Bone metastasis of hepatocellular carcinoma: facts and hopes from clinical and translational perspectives

Abstract

Patients with hepatocellular carcinoma (HCC) and bone metastasis (BM) suffer from greatly reduced life quality and a dismal prognosis. However, BM in HCC has long been overlooked possibly due to its relatively low prevalence in previous decades. To date, no consensus or guidelines have been reached or formulated for the prevention and management of HCC BM. Our narrative review manifests the increasing incidence of HCC BM to sound the alarm for additional attention. The risk factors, diagnosis, prognosis, and therapeutic approaches of HCC BM are detailed to provide a panoramic view of this disease to clinicians and specialists. We further delineate an informative cancer bone metastatic cascade based on evidence from recent studies and point out the main factors responsible for the tumor-associated disruption of bone homeostasis and the formation of skeletal cancer lesions. We also present the advances in the pathological and molecular mechanisms of HCC BM to shed light on translational opportunities. Dilemmas and challenges in the treatment and investigation of HCC BM are outlined and discussed to encourage further endeavors in the exploration of underlying pathogenic and molecular mechanisms, as well as the development of novel effective therapies for HCC patients with BM.

Keywords

HCC / bone / osteotropism / clinical / basic researches / advances

References

[1] Coleman RE, Croucher PI, Padhani AR, Clézardin P, Chow E, Fallon M, Guise T, Colangeli S, Capanna R, Costa L. Bone metastases. Nat Rev Dis Primers 2020; 6( 1): 83

[2] Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 1989; 8( 2): 98– 101

[3] Longo V, Brunetti O, D’Oronzo S, Ostuni C, Gatti P, Silvestris F. Bone metastases in hepatocellular carcinoma: an emerging issue. Cancer Metastasis Rev 2014; 33( 1): 333– 342

[4] Schlageter M, Quagliata L, Matter M, Perrina V, Tornillo L, Terracciano L. Clinicopathological features and metastatic pattern of hepatocellular carcinoma: an autopsy study of 398 patients. Pathobiology 2016; 83( 6): 301– 307

[5] Hirai T, Shinoda Y, Tateishi R, Asaoka Y, Uchino K, Wake T, Kobayashi H, Ikegami M, Sawada R, Haga N, Koike K, Tanaka S. Early detection of bone metastases of hepatocellular carcinoma reduces bone fracture and paralysis. Jpn J Clin Oncol 2019; 49( 6): 529– 536

[6] Heindel W, Gübitz R, Vieth V, Weckesser M, Schober O, Schäfers M. The diagnostic imaging of bone metastases. Dtsch Arztebl Int 2014; 111( 44): 741– 747

[7] Xiang L, Gilkes DM. The contribution of the immune system in bone metastasis pathogenesis. Int J Mol Sci 2019; 20( 4): 999

[8] Wang K, Gu Y, Liao Y, Bang S, Donnelly CR, Chen O, Tao X, Mirando AJ, Hilton MJ, Ji RR. PD-1 blockade inhibits osteoclast formation and murine bone cancer pain. J Clin Invest 2020; 130( 7): 3603– 3620

[9] Nakashima T, Okuda K, Kojiro M, Jimi A, Yamaguchi R, Sakamoto K, Ikari T. Pathology of hepatocellular carcinoma in Japan. 232 Consecutive cases autopsied in ten years. Cancer 1983; 51( 5): 863– 877

[10] Liaw CC, Ng KT, Chen TJ, Liaw YF. Hepatocellular carcinoma presenting as bone metastasis. Cancer 1989; 64( 8): 1753– 1757

[11] Fukutomi M, Yokota M, Chuman H, Harada H, Zaitsu Y, Funakoshi A, Wakasugi H, Iguchi H. Increased incidence of bone metastases in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2001; 13( 9): 1083– 1088

[12] Oweira H, Petrausch U, Helbling D, Schmidt J, Mehrabi A, Schöb O, Giryes A, Abdel-Rahman O. Prognostic value of site-specific extra-hepatic disease in hepatocellular carcinoma: a SEER database analysis. Expert Rev Gastroenterol Hepatol 2017; 11( 7): 695– 701

[13] Zhan H, Zhao X, Lu Z, Yao Y, Zhang X. Correlation and survival analysis of distant metastasis site and prognosis in patients with hepatocellular carcinoma. Front Oncol 2021; 11 : 652768

