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Role of RANKL in cancer development and metastasis

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Abstract

Bone metastasis involves tumor-induced osteoclast activation, resulting in skeletal tumor progression as well as skeletal disorders. Aberrant expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for osteoclast differentiation, induced by the metastatic tumor cells is responsible for the pathological bone resorption in bone metastasis. A fully human anti-RANKL neutralizing antibody has been developed to block osteoclast activation and is now used for the treatment of patients with bone metastasis and multiple myeloma. On the other hand, numerous studies have revealed that the RANKL/RANK system also contributes to primary tumorigenesis as well as metastasis through osteoclast-independent processes. Furthermore, emerging clinical and preclinical evidence has suggested anti-tumor immune effects of RANKL blockade when added to immune checkpoint inhibitor therapies. Study on the pleiotropic functions of RANKL in tumorigenesis and metastasis is now expanding beyond the bone field and has been established as one of the most important areas of “RANKL biology”.

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References

  1. Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, Sawa S, Nitta T, Takayanagi H (2017) Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev 97:1295–1349

    Article  CAS  PubMed  Google Scholar 

  2. Wilkinson AN, Viola R, Brundage MD (2008) Managing skeletal related events resulting from bone metastases. BMJ 337:a2041

    Article  PubMed  Google Scholar 

  3. Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2:584–593

    Article  CAS  PubMed  Google Scholar 

  4. Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, Goncalves F (2017) Bone metastases: an overview. Oncol Rev 11:321

    PubMed  PubMed Central  Google Scholar 

  5. Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 1:571–573

    Article  Google Scholar 

  6. Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350:1655–1664

    Article  CAS  PubMed  Google Scholar 

  7. Weilbaecher KN, Guise TA, McCauley LK (2011) Cancer to bone: a fatal attraction. Nat Rev Cancer 11:411–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Morony S, Capparelli C, Sarosi I, Lacey DL, Dunstan CR, Kostenuik PJ (2001) Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res 61:4432–4436

    CAS  PubMed  Google Scholar 

  9. Canon JR, Roudier M, Bryant R, Morony S, Stolina M, Kostenuik PJ, Dougall WC (2008) Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 25:119–129

    Article  CAS  PubMed  Google Scholar 

  10. Nakai Y, Okamoto K, Terashima A, Ehata S, Nishida J, Imamura T, Ono T (2019) Takayanagi H Efficacy of an orally active small-molecule inhibitor of RANKL in bone metastasis. Bone Res 7:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Logothetis CJ, Lin SH (2005) Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer 5:21–28

    Article  CAS  PubMed  Google Scholar 

  12. Wong SK, Mohamad NV, Giaze TR, Chin KY, Mohamed N, Ima-Nirwana S (2019) Prostate cancer and bone metastases: the underlying mechanisms. Int J Mol Sci 20:2587

    Article  CAS  PubMed Central  Google Scholar 

  13. Zhang J, Dai J, Qi Y, Lin DL, Smith P, Strayhorn C, Mizokami A, Fu Z, Westman J, Keller ET (2001) Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone. J Clin Invest 107:1235–1244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kiefer JA, Vessella RL, Quinn JE, Odman AM, Zhang J, Keller ET, Kostenuik PJ, Dunstan CR, Corey E (2004) The effect of osteoprotegerin administration on the intra-tibial growth of the osteoblastic LuCaP 23.1 prostate cancer xenograft. Clin Exp Metastasis 21:381–387

    Article  CAS  PubMed  Google Scholar 

  15. Li X, Liu Y, Wu B, Dong Z, Wang Y, Lu J, Shi P, Bai W, Wang Z (2014) Potential role of the OPG/RANK/RANKL axis in prostate cancer invasion and bone metastasis. Oncol Rep 32:2605–2611

    Article  CAS  PubMed  Google Scholar 

  16. Holen I, Croucher PI, Hamdy FC (2002) Eaton CL osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. Cancer Res 62:1619–1623

    CAS  PubMed  Google Scholar 

  17. Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M, Dimopoulos MA (2018) Pathogenesis of bone disease in multiple myeloma: from bench to bedside. Blood Cancer J 8:7

    Article  PubMed  PubMed Central  Google Scholar 

  18. Abe M, Hiura K, Wilde J, Moriyama K, Hashimoto T, Ozaki S, Wakatsuki S, Kosaka M, Kido S, Inoue D, Matsumoto T (2002) Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma. Blood 100:2195–2202

