RANK-RANKL signalling in cancer

Bioscience Reports

Volumn 36, Issue 4, 2016, Pages

  Renema, Nathalie ^a   Navet, Benjamin ^a   Heymann, Marie Françoise ^a,b,c   Lezot, Frédéric ^a   Heymann, Dominique ^a,b,c  

^a UNIVERSITÉ DE NANTES   (France)

^b NANTES UNIVERSITY HOSPITAL   (France)

^c UNIVERSITY OF SHEFFIELD   (United Kingdom)

Author keywords

Microenvironment; Oncogenesis; RANK; RANKL

Indexed keywords

DENOSUMAB; EVEROLIMUS; GEMCITABINE; LGR4 PROTEIN; MEMBRANE RECEPTOR; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPROTEGERIN; PEMETREXED; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B; RECOMBINANT INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG; ZOLEDRONIC ACID; G PROTEIN COUPLED RECEPTOR; LGR4 PROTEIN, HUMAN; TNFRSF11A PROTEIN, HUMAN; TNFRSF11B PROTEIN, HUMAN; TNFSF11 PROTEIN, HUMAN;

ADVANCED CANCER; ANGIOGENESIS; BONE METASTASIS; BONE TUMOR; BREAST CANCER; CANCER CELL; CARCINOGENESIS; CELL MOTILITY; DRUG DOSE ESCALATION; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; IMMUNOCOMPETENT CELL; LOADING DRUG DOSE; METASTASIS; MULTICENTER STUDY (TOPIC); MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; NON SMALL CELL LUNG CANCER; NONHUMAN; OSTEOCLASTOMA; OSTEOSARCOMA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; TUMOR MICROENVIRONMENT; CLASSIFICATION; CLINICAL TRIAL (TOPIC); DISEASE EXACERBATION; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; NEOPLASM; PATHOLOGY;

CLINICAL TRIALS AS TOPIC; DISEASE PROGRESSION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NEOPLASM METASTASIS; NEOPLASMS; OSTEOPROTEGERIN; RANK LIGAND; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR-KAPPA B; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84988380539     PISSN: 01448463     EISSN: 15734935     Source Type: Journal    
DOI: 10.1042/BSR20160150     Document Type: Review

References (162)

1. Bissell, M.J. and Hines, W.C. (2011) Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320-329
2. Molon, B., Cali, B. and Viola, A. (2016) T cells and cancer: how metabolism shapes immunity. Front. Immunol. 7, 20
3. Paget, S. (1889) The distribution of secondary growths in cancer of the breast. Lancet 133, 571-573
4. Plaks, V., Kong, N. and Werb, Z. (2015) The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16, 225-238
5. Ordóñez-Morán, P. and Huelsken, J. (2014) Complex metastatic niches: already a target for therapy? Curr. Opin. Cell Biol. 31, 29-38
6. Molofsky, A.V., Pardal, R. and Morrison, S.J. (2004) Diverse mechanisms regulate stem cell self-renewal. Curr. Opin. Cell Biol. 16, 700-707
7. Wan, L., Pantel, K. and Kang, Y. (2013) Tumor metastasis: moving new biological insights into the clinic. Nat. Med. 19, 1450-1464
8. Shiozawa, Y., Berry, J.E., Eber, M.R., Jung, Y., Yumoto, K., Cackowski, F.C., Yoon, H.J., Parsana, P., Mehra, R., Wang, J. et al. (2016), The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer. Oncotarget, doi: 10.18632/oncotarget.9251
9. Weidle, U.H., Birzele, F., Kollmorgen, G. and Rüger, R. (2016) Molecular mechanisms of bone metastasis. Cancer Genomics Proteomics 13, 1-12
10. Lu, X., Mu, E., Wei, Y., Riethdorf, S., Yang, Q., Yuan, M., Yan, J., Hua, Y., Tiede, B.J., Lu, X. et al. (2011) VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell 20, 701-714
11. Wang, N., Docherty, F.E., Brown, H.K., Reeves, K.J., Fowles, A.C., Ottewell, P.D., Dear, T.N., Holen, I., Croucher, P.I. and Eaton, C.L. (2014) Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis: evidence from in vivo models. J. Bone Miner. Res. 29, 2688-2696
12. Spill, F., Reynolds, D.S., Kamm, R.D. and Zaman, M.H. (2016) Impact of the physical microenvironment on tumor progression and metastasis. Curr. Opin. Biotechnol. 40, 41-48
13. Meads, M.B., Hazlehurst, L.A. and Dalton, W.S. (2008) The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin. Cancer Res. 14, 2519-2526
14. David, E., Blanchard, F., Heymann, M.F., De Pinieux, G., Gouin, F., Rédini, F. and Heymann, D. (2011) The bone niche of chondrosarcoma: a sanctuary for drug resistance, tumour growth and also a source of new therapeutic targets sarcoma. Sarcoma 2011, 932451
15. Jones, V.S., Huang, R.Y., Chen, L.P., Chen, Z.S., Fu, L. and Huang, R.P. (2016) Cytokines in cancer drug resistance: cues to new therapeutic strategies. Biochim. Biophys. Acta 1865, 255-265
16. Landskron, G., De la Fuente, M., Thuwajit, P. and Hermoso, M.A. (2014) Chronic inflammation and cytokines in the tumor microenvironment. J. Immunol. Res. 2014, 149185
17. Dinarello, C.A. (2006) The paradox of pro-inflammatory cytokines in cancer. Cancer Metastasis Rev. 25, 307-313