[14] Santini D, Pantano F, Riccardi F, Di Costanzo GG, Addeo R, Guida FM, Ceruso MS, Barni S, Bertocchi P, Marinelli S, Marchetti P, Russo A, Scartozzi M, Faloppi L, Santoni M, Cascinu S, Maiello E, Silvestris F, Tucci M, Ibrahim T, Masi G, Gnoni A, Comandone A, Fazio N, Conti A, Imarisio I, Pisconti S, Giommoni E, Cinieri S, Catalano V, Palmieri VO, Infante G, Aieta M, Trogu A, Gadaleta CD, Brunetti AE, Lorusso V, Silvestris N. Natural history of malignant bone disease in hepatocellular carcinoma: final results of a multicenter bone metastasis survey. PLoS One 2014; 9( 8): e105268

[15] Harding JJ, Abu-Zeinah G, Chou JF, Owen DH, Ly M, Lowery MA, Capanu M, Do R, Kemeny NE, O’Reilly EM, Saltz LB, Abou-Alfa GK. Frequency, morbidity, and mortality of bone metastases in advanced hepatocellular carcinoma. J Natl Compr Canc Netw 2018; 16( 1): 50– 58

[16] Okazaki N, Yoshino M, Yoshida T, Hirohashi S, Kishi K, Shimosato Y. Bone metastasis in hepatocellular carcinoma. Cancer 1985; 55( 9): 1991– 1994

[17] Uka K, Aikata H, Takaki S, Shirakawa H, Jeong SC, Yamashina K, Hiramatsu A, Kodama H, Takahashi S, Chayama K. Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol 2007; 13( 3): 414– 420

[18] Uchino K, Tateishi R, Shiina S, Kanda M, Masuzaki R, Kondo Y, Goto T, Omata M, Yoshida H, Koike K. Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors. Cancer 2011; 117( 19): 4475– 4483

[19] Katyal S, Oliver JH 3rd, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology 2000; 216( 3): 698– 703

[20] Bhatia R, Ravulapati S, Befeler A, Dombrowski J, Gadani S, Poddar N. Hepatocellular carcinoma with bone metastases: incidence, prognostic significance, and management-single-center experience. J Gastrointest Cancer 2017; 48( 4): 321– 325

[21] Ho CL, Chen S, Cheng TK, Leung YL. PET/CT characteristics of isolated bone metastases in hepatocellular carcinoma. Radiology 2011; 258( 2): 515– 523

[22] Guo X, Xu Y, Wang X, Lin F, Wu H, Duan J, Xiong Y, Han X, Baklaushev VP, Xiong S, Chekhonin VP, Peltzer K, Wang G, Zhang C. Advanced hepatocellular carcinoma with bone metastases: prevalence, associated factors, and survival estimation. Med Sci Monit 2019; 25 : 1105– 1112

[23] Hu C, Yang J, Huang Z, Liu C, Lin Y, Tong Y, Fan Z, Chen B, Wang C, Zhao CL. Diagnostic and prognostic nomograms for bone metastasis in hepatocellular carcinoma. BMC Cancer 2020; 20( 1): 494

[24] Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006; 12( 20): 6243s– 6249s

[25] Seong J, Koom WS, Park HC. Radiotherapy for painful bone metastases from hepatocellular carcinoma. Liver Int 2005; 25( 2): 261– 265

[26] Goblirsch MJ, Zwolak PP, Clohisy DR. Biology of bone cancer pain. Clin Cancer Res 2006; 12( 20): 6231s– 6235s

[27] Monteserin L, Mesa A, Fernandez-Garcia MS, Gadanon-Garcia A, Rodriguez M, Varela M. Bone metastases as initial presentation of hepatocellular carcinoma. World J Hepatol 2017; 9( 29): 1158– 1165

[28] Doval DC, Bhatia K, Vaid AK, Pavithran K, Sharma JB, Hazarika D, Jena A. Spinal cord compression secondary to bone metastases from hepatocellular carcinoma. World J Gastroenterol 2006; 12( 32): 5247– 5252

[29] Yang HL, Liu T, Wang XM, Xu Y, Deng SM. Diagnosis of bone metastases: a meta-analysis comparing ¹⁸FDG PET, CT, MRI and BS. Eur Radiol 2011; 21( 12): 2604– 2617