    Article  CAS  PubMed  Google Scholar 

  19. Abe M, Hiura K, Ozaki S, Kido S, Matsumoto T (2009) Vicious cycle between myeloma cell binding to bone marrow stromal cells via VLA-4-VCAM-1 adhesion and macrophage inflammatory protein-1α and MIP-1β production. J Bone Miner Metab 27:16–23

    Article  CAS  PubMed  Google Scholar 

  20. Mori Y, Shimizu N, Dallas M, Niewolna M, Story B, Williams PJ, Mundy GR, Yoneda T (2004) Anti-α4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood 104:2149–2154

    Article  CAS  PubMed  Google Scholar 

  21. Lawson MA, McDonald MM, Kovacic N, Hua Khoo W, Terry RL et al (2015) Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat Commun 6:8983

    Article  CAS  PubMed  Google Scholar 

  22. Croucher PI, Shipman CM, Lippitt J, Perry M, Asosingh K, Hijzen A, Brabbs AC, van Beek EJ, Holen I, Skerry TM, Dunstan CR, Russell GR, Van Camp B, Vanderkerken K (2001) Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood 98:3534–3540

    Article  CAS  PubMed  Google Scholar 

  23. Pearse RN, Sordillo EM, Yaccoby S, Wong BR, Liau DF, Colman N, Michaeli J, Epstein J, Choi Y (2001) Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci U S A 98:11581–11586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A (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 28:5132–5139

    Article  CAS  PubMed  Google Scholar 

  25. Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong YY, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696

    Article  CAS  PubMed  Google Scholar 

  26. Zhang L, Teng Y, Zhang Y, Liu J, Xu L, Qu J, Hou K, Yang X, Liu Y, Qu X (2012) C-Src-mediated RANKL-induced breast cancer cell migration by activation of the ERK and Akt pathway. Oncol Lett 3:395–400

    Article  CAS  PubMed  Google Scholar 

  27. Zhang L, Teng Y, Zhang Y, Liu J, Xu L, Qu J, Hou K, Liu Y, Qu X (2012) Proteasome inhibitor bortezomib (PS-341) enhances RANKL-induced MDA-MB-231 breast cancer cell migration. Mol Med Rep 5:580–584

    PubMed  Google Scholar 

  28. Tang ZN, Zhang F, Tang P, Qi XW, Jiang J (2011) RANKL-induced migration of MDA-MB-231 human breast cancer cells via Src and MAPK activation. Oncol Rep 26:1243–1250

    CAS  PubMed  Google Scholar 

  29. Santini D, Schiavon G, Vincenzi B, Gaeta L, Pantano F, Russo A, Ortega C, Porta C, Galluzzo S, Armento G, La Verde N, Caroti C, Treilleux I, Ruggiero A, Perrone G, Addeo R, Clezardin P, Muda AO, Tonini G (2011) Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS ONE 6:e19234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Asano T, Okamoto K, Nakai Y, Tsutsumi M, Muro R, Suematsu A, Hashimoto K, Okamura T, Ehata S, Nitta T, Takayanagi H (2019) Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone. Nat Metab 1:868–875

    Article  PubMed  Google Scholar 

  31. Song FN, Duan M, Liu LZ, Wang ZC, Shi JY, Yang LX, Zhou J, Fan J, Gao Q, Wang XY (2014) RANKL promotes migration and invasion of hepatocellular carcinoma cells via NF-κB-mediated epithelial-mesenchymal transition. PLoS ONE 9:e108507

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mikami S, Katsube K, Oya M, Ishida M, Kosaka T, Mizuno R, Mochizuki S, Ikeda T, Mukai M, Okada Y (2009) Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J Pathol 218:530–539

    Article  CAS  PubMed  Google Scholar 

  33. Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET, Dougall WC (2008) RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate 68:92–104

    Article  CAS  PubMed  Google Scholar 

  34. Hikita A, Yana I, Wakeyama H, Nakamura M, Kadono Y, Oshima Y, Nakamura K, Seiki M, Tanaka S (2006) Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-κB ligand. J Biol Chem 281:36846–36855

    Article  CAS  PubMed  Google Scholar 

  35. Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, Sakai H (2000) Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-κB ligand: modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun 275:768–775