18. Dranoff, G. (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 4, 11-22
19. Grivennikov, S.I. and Karin, M. (2011) Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann. Rheum. Dis. 70, 104-108
20. Walsh, M.C. and Choi, Y. (2014) Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front. Immunol. 5, 511
21. Theoleyre, S., Wittrant, Y., KwanTat, S., Fortun, Y., Redini, F. and Heymann, D. (2004) The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 15, 457-475
22. Wittrant, Y., Théoleyre, S., Chipoy, C., Padrines, M., Blanchard, F., Heymann, D. and Rédini, F. (2004) RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim. Biophys. Acta 1704, 49-57
23. Yasuda, H. (2013) RANKL, a necessary chance for clinical application to osteoporosis and cancer-related bone diseases. World J. Orthop. 4, 207-217
24. Li, J., Yin, Q. and Wu, H. (2013) Structural basis of signal transduction in the TNF receptor superfamily. Adv. Immunol. 119, 135-153
25. Anderson, D.M., Maraskovsky, E., Billingsley, W.L., Dougall, W.C., Tometsko, M.E., Roux, E.R., Teepe, M.C., DuBose, R.F., Cosman, D. and Galibert, L. (1997) A homologue of the TNF receptor and its ligand enhance T cell growth and dendritic cell function. Nature 390, 175-179
26. Wong, B.R., Josien, R., Lee, S.Y., Sauter, B., Li, H.L., Steinman, R.M. and Choi, Y. (1997) TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a New TNF family member predominantly expressed in T cells, is a dendritic cell specific survival factor. J. Exp. Med. 186, 2075-2080
27. Lacey, D.L, Timms, E., Tan, H.L., Kelley, M.J., Dunstan, C.R., Burgess, T., Elliot, R., Colombero, A., Elliott, G., Scully, S. et al. (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165-176
28. Kong, Y.Y., Boyle, W.J. and Penninger, J.M. (1999) Osteoprotegerin ligand: a common link between osteoclastogenesis, lymph node formation and lymphocyte development. Immunol. Cell Biol. 77, 188-193
29. Kodaira, K., Kodaira, K., Mizuno, A., Yasuda, H., Shima, N., Murakami, A., Ueda, M. and Higashio, K. (1999) Cloning and characterization of the gene encoding mouse osteoclast differentiation factor. Gene 230, 121-127
30. Yasuda, H., Shima, N., Nakagawa, N., Mochizuki, S.I., Yano, K., Fujise, N., Sato, Y., Goto, M., Yamaguchi, K., Kuriyama, M. et al. (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. U.S.A. 95, 3597-3602
31. Ikeda, T., Kasai, M., Utsuyama, M. and Hirokawa, K. (2001) Determination of three isoforms of the Receptor activator of nuclear factor-kappa B ligand and their differential expression in bone and thymus. Endocrinology 142, 1419-1426
32. Lum, L., Wong, B.R., Josien, R., Becherer, J.D., Erdjument-Bromage, H., Schlondorff, J., Temps, P., Choi, Y. and Blodel, C.P. (1999) Evidence for a role of a tumor necrosis factor alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J. Biol. Chem. 274, 13613-13618
33. Hikita, A., Yana, I., Wakeyama, H., Nakamura, M., Kadono, Y., Oshima, Y., Nakamura, K., Seiki, M. and Tanaka, S. (2006) Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-kappaB ligand. J. Biol. Chem. 281, 36846-36855
34. Georges, S., Ruiz Velasco, C., Trichet, V., Fortun, Y., Heymann, D. and Padrines, M. (2009) Proteases and bone remodelling. Cytokine Growth Factor Rev. 20, 29-41
35. Kartsogiannis, V., Zhou, H., Horwood, N.J., Thomas, R.J., Hards, D.K., Quinn, J.M., Niforas, P., Ng, K.W., Martin, T.J. and Gillespie, M.T. (1999) Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone 25, 525-534
36. Collin-Osdoby, P., Rothe, L., Anderson, F., Nelson, M., Maloney, W. and Osdoby, P. (2001) Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J. Biol. Chem. 276, 20659-20672
37. Matsuzaki, K., Udagawa, N., Takahashi, N., Yamaguchi, K., Yasuda, H., Shima, N., Morinaga, T., Toyama, Y., Yabe, Y., Higashio, K. and Suda, T. (1998) Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. Biochem. Biophys. Res. Commun. 246, 199-204
38. Quinn, J.M., Elliott, J., Gillespie, M.T. and Martin, T.J. (1998) A combination of osteoclast differentiation factor and macrophage-colony stimulating factor is sufficient for both human and mouse osteoclast formation in vitro. Endocrinology 139, 4424-4427
39. Xiong, J., Piemontese, M., Onal, M., Campbell, J., Goellner, J.J., Dusevich, V., Bonewald, L., Manolagas, S.C. and O'Brien, C.A. (2015) Osteocytes not osteoblasts or lining cells are the main source of the RANKL required for osteoclast formation in remodeling bone. PLoS One 10, e0138189