[30] Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT. Bone imaging in metastatic breast cancer. J Clin Oncol 2004; 22( 14): 2942– 2953

[31] Chen CY, Wu K, Lin WH, Lan TY, Wang SY, Sun JS, Weng PW, Yen RF, Yang RS. High false negative rate of Tc-99m MDP whole-body BS in detecting skeletal metastases for patients with hepatoma. J Formos Med Assoc 2012; 111( 3): 140– 146

[32] Jin YJ, Lee HC, Lee D, Shim JH, Kim KM, Lim YS, Do KH, Ryu JS. Role of the routine use of chest computed tomography and bone scan in staging workup of hepatocellular carcinoma. J Hepatol 2012; 56( 6): 1324– 1329

[33] Chua S, Gnanasegaran G, Cook GJ. Miscellaneous cancers (lung, thyroid, renal cancer, myeloma, and neuroendocrine tumors): role of SPECT and PET in imaging bone metastases. Semin Nucl Med 2009; 39( 6): 416– 430

[34] Velloni F, Ramalho M, AlObaidy M, Matos AP, Altun E, Semelka RC. Bone metastases of hepatocellular carcinoma: appearance on MRI using a standard abdominal protocol. AJR Am J Roentgenol 2016; 206( 5): 1003– 1012

[35] Asenbaum U, Nolz R, Karanikas G, Furtner J, Woitek R, Simonitsch-Klupp I, Raderer M, Mayerhoefer ME. Bone marrow involvement in malignant lymphoma: evaluation of quantitative PET and MRI BIomarkers. Acad Radiol 2018; 25( 4): 453– 460

[36] Rashidi A Baratto L Theruvath AJ Greene EB Hawk KE Lu R Link MP Spunt SL Daldrup-Link HE. Diagnostic accuracy of 2-[¹⁸F]FDG-PET and whole-body DW-MRI for the detection of bone marrow metastases in children and young adults . Eur Radiol 2022; [Epub ahead of print] doi:10.1007/s00330-021-08529-x

[37] Sugiyama M, Sakahara H, Torizuka T, Kanno T, Nakamura F, Futatsubashi M, Nakamura S. ¹⁸F-FDG PET in the detection of extrahepatic metastases from hepatocellular carcinoma. J Gastroenterol 2004; 39( 10): 961– 968

[38] Yoon KT Kim JK Kim DY Ahn SH Lee JD Yun M Rha SY Chon CY Han KH. Role of ¹⁸F-fluorodeoxyglucose positron emission tomography in detecting extrahepatic metastasis in pretreatment staging of hepatocellular carcinoma . Oncology 2007; 72(Suppl 1): 104– 110

[39] Kim YK, Lee KW, Cho SY, Han SS, Kim SH, Kim SK, Park SJ. Usefulness ¹⁸F-FDG positron emission tomography/computed tomography for detecting recurrence of hepatocellular carcinoma in posttransplant patients. Liver Transpl 2010; 16( 6): 767– 772

[40] Fujimoto R, Higashi T, Nakamoto Y, Hara T, Lyshchik A, Ishizu K, Kawashima H, Kawase S, Fujita T, Saga T, Togashi K. Diagnostic accuracy of bone metastases detection in cancer patients: comparison between bone scintigraphy and whole-body FDG-PET. Ann Nucl Med 2006; 20( 6): 399– 408

[41] Nagaoka S, Itano S, Ishibashi M, Torimura T, Baba K, Akiyoshi J, Kurogi J, Matsugaki S, Inoue K, Tajiri N, Takada A, Ando E, Kuromatsu R, Kaida H, Kurogi M, Koga H, Kumashiro R, Hayabuchi N, Kojiro M, Sata M. Value of fusing PET plus CT images in hepatocellular carcinoma and combined hepatocellular and cholangiocarcinoma patients with extrahepatic metastases: preliminary findings. Liver Int 2006; 26( 7): 781– 788

[42] Ho CL, Chen S, Yeung DW, Cheng TK. Dual-tracer PET/CT imaging in evaluation of metastatic hepatocellular carcinoma. J Nucl Med 2007; 48( 6): 902– 909

[43] Yen RF, Chen CY, Cheng MF, Wu YW, Shiau YC, Wu K, Hong RL, Yu CJ, Wang KL, Yang RS. The diagnostic and prognostic effectiveness of F-18 sodium fluoride PET-CT in detecting bone metastases for hepatocellular carcinoma patients. Nucl Med Commun 2010; 31( 7): 637– 645

