RANK pathway in cancer: underlying resistance and therapeutic approaches

References

• Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390(6656):175–179.
   PubMed Web of Science ®Google Scholar
• Wong BR, Rho J, Arron J, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem. 1997;272(40):25190–25194.
   PubMed Web of Science ®Google Scholar
• Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999;13(18):2412–2424.
   PubMed Web of Science ®Google Scholar
• Mizuno A, Amizuka N, Irie K, et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun. 1998;247(3):610–615.
   PubMed Web of Science ®Google Scholar
• Lacey DL, Boyle WJ, Simonet WS, et al. Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab. Nat Rev Drug Discov. 2012;11(5):401–419.
   PubMed Web of Science ®Google Scholar
• Fata JE, Kong Y-Y, Li J, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000;103(1):41–50.
   PubMed Web of Science ®Google Scholar
• Schramek D, Leibbrandt A, Sigl V, et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 2010;468(7320):98–102.
   PubMed Web of Science ®Google Scholar
• Wu X, Li F, Dang L, et al. RANKL/RANK system-based mechanism for breast cancer bone metastasis and related therapeutic strategies. Front Cell Dev Biol. 2020;8:76.
   PubMed Web of Science ®Google Scholar
• Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. The Lancet. 2011;377(9773):1276–1287.
   PubMed Web of Science ®Google Scholar
• Miller PD. Denosumab: anti-RANKL antibody. Curr Osteoporos Rep. 2009;7(1):18–22.
   PubMedGoogle Scholar
• Tufail M, Wu C. Targeting the IGF-1R in prostate and colorectal cancer: reasons behind trial failure and future directions. Ther Deliv. 2022;13(3):167–186.
   PubMed Web of Science ®Google Scholar
• Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(S8):1588–1594.
   PubMedGoogle Scholar
• Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11(6):411–425.
   PubMed Web of Science ®Google Scholar
• Mundy GR. Mechanisms of bone metastasis. Cancer. 1997;80(S8):1546–1556.
   PubMedGoogle Scholar
• Kingsley LA, Fournier PG, Chirgwin JM, et al. Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6(10):2609–2617.
   PubMed Web of Science ®Google Scholar
• Dougall WC. Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis. Clin Cancer Res. 2012;18(2):326–335.
   PubMed Web of Science ®Google Scholar
• Paget S. The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev. 1989;8(2):98–101.
   PubMed Web of Science ®Google Scholar
• Thomas RJ, Guise TA, Yin JJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 1999;140(10):4451–4458.
   PubMed Web of Science ®Google Scholar
• Giuliani N, Colla S, Sala R, et al. Human myeloma cells stimulate the receptor activator of nuclear factor-κB ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. Blood. 2002;100(13):4615–4621.
   PubMed Web of Science ®Google Scholar
• Roux S, Mariette X. The high rate of bone resorption in multiple myeloma is due to RANK (receptor activator of nuclear factor-κB) and RANK ligand expression. Leuk Lymphoma. 2004;45(6):1111–1118.
   PubMed Web of Science ®Google Scholar
• Terpos E, Szydlo R, Apperley JF, et al. Soluble receptor activator of nuclear factor κB ligand–osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood. 2003;102(3):1064–1069.
   PubMed Web of Science ®Google Scholar
• Mikami S, Katsube K, Oya M, et al. Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J Pathol. 2009;218(4):530–539.
   PubMed Web of Science ®Google Scholar
• Sasaki A, Ishikawa K, Haraguchi N, et al. Receptor activator of nuclear factor-κB ligand (RANKL) expression in hepatocellular carcinoma with bone metastasis. Ann Surg Oncol. 2007;14(3):1191–1199.
   PubMed Web of Science ®Google Scholar
• Blake ML, Tometsko M, Miller R, et al. RANK expression on breast cancer cells promotes skeletal metastasis. Clin Exp Metastasis. 2014;31(2):233–245.
   PubMed Web of Science ®Google Scholar
• Huang L, Xu J, Wood DJ, et al. Gene expression of osteoprotegerin ligand, osteoprotegerin, and receptor activator of NF-κB in giant cell tumor of bone: possible involvement in tumor cell-induced osteoclast-like cell formation. Am J Pathol. 2000;156(3):761–767.