    Article  CAS  PubMed  Google Scholar 

  36. Miyamoto T, Arai F, Ohneda O, Takagi K, Anderson DM, Suda T (2000) An adherent condition is required for formation of multinuclear osteoclasts in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor κB ligand. Blood 96:4335–4343

    Article  CAS  PubMed  Google Scholar 

  37. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323

    Article  CAS  PubMed  Google Scholar 

  38. Xiong J, Cawley K, Piemontese M, Fujiwara Y, Zhao H, Goellner JJ, O’Brien CA (2018) Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nat Commun 9:2909

    Article  PubMed  PubMed Central  Google Scholar 

  39. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56

    Article  CAS  PubMed  Google Scholar 

  40. Jamieson-Gladney WL, Zhang Y, Fong AM, Meucci O, Fatatis A (2011) The chemokine receptor CX3CR1 is directly involved in the arrest of breast cancer cells to the skeleton. Breast Cancer Res 13:R91

    Article  PubMed  PubMed Central  Google Scholar 

  41. Shen F, Zhang Y, Jernigan DL, Feng X, Yan J, Garcia FU, Meucci O, Salvino JM, Fatatis A (2016) Novel small-molecule CX3CR1 antagonist impairs metastatic seeding and colonization of breast cancer cells. Mol Cancer Res 14:518–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Loberg RD, Day LL, Harwood J, Ying C, St John LN, Giles R, Neeley CK, Pienta KJ (2006) CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia 8:578–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jung K, Lein M (1846) Bone turnover markers in serum and urine as diagnostic, prognostic and monitoring biomarkers of bone metastasis. Biochim Biophys Acta 425–38:2014

    Google Scholar 

  44. Kraj M, Owczarska K, Sokołowska U, Centkowski P, Pogłód R, Kruk B (2005) Correlation of osteoprotegerin and sRANKL concentrations in serum and bone marrow of multiple myeloma patients. Arch Immunol Ther Exp (Warsz) 53:454–464

    CAS  Google Scholar 

  45. Rachner TD, Kasimir-Bauer S, Göbel A, Erdmann K, Hoffmann O, Browne A, Wimberger P, Rauner M, Hofbauer LC, Kimmig R, Bittner AK (2019) Prognostic value of RANKL/OPG serum levels and disseminated tumor cells in nonmetastatic breast cancer. Clin Cancer Res 25:1369–1378

    Article  CAS  PubMed  Google Scholar 

  46. Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, Cheresh DA, Karin M (2007) Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature 446:690–694

    Article  CAS  PubMed  Google Scholar 

  47. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470:548–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schramek D, Sigl V, Penninger JM (2011) RANKL and RANK in sex hormone-induced breast cancer and breast cancer metastasis. Trends Endocrinol Metab 22:188–194

    Article  CAS  PubMed  Google Scholar 

  49. Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, Boyle WJ, Khokha R, Penninger JM (2000) The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103:41–50

    Article  CAS  PubMed  Google Scholar 

  50. Kim NS, Kim HJ, Koo BK, Kwon MC, Kim YW, Cho Y, Yokota Y, Penninger JM, Kong YY (2006) Receptor activator of NF-kappaB ligand regulates the proliferation of mammary epithelial cells via Id2. Mol Cell Biol 26:1002–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, Hanada R, Joshi PA, Aliprantis A, Glimcher L, Pasparakis M, Khokha R, Ormandy CJ, Widschwendter M, Schett G, Penninger JM (2010) Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468:98–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468:103–107

    Article  CAS  PubMed  Google Scholar 

  53. Palafox M, Ferrer I, Pellegrini P, Vila S, Hernandez-Ortega S, Urruticoechea A, Climent F, Soler MT, Muñoz P, Viñals F, Tometsko M, Branstetter D, Dougall WC, González-Suárez E (2012) RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res 72:2879–2888

    Article  CAS  PubMed  Google Scholar 

  54. Sigl V, Owusu-Boaitey K, Joshi PA, Kavirayani A, Wirnsberger G et al (2016) RANKL/RANK control Brca1 mutation. Cell Res 26:761–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, Lok SW, Mann GB, Rohrbach K, Huang LY, Soriano R, Smyth GK, Dougall WC, Visvader JE, Lindeman GJ (2016) RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 22:933–939