40. Hsu, H., Lacey, D.L., Dunstan, C.R., Solovyev, I., Colombero, A., Timms, E., Tan, H.L., Elliott, G., Kelley, M.J., Sarosi, I. et al. (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc. Natl. Acad. Sci. U.S.A. 96, 3540-3545
41. Kong, Y.Y., Feige, U., Sarosi, I., Bolon, B., Tafuri, A., Morony, S., Capprelli, C., Li, J., Elliott, R., McCabe, S. et al. (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304-309
42. Takayanagi, H. (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, 292-304
43. Wong, B.R., Josien, R., Lee, S.Y., Vologodskaia, M., Steinman, R.M. and Choi, Y. (1998) The TRAF family of signal transducers mediates NF-kappaB Activation by the TRANCE receptor. J. Biol. Chem. 273, 28355-28359
44. Kanazawa, K. and Kudo, A. (2005) Self-assembled RANK induces osteoclastogenesis ligand-independently. J. Bone Miner. Res. 20, 2053-2060
45. Télétchéa, S., Stresing, V., Hervouet, S., Baud'huin, M., Heymann, M.F., Bertho, G., Charrier, C., Ando, K. and Heymann, D. (2014) Novel RANK antagonists for the treatment of bone resorptive disease: theoretical predictions and experimental validation. J. Bone Miner. Res. 29, 1466-1477
46. Arai, F., Miyamoto, T., Ohneda, O., Inada, T., Sudo, T., Brasel, K., Miyata, T., Anderson, D.M. and Suda, T. (1999) Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J. Exp. Med. 190, 1741-1754
47. Nakagawa, N., Kinosaki, M., Yamaguchi, K., Shima, N., Yasuda, H., Yano, K., Morinaga, T. and Higashio, K. (1998) RANK is essential signalling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem. Biophys. Res. Commun. 253, 396-400
48. Li, J., Sarosi, I., Yan, X.Q., Morony, S., Capparelli, C., Tan, H.L., McCabe, S., Elliott, R., Scully, S., Van, G. et al. (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc. Natl. Acad. Sci. U.S.A. 97, 1566-1571
49. Dougall, W.C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., Daro, E., Smith, J., Tometsko, M.E., Maliszewski, C.R. et al. (1999) RANK is essential for osteoclast and lymph node development. Genes Dev. 13, 2412-2424
50. Baud'huin, M., Lamoureux, F., Duplomb, L., Rédini, F. and Heymann, D. (2007) RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases. Cell. Mol. Life Sci. 64, 2334-2350
51. Santini, D., Perrone, G., Roato, I., Godio, L., Pantano, F., Grasso, D., Russo, A., Vincenzi, B., Fratto, M.E., Sabbatini, R. et al. (2011) Expression pattern of receptor activator of NFkB (RANK) in a series of primary solid tumors and related metastases. J. Cell Physiol. 226, 780-784
52. Santini, D., Schiavon, G., Vincenzi, B., Gaeta, L., Pantano, F., Russo, A., Ortega, C., Porta, C., Galluzzo, S., Armento, G. et al. (2011) Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS One 6, e19234
53. Bhatia, P., Sanders, M.M. and Hansen, M.F. (2005) Expression of receptor activator of nuclear factor-kappaB is inversely correlated with metastatic phenotype in breast carcinoma. Clin. Cancer Res. 11, 162-165
54. Park, H.S., Lee, A., Chae, B.J., Bae, J.S., Song, B.J. and Jung, S.S. (2014) Expression of receptor activator of nuclear factor kappa-B as a poor prognostic marker in breast cancer. J. Surg. Oncol. 110, 807-812
55. Pfitzner, B.M., Branstetter, D., Loibl, S., Denkert, C., Lederer, B., Schmitt, W.D., Dombrowski, F., Werner, M., Rüdiger, T., Dougall, W.C. and von Minckwitz, G. (2014) RANK expression as a prognostic and predictive marker in breast cancer. Breast Cancer Res. Treat. 145, 307-315
56. Jones, D.H., Nakashima, T., Sanchez, O.H., Kozieradzki, I., Komarova, S.V., Sarosi, I., Morony, S., Rubin, E., Sarao, R., Hojilla, C.V. et al. (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440, 692-696
57. Owen, S., Ye, L., Sanders, A.J., Mason, M.D. and Jiang, W.G. (2013) Expression profile of receptor activator of nuclear-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) in breast cancer. Anticancer Res. 33, 199-206
58. Van Poznak, C., Cross, S.S., Saggese, M., Hudis, C., Panageas, K.S., Norton, L., Coleman, R.E. and Holen, I. (2006) Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours. J. Clin. Pathol. 59, 56-63
59. Azim, Jr, H.A., Peccatori, F.A., Brohée, S., Branstetter, D., Loi, S., Viale, G., Piccart, M., Dougall, W.C., Pruneri, G. and Sotiriou, C. (2015) RANK-ligand (RANKL) expression in young breast cancer patients and during pregnancy. Breast Cancer Res. 17, 24
60. Hu, H., Wang, J., Gupta, A., Shidfar, A., Branstetter, D., Lee, O., Ivancic, D., Sullivan, M., Chatterton, Jr, R.T., Dougall, W.C. and Khan, S.A. (2014) RANKL expression in normal and malignant breast tissue responds to progesterone and is up-regulated during the luteal phase. Breast Cancer Res. Treat. 146, 515-523