   PubMed Web of Science ®Google Scholar
• Schneeweis LA, Willard D, Milla ME. Functional dissection of osteoprotegerin and its interaction with receptor activator of NF-κB ligand. J Biol Chem. 2005;280(50):41155–41164.
   PubMed Web of Science ®Google Scholar
• Singh AS, Chawla NS, Chawla SP. Giant-cell tumor of bone: treatment options and role of denosumab. Biologics. 2015;9:69.
   PubMedGoogle Scholar
• Lamoureux F, Richard P, Wittrant Y, et al. Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorption. Cancer Res. 2007;67(15):7308–7318.
   PubMed Web of Science ®Google Scholar
• Tufail M. Genome editing: an essential technology for cancer treatment. Med Omics. 2022;4:100015.
   Google Scholar
• Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. In Jaffe N, Bruland O, Bielack S, eds. Pediatric and adolescent osteosarcoma. Boston (MA): Springer; 2009; p. 3–13.
   Google Scholar
• Hsu CJ, Lin TY, Kuo CC, et al. Involvement of integrin up‐regulation in RANKL/RANK pathway of chondrosarcomas migration. J Cell Biochem. 2010;111(1):138–147.
   PubMed Web of Science ®Google Scholar
• Miller RE, Roudier M, Jones J, et al. RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. Mol Cancer Ther. 2008;7(7):2160–2169.
   PubMed Web of Science ®Google Scholar
• Chen G, Sircar K, Aprikian A, et al. Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer. 2006;107(2):289–298.
   PubMed Web of Science ®Google Scholar
• Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–822.
   PubMed Web of Science ®Google Scholar
• Henry DH, Costa L, Goldwasser F, et al. 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. 2011;29(9):1125–1132.
   PubMed Web of Science ®Google Scholar
• Chu GC-Y, Chung LW. RANK-mediated signaling network and cancer metastasis. Cancer Metastasis Rev. 2014;33(2–3):497–509.
   PubMed Web of Science ®Google Scholar
• Wong BR, Josien R, Lee SY, et al. 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. 1997;186(12):2075–2080.
   PubMed Web of Science ®Google Scholar
• Gonzalez-Suarez E, Jacob AP, Jones J, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468(7320):103–107.
   PubMed Web of Science ®Google Scholar
• Tan W, Zhang W, Strasner A, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling. Nature. 2011;470(7335):548–553.
   PubMed Web of Science ®Google Scholar
• Li H, Hong S, Qian J, et al. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood. 2010;116(2):210–217.
   PubMed Web of Science ®Google Scholar
• Chen N-J, Huang M-W, Hsieh S-L. Enhanced secretion of IFN-γ by activated Th1 cells occurs via reverse signaling through TNF-related activation-induced cytokine. J Immunol. 2001;166(1):270–276.
   PubMed Web of Science ®Google Scholar
• Zhang S, Wang X, Li G, et al. Osteoclast regulation of osteoblasts via RANK-RANKL reverse signal transduction in vitro. Mol Med Rep. 2017;16(4):3994–4000.
   PubMed Web of Science ®Google Scholar
• Tilborghs S, Corthouts J, Verhoeven Y, et al. The role of nuclear factor-kappa B signaling in human cervical cancer. Crit Rev Oncol Hematol. 2017;120:141–150.
   PubMed Web of Science ®Google Scholar
• Goswami S, Sharma-Walia N. Osteoprotegerin rich tumor microenvironment: implications in breast cancer. Oncotarget. 2016;7(27):42777–42791.
   PubMedGoogle Scholar
• Renema N, Navet B, Heymann M-F, et al. RANK–RANKL signalling in cancer. Biosci Rep. 2016;36(4):e00366.
   PubMed Web of Science ®Google Scholar
• Reid PE, Brown NJ, Holen I. Breast cancer cells stimulate osteoprotegerin (OPG) production by endothelial cells through direct cell contact. Mol Cancer. 2009;8(1):49.
   PubMedGoogle Scholar
• Liu Y, Wang J, Ni T, et al. CCL20 mediates RANK/RANKL-induced epithelial-mesenchymal transition in endometrial cancer cells. Oncotarget. 2016;7(18):25328–25339.
   PubMedGoogle Scholar
• Min JK, Kim YM, Kim YM, et al. 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. 2003;278(41):39548–39557.
