) Prevalence and significance of perineural invasion in invasive breast carcinoma. Conn Med 74:17–21

    PubMed  Google Scholar 

  104. Gobbi H, Jensen RA, Simpson JF, Olson SJ, Page DL (2001) Atypical ductal hyperplasia and ductal carcinoma in situ of the breast associated with perineural invasion. Hum Pathol 32:785–790. https://doi.org/10.1053/hupa.2001.27637

    Article  CAS  PubMed  Google Scholar 

  105. Wang X, Lan H, Shen T, Gu P, Guo F, Lin X, Jin K (2015) Perineural invasion: a potential reason of hepatocellular carcinoma bone metastasis. Int J Clin Exp Med 8:5839–5846

    PubMed  PubMed Central  Google Scholar 

  106. Liu F, Zhao J, Xie J, Xie L, Zhu J, Cai S, Zheng H, Xu Y (2016) Prognostic risk factors in patients with bone metastasis from colorectal cancer. Tumour Biol. https://doi.org/10.1007/s13277-016-5465-4

    Article  PubMed  Google Scholar 

  107. Michalek J, Brychtova S, Pink R, Dvorak Z (2019) Prognostic and predictive markers for perineural and bone invasion of oral squamous cell carcinoma. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 163:302–308. https://doi.org/10.5507/bp.2019.032

    Article  PubMed  Google Scholar 

  108. Braun S, Vogl FD, Naume B, Janni W, Osborne MP et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802. https://doi.org/10.1056/NEJMoa050434

    Article  CAS  PubMed  Google Scholar 

  109. Janni W, Vogl FD, Wiedswang G, Synnestvedt M, Fehm T, Jückstock J, Borgen E, Rack B, Braun S, Sommer H, Solomayer E, Pantel K, Nesland J, Friese K, Naume B (2011) Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse–a European pooled analysis. Clin Cancer Res 17:2967–2976. https://doi.org/10.1158/1078-0432.Ccr-10-2515

    Article  PubMed  Google Scholar 

  110. Giordano A, Gao H, Cohen EN, Anfossi S, Khoury J, Hess K, Krishnamurthy S, Tin S, Cristofanilli M, Hortobagyi GN, Woodward WA, Lucci A, Reuben JM (2013) Clinical relevance of cancer stem cells in bone marrow of early breast cancer patients. Ann Oncol 24:2515–2521. https://doi.org/10.1093/annonc/mdt223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yoneda T, Hiasa M, Okui T, Hata K (2021) Sensory nerves: a driver of the vicious cycle in bone metastasis? J Bone Oncol 30:100387. https://doi.org/10.1016/j.jbo.2021.100387

    Article  PubMed  PubMed Central  Google Scholar 

  112. Mogil JS (2019) The translatability of pain across species. Philos Trans R Soc Lond B Biol Sci 374:20190286. https://doi.org/10.1098/rstb.2019.0286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Iftinca M, Defaye M, Altier C (2021) TRPV1-targeted drugs in development for human pain conditions. Drugs 81:7–27. https://doi.org/10.1007/s40265-020-01429-2

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by Japan Society for the Promotion of Science, 20H03859, Toshiyuki Yoneda. This study is supported by the Project Development Team within the ICTSI NIH/NCRR (#TR000006), the IU Health Strategic Research Initiative in Oncology, and start-up fund of Indiana University School of Medicine for TY, Japan Society for the Promotion of Science Grants-in-aid for Research Activity Start-up and Postdoctoral Fellowship for Research Abroad to HM and TO, the Grants-in-Aid for Young Scientists (JSPS KAKENHI grant no. 18K17225) to TO, and the Grants-in-Aid for Scientific Research (JSPS KAKENHI grant no. 17H04377) to TY.

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Authors and Affiliations

  1. Department of Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka, 565-0871, Japan

    Toshiyuki Yoneda & Kenji Hata

  2. Department of Biomaterials and Bioengineering, University of Tokushima Graduate School of Dentistry, Tokushima, Tokushima, Japan

    Masahiro Hiasa

  3. Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan

    Tatsuo Okui

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  1. Toshiyuki Yoneda
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  2. Masahiro Hiasa
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  3. Tatsuo Okui
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  4. Kenji Hata
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Correspondence to Toshiyuki Yoneda.

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Yoneda, T., Hiasa, M., Okui, T. et al. Cancer–nerve interplay in cancer progression and cancer-induced bone pain. J Bone Miner Metab 41, 415–427 (2023). https://doi.org/10.1007/s00774-023-01401-6

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  • DOI: https://doi.org/10.1007/s00774-023-01401-6

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