61. Shang, W.Q., Li, H., Liu, L.B., Chang, K.K., Yu, J.J., Xie, F., Li, M.Q. and Yu, J.J. (2015) RANKL/RANK interaction promotes the growth of cervical cancer cells by strengthening the dialogue between cervical cancer cells and regulation of IL-8 secretion. Oncol. Rep. 34, 3007-3016
62. Hsu, C.J., Lin, T.Y., Kuo, C.C., Tsai, C.H., Lin, M.Z., Hsu, H.C., Fong, Y.C. and Tang, C.H. (2010) Involvement of integrin up-regulation in RANKL/RANK pathway of chondrosarcomas migration. J. Cell Biochem. 111, 138-147
63. Grimaud, E., Soubigou, L., Couillaud, S., Coipeau, P., Moreau, A., Passuti, N., Gouin, F., Redini, F. and Heymann, D. (2003) Receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio is increased in severe osteolysis. Am. J. Pathol. 163, 2021-2031
64. Yin, J., Wang, L., Tang, W., Wang, X., Lv, L., Shao, A., Shi, Y., Ding, G., Chen, S. and Gu, H. (2014) RANK rs1805034 T>C polymorphism is associated with susceptibility of esophageal cancer in a Chinese population. PLoS One 9, e101705
65. Atkins, G.J., Kostakis, P., Vincent, C., Farrugia, A.N., Houchins, J.P., Findlay, D.M., Evdokiou, A. and Zannettino, A.C. (2006) RANK expression as a cell surface marker of human osteoclast precursors in peripheral blood, bone marrow, and giant cell tumors of bone. J. Bone Miner. Res. 21, 1339-1349
66. Branstetter, D.G., Nelson, S.D., Manivel, J.C., Blay, J.Y., Chawla, S., Thomas, D.M., Jun, S. and Jacobs, I. (2012) Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin. Cancer Res. 18, 4415-4424
67. Song, F.N., Duan, M., Liu, L.Z., Wang, Z.C., Shi, J.Y., Yang, L.X., Zhou, J., Fan, J., Gao, Q. and Wang, X.Y. (2014) RANKL promotes migration and invasion of hepatocellular carcinoma cells via NF->B-mediated epithelial-mesenchymal transition. PLoS One 9, e108507
68. Sasaki, A., Ishikawa, K., Haraguchi, N., Inoue, H., Ishio, T., Shibata, K., Ohta, M., Kitano, S. and Mori, M. (2007) Receptor activator of nuclear factor-kappaB ligand (RANKL) expression in hepatocellular carcinoma with bone metastasis. Ann. Surg. Oncol. 14, 1191-1199
69. Peng, X., Guo, W., Ren, T., Lou, Z., Lu, X., Zhang, S., Lu, Q. and Sun, Y. (2013) Differential expression of the RANKL/RANK/OPG system is associated with bone metastasis in human non-small cell lung cancer. PLoS One 8, e58361
70. Fiumara, P., Snell, V., Li, Y., Mukhopadhyay, A., Younes, M., Gillenwater, A.M., Cabanillas, F., Aggarwal, B.B. and Younes, A. (2001) Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. Blood 98, 2784-2790
71. Nosaka, K., Miyamoto, T., Sakai, T., Mitsuya, H., Suda, T. and Matsuoka, M. (2002) Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor kappaB ligand on adult T-cell leukemia cells. Blood 99, 634-640
72. Barcala, V., Ruybal, P., Garcia Rivello, H., Waldner, C., Ascione, A. and Mongini, C. (2003) RANKL expression in a case of follicular lymphoma. Eur. J. Haematol. 70, 417-419
73. Jones, D.H., Nakashima, T., Sanchez, O.H., Kozieradzki, I., Komarova, S.V., Sarosi, I., Morony, S., Rubin, E., Sarao, R., Hojilla, C.V. et al. (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440, 692-696
74. Kupas, V., Weishaupt, C., Siepmann, D., Kaserer, M.L., Eickelmann, M., Metze, D., Luger, T.A., Beissert, S. and Loser, K. (2011) RANK is expressed in metastatic melanoma and highly upregulated on melanoma-initiating cells. J. Invest. Dermatol. 131, 944-955
75. Roux, S., Meignin, V., Quillard, J., Meduri, G., Guiochon-Mantel, A., Fermand, J.P., Milgrom, E. and Mariette, X. (2002) RANK (receptor activator of nuclear factor-kappaB) and RANKL expression in multiple myeloma. Br. J. Haematol. 117, 86-92
76. Farrugia, A.N., Atkins, G.J., To, L.B., Pan, B., Horvath, N., Kostakis, P., Findlay, D.M., Bardy, P. and Zannettino, A.C. (2003) Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res. 63, 5438-5445
77. Granchi, D., Amato, I., Battistelli, L., Avnet, S., Capaccioli, S., Papucci, L., Donnini, M., Pellacani, A., Brandi, M.L., Giunti, A. and Baldini, N. (2004) In vitro blockade of receptor activator of nuclear factor-kappaB ligand prevents osteoclastogenesis induced by neuroblastoma cells. Int. J. Cancer 111, 829-838
78. Chuang, F.H., Hsue, S.S., Wu, C.W. and Chen, Y.K. (2009) Immunohistochemical expression of RANKL, RANK, and OPG in human oral squamous cell carcinoma. J. Oral Pathol. Med. 38, 753-738
79. Mori, K., Le Goff, B., Berreur, M., Riet, A., Moreau, A., Blanchard, F., Chevalier, C., Guisle-Marsollier, I., Léger, J., Guicheux, J. et al. (2007) Human osteosarcoma cells express functional receptor activator of nuclear factor-kappa B. J. Pathol. 11, 555-562