   PubMed Web of Science ®Google Scholar
• Karamouzis MV, Likaki-Karatza E, Ravazoula P, et al. Non-palpable breast carcinomas: correlation of mammographically detected malignant-appearing microcalcifications and molecular prognostic factors. Int J Cancer. 2002;102(1):86–90.
   PubMed Web of Science ®Google Scholar
• Tot T, Gere M, Hofmeyer S, et al. The clinical value of detecting microcalcifications on a mammogram. Semin Cancer Biol. 2021;72:165–174.
   PubMed Web of Science ®Google Scholar
• Jones DH, Nakashima T, Sanchez OH, et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006;440(7084):692–696.
   PubMed Web of Science ®Google Scholar
• Jacob A, Branstetter D, Rohrbach K, et al. P3-01-14: RANK and RANK ligand (RANKL) expression in invasive breast carcinoma and human breast cancer cell lines. AACR. 2011;71(24 Suppl):P3-01-14.
   Google Scholar
• Chawla S, Henshaw R, Seeger L, et al. 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. 2013;14(9):901–908.
   PubMed Web of Science ®Google Scholar
• Palafox M, Ferrer I, Pellegrini P, et al. RANK induces epithelial–mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res. 2012;72(11):2879–2888.
   PubMed Web of Science ®Google Scholar
• Sousa S, Gineyts E, Geraci S, et al. RANK-RANKL signaling inhibition delays early breast cancer bone metastasis formation. Cancer Res. 2018;78(13 Suppl):29.
   Web of Science ®Google Scholar
• Vargas G, Bouchet M, Bouazza L, et al. ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors. Oncogene. 2019;38(7):950–964.
   PubMed Web of Science ®Google Scholar
• Infante M, Fabi A, Cognetti F, et al. RANKL/RANK/OPG system beyond bone remodeling: involvement in breast cancer and clinical perspectives. J Exp Clin Cancer Res. 2019;38(1):12.
   PubMed Web of Science ®Google Scholar
• Asano T, Okamoto K, Nakai Y, et al. Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone. Nat Metab. 2019;1(9):868–875.
   PubMedGoogle Scholar
• Langley RR, Fidler IJ. The seed and soil hypothesis revisited—the role of tumor‐stroma interactions in metastasis to different organs. Int J Cancer. 2011;128(11):2527–2535.
   PubMed Web of Science ®Google Scholar
• Ben-Baruch A. Site-specific metastasis formation: chemokines as regulators of tumor cell adhesion, motility and invasion. Cell Adh Migr. 2009;3(4):328–333.
   PubMed Web of Science ®Google Scholar
• Azim H, Azim HA. Targeting RANKL in breast cancer: bone metastasis and beyond. Expert Rev Anticancer Ther. 2013;13(2):195–201.
   PubMed Web of Science ®Google Scholar
• Sanders JL, Chattopadhyay N, Kifor O, et al. Extracellular calcium-sensing receptor expression and its potential role in regulating parathyroid hormone-related peptide secretion in human breast cancer cell lines. Endocrinology. 2000;141(12):4357–4364.
   PubMed Web of Science ®Google Scholar
• Whyte MP, Obrecht SE, Finnegan PM, et al. Osteoprotegerin deficiency and juvenile Paget’s disease. N Engl J Med. 2002;347(3):175–184.
   PubMed Web of Science ®Google Scholar
• Samani AA, Yakar S, LeRoith D, et al. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007;28(1):20–47.
   PubMed Web of Science ®Google Scholar
• Maki RG. Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J Clin Oncol. 2010;28(33):4985–4995.
   PubMed Web of Science ®Google Scholar
• Soki FN, Park SI, McCauley LK. The multifaceted actions of PTHrP in skeletal metastasis. Future Oncol. 2012;8(7):803–817.
   PubMed Web of Science ®Google Scholar
• Le Pape F, Vargas G, Clézardin P. The role of osteoclasts in breast cancer bone metastasis. J Bone Oncol. 2016;5(3):93–95.
   PubMed Web of Science ®Google Scholar
• Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007;26(45):6469–6487.
   PubMed Web of Science ®Google Scholar
• Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3(2):224–237.