[44] He J, Zeng ZC, Tang ZY, Fan J, Zhou J, Zeng MS, Wang JH, Sun J, Chen B, Yang P, Pan BS. Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma receiving external beam radiotherapy. Cancer 2009; 115( 12): 2710– 2720

[45] Uei H, Tokuhashi Y, Maseda M. Treatment outcomes of patients with spinal metastases derived from hepatocellular carcinoma. Int J Clin Oncol 2018; 23( 5): 886– 893

[46] Bollen L, Dijkstra SPD, Bartels RHMA, de Graeff A, Poelma DLH, Brouwer T, Algra PR, Kuijlen JMA, Minnema MC, Nijboer C, Rolf C, Sluis T, Terheggen MAMB, van der Togt-van Leeuwen ACM, van der Linden YM, Taal W. Clinical management of spinal metastases—The Dutch national guideline. Eur J Cancer 2018; 104 : 81– 90

[47] Sodji Q, Kaminski J, Willey C, Kim N, Mourad W, Vender J, Dasher B. Management of metastatic spinal cord compression. South Med J 2017; 110( 9): 586– 593

[48] Chang SS, Luo JC, Chao Y, Chao JY, Chi KH, Wang SS, Chang FY, Lee SD, Yen SH. The clinical features and prognostic factors of hepatocellular carcinoma patients with spinal metastasis. Eur J Gastroenterol Hepatol 2001; 13( 11): 1341– 1345

[49] Choi C, Seong J. Predictive factors of palliative radiotherapy response and survival in patients with spinal metastases from hepatocellular carcinoma. Gut Liver 2015; 9( 1): 94– 102

[50] Hayashi S, Tanaka H, Hoshi H. External beam radiotherapy for painful bone metastases from hepatocellular carcinoma: multiple fractions compared with an 8-Gy single fraction. Nagoya J Med Sci 2014; 76( 1-2): 91– 99

[51] Katamura Y, Aikata H, Hashimoto Y, Kimura Y, Kawaoka T, Takaki S, Waki K, Hiramatsu A, Kawakami Y, Takahashi S, Kenjo M, Chayama K. Zoledronic acid delays disease progression of bone metastases from hepatocellular carcinoma. Hepatol Res 2010; 40( 12): 1195– 1203

[52] Chang UK, Kim MS, Han CJ, Lee DH. Clinical result of stereotactic radiosurgery for spinal metastasis from hepatocellular carcinoma: comparison with conventional radiation therapy. J Neurooncol 2014; 119( 1): 141– 148

[53] Kim T, Cha HJ, Kim JW, Seong J, Lee IJ. High dose and compartmental target volume may improve patient outcome after radiotherapy for pelvic bone metastases from hepatocellular carcinoma. Oncotarget 2016; 7( 33): 53921– 53929

[54] Lee MH, Lee SH, Kim ES, Eoh W, Chung SS, Lee CS. Survival-related factors of spinal metastasis with hepatocellular carcinoma in current surgical treatment modalities: a single institute experience. J Korean Neurosurg Soc 2015; 58( 5): 448– 453

[55] He J, Shi S, Ye L, Ma G, Pan X, Huang Y, Zeng Z. A randomized trial of conventional fraction versus hypofraction radiotherapy for bone metastases from hepatocellular carcinoma. J Cancer 2019; 10( 17): 4031– 4037

[56] Lu Y, Hu JG, Lin XJ, Li XG. Bone metastases from hepatocellular carcinoma: clinical features and prognostic factors. Hepatobiliary Pancreat Dis Int 2017; 16( 5): 499– 505

[57] Rim CH, Choi C, Choi J, Seong J. Establishment of a disease-specific graded prognostic assessment for hepatocellular carcinoma patients with spinal metastasis. Gut Liver 2017; 11( 4): 535– 542

[58] Kim S, Choi Y, Kwak DW, Lee HS, Hur WJ, Baek YH, Lee SW. Prognostic factors in hepatocellular carcinoma patients with bone metastases. Radiat Oncol J 2019; 37( 3): 207– 214