80. Lee, J.A., Jung, J.S., Kim, D.H., Lim, J.S., Kim, M.S., Kong, C.B., Song, W.S., Cho, W.H., Jeon, D.G., Lee, S.Y. and Koh, J.S. (2011) RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma. Pediatr. Blood Cancer 56, 738-743
81. Chen, G., Sircar, K., Aprikian, A., Potti, A., Goltzman, D. and Rabbani, S.A. (2006) Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer 107, 289-298
82. Armstrong, A.P., Miller, R.E., Jones, J.C., Zhang, J., Keller, E.T. and Dougall, W.C. (2008) RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate 68, 92-104
83. Odero-Marah, V.A., Wang, R., Chu, G., Zayzafoon, M., Xu, J., Shi, C., Marshall, F.F., Zhau, H.E. and Chung, L.W. (2008) Receptor activator of NF-kappaB ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells. Cell Res. 18, 858-870
84. Mikami, S., Katsube, K., Oya, M., Ishida, M., Kosaka, T., Mizuno, R., Mochizuki, S., Ikeda, T., Mukai, M. and Okada, Y. (2009) Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J. Pathol. 218, 530-539
85. Heymann, M.F., Riet, A., Le Goff, B., Battaglia, S., Paineau, J. and Heymann, D. (2008) OPG, RANK and RANK ligand expression in thyroid lesions. Regul. Pept. 148, 46-53
86. Park, H.S., Lee, A., Chae, B.J., Bae, J.S., Song, B.J. and Jung, S.S. (2014) Expression of receptor activator of nuclear factor kappa-B as a poor prognostic marker in breast cancer. J. Surg. Oncol. 110, 807-812
87. Pfitzner, B.M., Branstetter, D., Loibl, S., Denkert, C., Lederer, B., Schmitt, W.D., Dombrowski, F., Werner, M., Rüdiger, T., Dougall, W.C. and von Minckwitz, G. (2014) RANK expression as a prognostic and predictive marker in breast cancer. Breast Cancer Res. Treat. 145, 307-315
88. Zhang, L., Teng, Y., Zhang, Y., Liu, J., Xu, L., Qu, J., Hou, K., Yang, X., Liu, Y. and Qu, X. (2012) Receptor activator for nuclear factor êB expression predicts poor prognosis in breast cancer patients with bone metastasis but not in patients with visceral metastasis. J. Clin. Pathol. 65, 36-40
89. Trieb, K. and Windhager, R. (2015) Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma. Oncol. Lett. 10, 1813-1815
90. Bago-Horvath, Z., Schmid, K., Rössler, F., Nagy-Bojarszky, K., Funovics, P. and Sulzbacher, I. (2014) Impact of RANK signalling on survival and chemotherapy response in osteosarcoma. Pathology 46, 411-415
91. Papanastasiou, A.D., Sirinian, C. and Kalofonos, H.P. (2012) Identification of novel human receptor activator of nuclear factor-kB isoforms generated through alternative splicing: implications in breast cancer cell survival and migration. Breast Cancer Res. 14, R112
92. Lee, J.A., Jung, J.S., Kim, D.H., Lim, J.S., Kim, M.S., Kong, C.B., Song, W.S., Cho, W.H., Jeon, D.G., Lee, S.Y. and Koh, J.S. (2011) RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma. Pediatr. Blood Cancer. 56, 738-743
93. Cathomas, R., Rothermundt, C., Bode, B., Fuchs, B., von Moos, R. and Schwitter, M. (2015) RANK ligand blockade with denosumab in combination with sorafenib in chemorefractory osteosarcoma: a possible step forward? Oncology 88, 257-260
94. Roux, S., Amazit, L., Meduri, G., Guiochon-Mantel, A., Milgrom, E. and Mariette, X. (2002) RANK (receptor activator of nuclear factor kappa B) and RANK ligand are expressed in giant cell tumors of bone. Am. J. Clin. Pathol. 117, 210-216
95. Chawla, S., Henshaw, R., Seeger, L., Choy, E., Blay, J.Y., Ferrari, S., Kroep, J., Grimer, R., Reichardt, P., Rutkowski, P. et al. (2013) Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 14, 901-908
96. Raju, R., Balakrishnan, L., Nanjappa, V., Bhattacharjee, M., Getnet, D., Muthusamy, B., Kurian Thomas, J., Sharma, J., Rahiman, B.A. et al. (2011) A comprehensive manually curated reaction map of RANKL/RANK-signaling pathway. Database (Oxford) 2011, bar021
97. Galibert, L., Tometsko, M.E., Anderson, D.M., Cosman, D. and Dougall, W.C. (1998) The Involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. J. Biol. Chem. 273, 34120-23427
98. Lomaga, M.A., Yeh, W.C., Sarosi, I., Duncan, G.S., Furlonger, C., Ho, A., Morony, S., Capparelli, C., Van, G., Kaufman, S. et al. (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes. Dev. 13, 1015-1024
99. Jin, G., Akiyama, T., Koga, T., Takayanagi, H., Tanaka, S. andInoue, J.I. (2005) RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis. EMBO J. 24, 790-799
100. Darnay, B.G., Ni, J., Moore, P.A. and Aggarwal, B.B. (1999) Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. J. Biol. Chem. 274, 7724-7731
101. Kim, H.H., Lee, D.E., Shin, J.N., Lee, Y.S., Jeon, Y.M., Chung, C.H., Ni, J., Kwon, B.S. and Lee, Z.H. (1999) Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett. 443, 297-302