   PubMed Web of Science ®Google Scholar
• Kancha RK, Von Bubnoff N, Bartosch N, et al. Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS One. 2011;6(10):e26760.
   PubMed Web of Science ®Google Scholar
• Sanz-Moreno A, Palomeras S, Pedersen K, et al. RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer. Breast Cancer Res. 2021;23(1):42.
   PubMed Web of Science ®Google Scholar
• Gomes I, de Almeida BP, Dâmaso S, et al. Expression of receptor activator of NFkB (RANK) drives stemness and resistance to therapy in ER + HER2- breast cancer. Oncotarget. 2020;11(19):1714–1728.
   PubMedGoogle Scholar
• Tsubaki M, Takeda T, Yoshizumi M, et al. RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines. Tumour Biol. 2016;37(7):9099–9110.
   PubMedGoogle Scholar
• Mashimo K, Tsubaki M, Takeda T, et al. RANKL-induced c-Src activation contributes to conventional anti-cancer drug resistance and dasatinib overcomes this resistance in RANK-expressing multiple myeloma cells. Clin Exp Med. 2019;19(1):133–141.
   PubMed Web of Science ®Google Scholar
• van Dam PA, Verhoeven Y, Trinh XB, et al. RANK/RANKL signaling inhibition may improve the effectiveness of checkpoint blockade in cancer treatment. Crit Rev Oncol Hematol. 2019;133:85–91.
   PubMed Web of Science ®Google Scholar
• Morony S, Warmington K, Adamu S, et al. The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy. Endocrinology. 2005;146(8):3235–3243.
   PubMed Web of Science ®Google Scholar
• Canon JR, Roudier M, Bryant R, et al. Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis. 2008;25(2):119–129.
   PubMed Web of Science ®Google Scholar
• Body JJ, Greipp P, Coleman RE, et al. A phase I study of AMGN‐0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer. 2003;97(3 Suppl):887–892.
   PubMed Web of Science ®Google Scholar
• Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998;273(23):14363–14367.
   PubMed Web of Science ®Google Scholar
• Cummings SR, Martin JS, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765.
   PubMed Web of Science ®Google Scholar
• Stopeck AT, Lipton A, Body J-J, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132–5139.
   PubMed Web of Science ®Google Scholar
• Martin M, Bell R, Bourgeois H, et al. Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res. 2012;18(17):4841–4849.
   PubMed Web of Science ®Google Scholar
• Abrahamsen B, Teng A. Technology evaluation: denosumab, Amgen. Curr Opin Mol Ther. 2005;7(6):604–610.
   PubMedGoogle Scholar
• Baron R, Ferrari S, Russell RGG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011;48(4):677–692.
   PubMed Web of Science ®Google Scholar
• Coleman R, Finkelstein DM, Barrios C, et al. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21(1):60–72.
   PubMed Web of Science ®Google Scholar
• Presurgical trial of denosumab in breast cancer. 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT02900469?cond=NCT02900469&draw=2&rank=1.
   Google Scholar
• Stefanovic S, Diel I, Sinn P, et al. Disseminated tumor cells in the bone marrow of patients with operable primary breast cancer: prognostic impact in immunophenotypic subgroups and clinical implication for bisphosphonate treatment. Ann Surg Oncol. 2016;23(3):757–766.
   PubMed Web of Science ®Google Scholar
• Ueno NT, Tahara RK, Saigal B, et al. Phase II study of Ra-223 combined with hormonal therapy and denosumab for treatment of hormone receptor-positive breast cancer with bone-dominant metastasis. JCO. 2018;36(15_suppl):1065–1065.
   Web of Science ®Google Scholar
• Study to determine treatment effects of denosumab in patients with breast cancer receiving aromatase inhibitor therapy. 2021. Available from: https://clinicaltrials.gov/ct2/show/NCT00556374?cond=NCT00556374&draw=2&rank=1.
   Google Scholar
• Lipton A. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. Breast Dis. 2009;20(2):195–196.
   Google Scholar
• Denosumab (AMG 162) in bisphosphonate naive metastatic breast cancer. 2014. Available from: https://clinicaltrials.gov/ct2/show/NCT00091832?cond=NCT00091832&draw=2&rank=1.
   Google Scholar
• RANKL inhibition and breast tissue biomarkers. 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT03629717?cond=NCT03629717&draw=2&rank=1.