[59] Gwilliam B, Keeley V, Todd C, Roberts C, Gittins M, Kelly L, Barclay S, Stone P. Prognosticating in patients with advanced cancer—observational study comparing the accuracy of clinicians’ and patients’ estimates of survival. Ann Oncol 2013; 24( 2): 482– 488

[60] Kubota H, Soejima T, Sulaiman NS, Sekii S, Matsumoto Y, Ota Y, Tsujino K, Fujita I, Fujimoto T, Morishita M, Ikegaki J, Matsumoto K, Sasaki R. Predicting the survival of patients with bone metastases treated with radiation therapy: a validation study of the Katagiri scoring system. Radiat Oncol 2019; 14( 1): 13

[61] Bartels RH, Feuth T, van der Maazen R, Verbeek AL, Kappelle AC, André Grotenhuis J, Leer JW. Development of a model with which to predict the life expectancy of patients with spinal epidural metastasis. Cancer 2007; 110( 9): 2042– 2049

[62] van der Linden YM, Dijkstra SP, Vonk EJ, Marijnen CA, Leer JW; Dutch Bone Metastasis Study Group. Prediction of survival in patients with metastases in the spinal column: results based on a randomized trial of radiotherapy. Cancer 2005; 103( 2): 320– 328

[63] Bollen L, van der Linden YM, Pondaag W, Fiocco M, Pattynama BP, Marijnen CA, Nelissen RG, Peul WC, Dijkstra PD. Prognostic factors associated with survival in patients with symptomatic spinal bone metastases: a retrospective cohort study of 1,043 patients. Neuro-oncol 2014; 16( 7): 991– 998

[64] Hayashi S, Tanaka H, Hoshi H. Palliative external-beam radiotherapy for bone metastases from hepatocellular carcinoma. World J Hepatol 2014; 6( 12): 923– 929

[65] Rutter CE, Yu JB, Wilson LD, Park HS. Assessment of national practice for palliative radiation therapy for bone metastases suggests marked underutilization of single-fraction regimens in the United States. Int J Radiat Oncol Biol Phys 2015; 91( 3): 548– 555

[66] Jung IH, Yoon SM, Kwak J, Park JH, Song SY, Lee SW, Ahn SD, Choi EK, Kim JH. High-dose radiotherapy is associated with better local control of bone metastasis from hepatocellular carcinoma. Oncotarget 2017; 8( 9): 15182– 15192

[67] Choi J, Lee EJ, Yang SH, Im YR, Seong J. A prospective phase II study for the efficacy of radiotherapy in combination with zoledronic acid in treating painful bone metastases from gastrointestinal cancers. J Radiat Res (Tokyo) 2019; 60( 2): 242– 248

[68] Uemura A, Fujimoto H, Yasuda S, Osaka I, Goto N, Shinozaki M, Ito H. Transcatheter arterial embolization for bone metastases from hepatocellular carcinoma. Eur Radiol 2001; 11( 8): 1457– 1462

[69] Barbosa JS, Almeida Paz FA, Braga SS. Bisphosphonates, old friends of bones and new trends in clinics. J Med Chem 2021; 64( 3): 1260– 1282

[70] Honda Y, Takahashi S, Zhang Y, Ono A, Murakami E, Shi N, Kawaoka T, Miki D, Tsuge M, Hiraga N, Abe H, Ochi H, Imamura M, Aikata H, Chayama K. Effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway. J Gastroenterol Hepatol 2015; 30( 3): 619– 627

[71] Montella L, Addeo R, Palmieri G, Caraglia M, Cennamo G, Vincenzi B, Guarrasi R, Mamone R, Faiola V, Frega N, Capasso E, Maiorino L, Leopardo D, Pizza C, Montesarchio V, Del Prete S. Zoledronic acid in the treatment of bone metastases by hepatocellular carcinoma: a case series. Cancer Chemother Pharmacol 2010; 65( 6): 1137– 1143

[72] 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. 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

[73] Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C. 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

[74] Lipton A, Siena S, Rader M, Bilynskyy B, Viniegra M, Richardson G, Beuzeboc P, Clemens M, Ke C, Jun S. 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; 21 : 380

[75] Body JJ, Lipton A, Gralow J, Steger GG, Gao G, Yeh H, Fizazi K. Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure. J Bone Miner Res 2010; 25( 3): 440– 446

[76] Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A, Brown S; American Society of Clinical Oncology. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003; 21( 21): 4042– 4057