102. Simonet, W.S., Lacey, D.L., Dunstan, C.R., Kelley, M., Chang, M.S., Lüthy, R., Nguyen, H.Q., Wooden, S., Bennett, L., Boone, T. et al. (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309-319
103. Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S., Tomoyasu, A., Yano, K., Goto, M., Murakami, A. et al. (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. U.S.A. 95, 3597-3602
104. Baud'huin, M., Duplomb, L., Teletchea, S., Lamoureux, F., Ruiz-Velasco, C., Maillasson, M., Redini, F., Heymann, M.F. and Heymann, D. (2013) Osteoprotegerin: multiple partners for multiples functions. Cytokine Growth Factor Rev. 24, 401-409
105. Gonda, T.A., Tu, S. and Wang, T.C. (2009) Chronic inflammation, the tumor microenvironment and carcinogenesis. Cell Cycle 8, 2005-2013
106. Kwan Tat, S., Padrines, M., Theoleyre, S., Couillaud-Battaglia, S., Heymann, D., Redini, F. and Fortun, Y. (2006) OPG/membranous-RANKL complex is internalized via the clathrin pathway before a lysosomal and a proteasomal degradation. Bone 39, 706-715
107. Théoleyre, S., Kwan Tat, S., Vusio, P., Blanchard, F., Gallagher, J., Ricard-Blum, S., Fortun, Y., Padrines, M., Rédini, F. and Heymann, D. (2006) Characterization of osteoprotegerin binding to glycosaminoglycans by surface plasmon resonance: role in the interactions with receptor activator of nuclear factor kappaB ligand (RANKL) and RANK. Biochem. Biophys. Res. Commun. 347, 460-467
108. Standal, T., Seidel, C., Hjertner, Ø., Plesner, T., Sanderson, R.D., Waage, A., Borset, M. and Sundan, A. (2002) Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 100, 3002-3007
109. Lamoureux, F., Picarda, G., Garrigue-Antar, L., Baud'huin, M., Trichet, V., Vidal, A., Miot-Noirault, E., Pitard, B., Heymann, D. and Rédini, F. (2009) Glycosaminoglycans as potential regulators of osteoprotegerin therapeutic activity in osteosarcoma. Cancer Res. 69, 526-536
110. Emery, J.G., McDonnell, P., Burke, M.B., Deen, K.C., Lyn, S., Silverman, C., Dul, E., Appelbaum, E.R., Eichman, C., DiPrinzio, R. et al. (1998) Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J. Biol. Chem. 273, 14363-14367
111. Holen, I., Croucher, P.I., Hamdy, F.C. and Eaton, C.L. (2002) Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. Cancer Res. 62, 1619-1623
112. Baud'huin, M., Duplomb, L., Téletchéa, S., Charrier, C., Maillasson, M., Fouassier, M. and Heymann, D. (2009) Factor VIII-von Willebrand factor complex inhibits osteoclastogenesis and controls cell survival. J. Biol. Chem. 284, 31704-31713
113. Luo, J., Yang, Z., Ma, Y., Yue, Z., Lin, H., Qu, G., Huang, J., Dai, W., Li, C., Zheng, C. et al. (2016) LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat. Med. 22, 539-546
114. Styrkarsdottir, U., Thorleifsson, G., Sulem, P., Gudbjartsson, D.F., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Oddsson, A., Helgason, A., Magnusson, O.T. et al. (2013) Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 497, 517-520
115. Zhu, Y.B., Xu, L., Chen, M., Ma, H.N. and Lou, F. (2013) GPR48 promotes multiple cancer cell proliferation via activation of Wnt signaling. Asian Pac. J. Cancer Prev. 14, 4775-4578
116. Liang, F., Yue, J., Wang, J., Zhang, L., Fan, R., Zhang, H. and Zhang, Q. (2015) GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway. Med. Oncol. 32, 49
117. Luo, W., Rodriguez, M., Valdez, J.M., Zhu, X., Tan, K., Li, D., Siwko, S., Xin, L. and Liu, M. (2013) Lgr4 is a key regulator of prostate development and prostate stem cell differentiation. Stem Cells 31, 2492-2505
118. Liu, J., Wei, W., Guo, C.A., Han, N., Pan, J.F., Fei, T. and Yan, Z.Q. (2013) Stat3 upregulates leucine-rich repeat-containing g protein-coupled receptor 4 expression in osteosarcoma cells. Biomed. Res. Int. 2013, 310691
119. Fata, J.E., Kong, Y.Y., Li, J., Sasaki, T., Irie-Sasaki, J., Moorehead, R.A., Elliott, R., Scully, S., Voura, E.B., Lacey, D.L. et al. (2000) The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103, 41-50
120. Kim, N.S., Kim, H.J., Koo, B.K., Kwon, M.C., Kim, Y.W., Cho, Y., Yokota, Y., Penninger, J.M. and Kong, Y.Y. (2006) Receptor activator of NF-kappaB ligand regulates the proliferation of mammary epithelial cells via Id2. Mol. Cell Biol. 26, 1002-1013
121. Gonzalez-Suarez, E., Branstetter, D., Armstrong, A., Dinh, H., Blumberg, H. and Dougall, W.C. (2007) RANK overexpression in transgenic mice with mouse mammary tumor virus promoter controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini. Mol. Cell. Biol. 27, 1442-1454