   Google Scholar
• Biomarker study of the antitumoral activity of denosumab in the pre-operative setting of early breast cancer (D-BIOMARK). 2021. Available from: https://clinicaltrials.gov/ct2/show/NCT03691311?cond=NCT03691311&draw=2&rank=1.
   Google Scholar
• Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks. 2021. Available from: https://clinicaltrials.gov/ct2/show/NCT02051218?cond=NCT02051218&draw=2&rank=1.
   Google Scholar
• Denosumab and MRI breast imaging (Dmab). 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT02613416?cond=NCT02613416&draw=2&rank=1.
   Google Scholar
• 4-Weekly versus 12-weekly administration of bone-targeted agents in patients with bone metastases (REaCT-BTA). 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT02721433?cond=NCT02721433&draw=2&rank=1.
   Google Scholar
• Open-label access protocol of denosumab for subjects with advanced cancer. 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT01419717?cond=NCT01419717&draw=2&rank=1.
   Google Scholar
• Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. JCO. 2009;27(10):1564–1571.
   PubMed Web of Science ®Google Scholar
• Fizazi K, Bosserman L, Gao G, et al. Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. J Urol. 2009;182(2):509–516.
   PubMed Web of Science ®Google Scholar
• Open label extension to SRE studies in United Kingdom and Czech Republic only. 2014. Available from: https://clinicaltrials.gov/ct2/show/NCT00950911?cond=NCT00950911&draw=2&rank=1.
   Google Scholar
• Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid (ZA) for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials. Ann Oncol. 2010;16:400.
   Google Scholar
• Saad F, Brown J, Van Poznak C, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol. 2012;23(5):1341–1347.
   PubMed Web of Science ®Google Scholar
• Dizdarevic S, McCready R, Vinjamuri S. Radium-223 dichloride in prostate cancer: proof of principle for the use of targeted alpha treatment in clinical practice. Eur J Nucl Med Mol Imaging. 2020;47(1):192–217.
   PubMed Web of Science ®Google Scholar
• García Vicente AM, Amo-Salas M, Cassinello Espinosa J, et al. Interim and end-treatment 18F-Fluorocholine PET/CT and bone scan in prostate cancer patients treated with radium 223 dichloride. Sci Rep. 2021;11(1):1–12.
   PubMed Web of Science ®Google Scholar
• Fournier PG, Stresing V, Ebetino FH, et al. How do bisphosphonates inhibit bone metastasis in vivo. Neoplasia. 2010;12(7):571–578.
   PubMed Web of Science ®Google Scholar
• Stresing V, Daubiné F, Benzaid I, et al. Bisphosphonates in cancer therapy. Cancer Lett. 2007;257(1):16–35.
   PubMed Web of Science ®Google Scholar
• Mori K, Le Goff B, Berreur M, et al. Human osteosarcoma cells express functional receptor activator of nuclear factor‐kappa B. J Pathol. 2007;211(5):555–562.
   PubMed Web of Science ®Google Scholar
• Armstrong AP, Miller RE, Jones JC, et al. RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate. 2008;68(1):92–104.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Zhou H, Brennan K, et al. Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumour actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis. Bone. 2007;40(2):471–478.
   PubMed Web of Science ®Google Scholar
• Casimiro S, Mohammad KS, Pires R, et al. RANKL/RANK/MMP-1 molecular triad contributes to the metastatic phenotype of breast and prostate cancer cells in vitro. PLoS One. 2013;8(5):e63153.
   PubMed Web of Science ®Google Scholar
• Canon J, Bryant R, Roudier M, et al. RANKL inhibition combined with tamoxifen treatment increases anti-tumor efficacy and prevents tumor-induced bone destruction in an estrogen receptor-positive breast cancer bone metastasis model. Breast Cancer Res Treat. 2012;135(3):771–780.
   PubMed Web of Science ®Google Scholar
• Luo J, Yang Z, Ma Y, et al. LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat Med. 2016;22(5):539–546.
   PubMed Web of Science ®Google Scholar
• Casimiro S, Vilhais G, Gomes I, et al. The roadmap of RANKL/RANK pathway in cancer. Cells. 2021;10(8):1978.
   PubMed Web of Science ®Google Scholar