[77] Coleman RE, Major P, Lipton A, Brown JE, Lee KA, Smith M, Saad F, Zheng M, Hei YJ, Seaman J, Cook R. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 2005; 23( 22): 4925– 4935

[78] Su GL, Altayar O, O’Shea R, Shah R, Estfan B, Wenzell C, Sultan S, Falck-Ytter Y. AGA Clinical Practice Guideline on Systemic Therapy for Hepatocellular Carcinoma. Gastroenterology 2022; 162( 3): 920– 934

[79] Du J, Qian X, Liu B. Long-term progression-free survival in a case of hepatocellular carcinoma with vertebral metastasis treated with a reduced dose of sorafenib: case report and review of the literature. Oncol Lett 2013; 5( 1): 381– 385

[80] Harding JJ, Abou-Alfa GK. Treating advanced hepatocellular carcinoma: how to get out of first gear. Cancer 2014; 120( 20): 3122– 3130

[81] Zhang D, Xu W, Liu T, Yin H, Yang X, Wu Z, Xiao J. Surgery and prognostic factors of patients with epidural spinal cord compression caused by hepatocellular carcinoma metastases: retrospective study of 36 patients in a single center. Spine 2013; 38( 17): E1090– E1095

[82] Cho HS, Oh JH, Han I, Kim HS. Survival of patients with skeletal metastases from hepatocellular carcinoma after surgical management. J Bone Joint Surg Br 2009; 91( 11): 1505– 1512

[83] van der Linden E, Kroft LJ, Dijkstra PD. Treatment of vertebral tumor with posterior wall defect using image-guided radiofrequency ablation combined with vertebroplasty: preliminary results in 12 patients. J Vasc Interv Radiol 2007; 18( 6): 741– 747

[84] Zheng L, Chen Z, Sun M, Zeng H, Zuo D, Hua Y, Cai Z. A preliminary study of the safety and efficacy of radiofrequency ablation with percutaneous kyphoplasty for thoracolumbar vertebral metastatic tumor treatment. Med Sci Monit 2014; 20 : 556– 563

[85] Miyachi Y, Kaido T, Yao S, Shirai H, Kobayashi A, Hamaguchi Y, Kamo N, Yagi S, Uemoto S. Bone mineral density as a risk factor for patients undergoing surgery for hepatocellular carcinoma. World J Surg 2019; 43( 3): 920– 928

[86] Facchini G, Di Tullio P, Battaglia M, Bartalena T, Tetta C, Errani C, Mavrogenis AF, Rossi G. Palliative embolization for metastases of the spine. Eur J Orthop Surg Traumatol 2016; 26( 3): 247– 252

[87] Kim W, Han I, Jae HJ, Kang S, Lee SA, Kim JS, Kim HS. Preoperative embolization for bone metastasis from hepatocellular carcinoma. Orthopedics 2015; 38( 2): e99– e105

[88] Ma J, Tullius T, Van Ha TG. Update on preoperative embolization of bone metastases. Semin Intervent Radiol 2019; 36( 3): 241– 248

[89] Sakaguchi M, Maebayashi T, Aizawa T, Ishibashi N, Fukushima S, Saito T. Radiation therapy and palliative care prolongs the survival of hepatocellular carcinoma patients with bone metastases. Intern Med 2016; 55( 9): 1077– 1083

[90] Obenauf AC, Massagué J. Surviving at a distance: organ-specific metastasis. Trends Cancer 2015; 1( 1): 76– 91

[91] Satcher RL, Zhang XH. Evolving cancer-niche interactions and therapeutic targets during bone metastasis. Nat Rev Cancer 2022; 22( 2): 85– 101

[92] Wang H, Zhang W, Bado I, Zhang XH. Bone tropism in cancer metastases. Cold Spring Harb Perspect Med 2020; 10( 10): a036848

[93] Wang M, Xia F, Wei Y, Wei X. Molecular mechanisms and clinical management of cancer bone metastasis. Bone Res 2020; 8( 1): 30

[94] Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer 2011; 11( 6): 411– 425

[95] Clézardin P, Coleman R, Puppo M, Ottewell P, Bonnelye E, Paycha F, Confavreux CB, Holen I. Bone metastasis: mechanisms, therapies, and biomarkers. Physiol Rev 2021; 101( 3): 797– 855

[96] Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK. EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol 2020; 30( 10): 764– 776