122. Gonzalez-Suarez, E., Jacob, A.P., Jones, J., Miller, R., Roudier-Meyer, M.P., Erwert, R., Pinkas, J., Branstetter, D. and Dougall, W.C. (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468, 103-137
123. Palafox, M., Ferrer, I., Pellegrini, P., Vila, S., Hernandez-Ortega, S., Urruticoechea, A., Climent, F., Soler, M.T., Muñoz, P., Viñals, F. et al. (2012) RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res. 72, 2879-2888
124. Yamada, T., Tsuda, M., Takahashi, T., Totsuka, Y., Shindoh, M. and Ohba, Y. (2011) RANKL expression specifically observed in vivo promotes epithelial mesenchymal transition and tumor progression. Am. J. Pathol. 178, 2845-2856
125. Liu, Y., Wang, J., Ni, T., Wang, L., Wang, Y. and Sun, X. (2016), CCL20 mediates RANK/RANKL-induced epithelial-mesenchymal transition in endometrial cancer cells. Oncotarget, doi: 10.18632/oncotarget.8291
126. Mori, K., Le Goff, B., Charrier, C., Battaglia, S., Heymann, D. and Rédini, F. (2007) DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process. Bone 40, 981-890
127. Li, X., Liu, Y., Wu, B., Dong, Z., Wang, Y., Lu, J., Shi, P., Bai, W. and Wang, Z. (2014) Potential role of the OPG/RANK/RANKL axis in prostate cancer invasion and bone metastasis. Oncol. Rep. 32, 2605-2611
128. Shin, M., Matsuo, K., Tada, T., Fukushima, H., Furuta, H., Ozeki, S., Kadowaki, T., Yamamoto, K., Okamoto, M. and Jimi, E. (2011) The inhibition of RANKL/RANK signaling by osteoprotegerin suppresses bone invasion by oral squamous cell carcinoma cells. Carcinogenesis 32, 1634-1640
129. Chen, L.M., Kuo, C.H., Lai, T.Y., Lin, Y.M., Su, C.C., Hsu, H.H., Tsai, F.J., Tsai, C.H., Huang, C.Y. and Tang, C.H. (2011) RANKL increases migration of human lung cancer cells through intercellular adhesion molecule-1 up-regulation. J. Cell. Biochem. 112, 933-941
130. Song, F.N., Duan, M., Liu, L.Z., Wang, Z.C., Shi, J.Y., Yang, L.X., Zhou, J., Fan, J., Gao, Q. and Wang, X.Y. (2014) RANKL promotes migration and invasion of hepatocellular carcinoma cells via NF-êB-mediated epithelial-mesenchymal transition. PLoS One 9, e108507
131. Wang, J., Sun, X., Zhang, H., Wang, Y. and Li, Y. (2015) MPA influences tumor cell proliferation, migration, and invasion induced by RANKL through PRB involving the MAPK pathway in endometrial cancer. Oncol. Rep. 33, 799-809
132. Golden, D., Saria, E.A. and Hansen, M.F. (2015) Regulation of osteoblast migration involving receptor activator of nuclear factor-kappa B (RANK) signaling. J. Cell Physiol. 230, 2951-2960
133. Beristain, A.G., Narala, S.R., Di Grappa, M.A. and Khokha, R. (2012) Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells. J. Cell Sci. 125, 943-955
134. Mikami, S., Katsube, K., Oya, M., Ishida, M., Kosaka, T., Mizuno, R., Mochizuki, S., Ikeda, T., Mukai, M. and Okada, Y. (2009) Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J. Pathol. 218, 530-539
135. Min, J.K., Kim, Y.M., Kim, Y.M., Kim, E.C., Gho, Y.S., Kang, I.J., Lee, S.Y., Kong, Y.Y. and Kwon, Y.G. (2003) Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kappa B (RANK) in endothelial cells: concomitant increase of angiogenic responses to RANK ligand. J. Biol. Chem. 278, 39548-39557
136. Kim, Y.M., Kim, Y.M., Lee, Y.M., Kim, H.S., Kim, J.D., Choi, Y., Kim, K.W., Lee, S.Y. and Kwon, Y.G. (2002) TNFrelated activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells. J. Biol. Chem. 277, 6799-6805
137. Kim, H.H., Shin, H.S., Kwak, H.J., Ahn, K.Y., Kim, J.H., Lee, H.J., Lee, M.S., Lee, Z.H. and Koh, G.Y. (2003) RANKL regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway. FASEB J. 17, 2163-216
138. Benslimane-Ahmim, Z., Heymann, D., Dizier, B., Lokajczyk, A., Brion, R., Laurendeau, I., Bièche, I., Smadja, D.M., Galy-Fauroux, I., Colliec-Jouault, S. et al. (2011) Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony-forming cells properties. J. Thromb. Haemost. 9, 834-843
139. Min, J.K., Cho, Y.L., Choi, J.H., Kim, Y., Kim, J.H., Yu, Y.S., Rho, J., Mochizuki, N., Kim, Y.M., Oh, G.T. and Kwon, Y.G. (2007) Receptor activator of nuclear factor-kB ligand increases vascular permeability: impaired permeability and angiogenesis in eNOS-deficient mice. Blood 109, 1496-1502
140. Mueller, C.G. and Hess, E. (2012) Emerging functions of RANKL in lymphoid tissues. Front. Immunol. 3, 261
141. Kong, Y.Y., Yoshida, H., Sarosi, I., Tan, H.L., Timms, E., Capparelli, C., Morony, S., Oliveira-dos-Santos, A.J., Van, G., Itie, A. et al. (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315-323
142. Akiyama, T., Shimo, Y., Yanai, H., Qin, J., Ohshima, D., Maruyama, Y., Asaumi, Y., Kitazawa, J., Takayanagi, H., Penninger, J.M. et al. (2008) The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29, 423-437