    Article  CAS  PubMed  Google Scholar 

  56. Rao S, Sigl V, Wimmer RA, Novatchkova M, Jais A et al (2017) RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer. Genes Dev 31:2099–2112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Smyth MJ, Yagita H, McArthur GA (2016) Combination anti-CTLA-4 and anti-RANKL in metastatic melanoma. J Clin Oncol 34:e104–e106

    Article  CAS  PubMed  Google Scholar 

  58. Liede A, Hernandez RK, Wade SW, Bo R, Nussbaum NC, Ahern E, Dougall WC, Smyth MJ (2018) An observational study of concomitant immunotherapies and denosumab in patients with advanced melanoma or lung cancer. Oncoimmunology 7:e1480301

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ahern E, Harjunpää H, Barkauskas D, Allen S, Takeda K, Yagita H, Wyld D, Dougall WC, Teng MWL, Smyth MJ (2017) Co-administration of RANKL and CTLA4 antibodies enhances lymphocyte-mediated antitumor immunity in mice. Clin Cancer Res 23:5789–5801

    Article  CAS  PubMed  Google Scholar 

  60. Ahern E, Harjunpää H, O’Donnell JS, Allen S, Dougall WC, Teng MWL, Smyth MJ (2018) RANKL blockade improves efficacy of PD1-PD-L1 blockade or dual PD1-PD-L1 and CTLA4 blockade in mouse models of cancer. Oncoimmunology 7:e1431088

    Article  PubMed  PubMed Central  Google Scholar 

  61. Dougall WC, Roman Aguilera A, Smyth MJ (2019) Dual targeting of RANKL and PD-1 with a bispecific antibody improves anti-tumor immunity. Clin Transl Immunol 8:e01081

    Article  Google Scholar 

  62. Jiao S, Subudhi SK, Aparicio A, Ge Z, Guan B, Miura Y, Sharma P (2019) Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy. Cell 179:1177–90.e13

    Article  CAS  PubMed  Google Scholar 

  63. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H (2011) Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125–1132

    Article  CAS  PubMed  Google Scholar 

  64. Scagliotti GV, Hirsh V, Siena S, Henry DH, Woll PJ, Manegold C, Solal-Celigny P, Rodriguez G, Krzakowski M, Mehta ND, Lipton L, García-Sáenz JA, Pereira JR, Prabhash K, Ciuleanu TE, Kanarev V, Wang H, Balakumaran A, Jacobs I (2012) Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol 7:1823–1829

    Article  CAS  PubMed  Google Scholar 

  65. Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, Legieć W, Krejčí M, Laribi K, Zhu L, Cheng P, Warner D, Roodman GD (2018) Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol 19:370–381

    Article  CAS  PubMed  Google Scholar 

  66. Gnant M, Pfeiler G, Steger GG, Egle D, Greil R, Fitzal F, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Jakesz R, Marth C, Sevelda P, Mlineritsch B, Exner R, Fesl C, Frantal S, Singer CF (2019) Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:339–351

    Article  CAS  PubMed  Google Scholar 

  67. Peters S, Danson S, Hasan B, Dafni U, Reinmuth N et al (2020) A randomized open-label phase III trial evaluating the addition of denosumab to standard first-line treatment in advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial. J Thorac Oncol 15:1647–1656

    Article  CAS  PubMed  Google Scholar 

  68. Smith MR, Saad F, Coleman R, Shore N, Fizazi K et al (2012) Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 379:39–46

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research B (18H02919) and Challenging Research (Pioneering) (17K19582) from the Japan Society for the Promotion of Science (JSPS); The Japanese Society for Bone and Mineral Research Rising Stars Grant; and grants from Astellas Foundation for Research on Metabolic Disorders, The Tokyo Society of Medical Sciences, Taiju Life Social Welfare Foundation, MSD K.K., Astellas Research Support, Mitsubishi Tanabe Pharma Corporation Research Support and Kobayashi Foundation for Cancer Research.

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  1. Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan

    Kazuo Okamoto

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Correspondence to Kazuo Okamoto.

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The Department of Osteoimmunology is an endowment department, supported with an unrestricted grant from AYUMI Pharmaceutical Corporation, Chugai Pharmaceutical, MIKI HOUSE and Noevir.

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Okamoto, K. Role of RANKL in cancer development and metastasis. J Bone Miner Metab 39, 71–81 (2021). https://doi.org/10.1007/s00774-020-01182-2

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