143. Akiyama, T., Shinzawa, M., Qin, J. and Akiyama, N. (2013) Regulations of gene expression in medullary thymic epithelial cells required for preventing the onset of autoimmune diseases. Front. Immunol. 4, 249
144. Khan, I.S., Mouchess, M.L., Zhu, M.L., Conley, B., Fasano, K.J., Hou, Y., Fong, L. and Su, M.A. (2014) Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J. Exp. Med. 211, 761-768
145. Cook, J. and Hagemann, T. (2013) Tumour-associated macrophages and cancer. Curr. Opin. Pharmacol. 13, 595-601
146. Breuil, V., Schmid-Antomarchi, H., Schmid-Alliana, A., Rezzonico, R., Euller-Ziegler, L. and Rossi, B. (2003) The receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) is a new chemotactic for human monocytes. FASEB J. 17, 2163-2165
147. Kambayashi, Y., Fujimura, T., Furudate, S., Asano, M., Kakizaki, A. and Aiba, S. (2015) The possible interaction between receptor activator of nuclear factor kappa-B ligand expressed by extramammary paget cells and its ligand on dermal macrophages. J. Invest. Dermatol. 135, 2547-2550
148. Fujimura, T., Kambayashi, Y., Furudate, S., Asano, M., Kakizaki, A. and Aiba, S. (2015) Receptor activator of NF-[kappa]B ligand promotes the production of CCL17 from RANK + M2 macrophages. J. Invest. Dermatol. 135, 2884-2887
149. Tan, W., Zhang, W., Strasner, A., Grivennikov, S., Cheng, J.Q., Hoffman, R.M. and Karin, M. (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548-553
150. Monteiro, A.C., Leal, A.C., Gonçalves-Silva, T., Mercadante, A.C., Kestelman, F., Chaves, S.B., Azevedo, R.B., Monteiro, J.P. and Bonomo, A.T. (2013) Cells induce pre-metastatic osteolytic disease and help bone metastases establishment in a mouse model of metastatic breast cancer. PLoS One 8, e68171
151. Esposito, M. and Kang, Y. (2014) Targeting tumor-stromal interactions in bone metastasis. Pharmacol. Ther. 141, 222-233
152. Bekker, P.J., Holloway, D., Nakanishi, A., Arrighi, M., Leese, P.T. and Dunstan, C.R. (2001) The effect of a single dose of osteoprotegerin in postmenopausal women. J. Bone Miner. Res. 16, 348-360
153. Gobin, B., Baud'huin, M., Isidor, B., Heymann, D. and Heymann, M.F. (2012) Monoclonal antibodies targeting RANKL in bone metastasis treatment. In Monoclonal antibodies in oncology (Fatih, M., ed.), pp. 42-53, Uckum, eBook Future Medicine Ltd
154. Bekker, P.J., Holloway, D.L., Rasmussen, A.S., Murphy, R., Martin, S.W., Leese, P.T., Holmes, G.B., Dunstan, C.R. and DePaoli, A.M.A. (2004) single-dose placebo-controlled study of AMG162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J. Bone Miner. Res. 19, 1059-1066
155. Picarda, G., Matous, E., Amiaud, J., Charrier, C., Lamoureux, F., Heymann, M.F., Tirode, F., Pitard, B., Trichet, V., Heymann, D. and Redini, F. (2013) Osteoprotegerin inhibits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL. J. Bone Oncol. 2, 95-104
156. Lamoureux, F., Richard, P., Wittrant, Y., Battaglia, S., Pilet, P., Trichet, V., Blanchard, F., Gouin, F., Pitard, B., Heymann, D. and Redini, F. (2007) Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorption. Cancer Res. 67, 7308-7318
157. Lamoureux, F., Picarda, G., Rousseau, J., Gourden, C., Battaglia, S., Charrier, C., Pitard, B., Heymann, D. and Rédini, F. (2008) Therapeutic efficacy of soluble receptor activator of nuclear factor-kappa B-Fc delivered by nonviral gene transfer in a mouse model of osteolytic osteosarcoma. Mol. Cancer Ther. 7, 3389-3398
158. Zheng, Y., Zhou, H., Fong-Yee, C., Modzelewski, J.R., Seibel, M.J. and Dunstan, C.R. (2008) Bone resorption increases tumour growth in a mouse model of osteosclerotic breast cancer metastasis. Clin. Exp. Metastasis 25, 559-567
159. Miller, R.E., Roudier, M., Jones, J., Armstrong, A., Canon, J. and Dougall, W.C. (2008) RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. Mol. Cancer Ther. 7, 2160-2169
160. Miller, R.E., Jones, J.C., Tometsko, M., Blake, M.L. and Dougall, W.C. (2014) RANKL inhibition blocks osteolytic lesions and reduces skeletal tumor burden in models of non-small-cell lung cancer bone metastases. J. Thorac. Oncol. 9, 345-354
161. Vanderkerken, K., De Leenheer, E., Shipman, C., Asosingh, K., Willems, A., Van Camp, B. and Croucher, P. (2003) Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma. Cancer Res. 63, 287-289
162. Lipton, A., Fizazi, K., Stopeck, A.T., Henry, D.H., Smith, M.R., Shore, N., Martin, M., Vadhan-Raj, S., Brown, J.E., Richardson, G.E. et al. (2016) Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics. Eur. J. Cancer 53, 75-83