[97] Mohme M, Riethdorf S, Pantel K. Circulating and disseminated tumour cells—mechanisms of immune surveillance and escape. Nat Rev Clin Oncol 2017; 14( 3): 155– 167

[98] Fidler IJ, Nicolson GL. Fate of recirculating B16 melanoma metastatic variant cells in parabiotic syngeneic recipients. J Natl Cancer Inst 1977; 58( 6): 1867– 1872

[99] Liotta LA, Vembu D, Saini RK, Boone C. In vivo monitoring of the death rate of artificial murine pulmonary micrometastases. Cancer Res 1978; 38( 5): 1231– 1236

[100] Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with ¹²⁵I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst 1970; 45( 4): 773– 782

[101] Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massagué J. Tumor self-seeding by circulating cancer cells. Cell 2009; 139( 7): 1315– 1326

[102] Zhang W, Bado IL, Hu J, Wan YW, Wu L, Wang H, Gao Y, Jeong HH, Xu Z, Hao X, Lege BM, Al-Ouran R, Li L, Li J, Yu L, Singh S, Lo HC, Niu M, Liu J, Jiang W, Li Y, Wong STC, Cheng C, Liu Z, Zhang XH. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell 2021; 184( 9): 2471– 2486.e20

[103] Mukai R, Tomimaru Y, Nagano H, Eguchi H, Mimori K, Tomokuni A, Asaoka T, Wada H, Kawamoto K, Marubashi S, Doki Y, Mori M. miR-615-3p expression level in bone marrow is associated with tumor recurrence in hepatocellular carcinoma. Mol Clin Oncol 2015; 3( 3): 487– 494

[104] Sugimachi K, Sakimura S, Tomokuni A, Uchi R, Hirata H, Komatsu H, Shinden Y, Iguchi T, Eguchi H, Masuda T, Morita K, Shirabe K, Eguchi H, Maehara Y, Mori M, Mimori K. Identification of recurrence-related microRNAs from bone marrow in hepatocellular carcinoma patients. J Clin Med 2015; 4( 8): 1600– 1611

[105] Deng L, Wang C, He C, Chen L. Bone mesenchymal stem cells derived extracellular vesicles promote TRAIL-related apoptosis of hepatocellular carcinoma cells via the delivery of microRNA-20a-3p. Cancer Biomark 2021; 30( 2): 223– 235

[106] Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, Smid M, Foekens JA, Massagué J. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 2013; 154( 5): 1060– 1073

[107] Hemingway F, Taylor R, Knowles HJ, Athanasou NA. RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF I and IGF II. Bone 2011; 48( 4): 938– 944

[108] Andrade K, Fornetti J, Zhao L, Miller SC, Randall RL, Anderson N, Waltz SE, McHale M, Welm AL. RON kinase: a target for treatment of cancer-induced bone destruction and osteoporosis. Sci Transl Med 2017; 9( 374): eaai9338

[109] D’Amico L, Roato I. The impact of immune system in regulating bone metastasis formation by osteotropic tumors. J Immunol Res 2015; 2015 : 143526

[110] Muscarella AM, Aguirre S, Hao X, Waldvogel SM, Zhang XH. Exploiting bone niches: progression of disseminated tumor cells to metastasis. J Clin Invest 2021; 131( 6): e143764

[111] Wu J, Lanier LL. Natural killer cells and cancer. Adv Cancer Res 2003; 90 : 127– 156

[112] Okamoto T, Yoneyama MS, Hatakeyama S, Mori K, Yamamoto H, Koie T, Saitoh H, Yamaya K, Funyu T, Fukuda M, Ohyama C, Tsuboi S. Core2 O-glycan-expressing prostate cancer cells are resistant to NK cell immunity. Mol Med Rep 2013; 7( 2): 359– 364

[113] Lo CH, Lynch CC. Multifaceted roles for macrophages in prostate cancer skeletal metastasis. Front Endocrinol (Lausanne) 2018; 9 : 247

[114] Soki FN, Cho SW, Kim YW, Jones JD, Park SI, Koh AJ, Entezami P, Daignault-Newton S, Pienta KJ, Roca H, McCauley LK. Bone marrow macrophages support prostate cancer growth in bone. Oncotarget 2015; 6( 34): 35782– 35796

[115] Lu X, Kang Y. Chemokine (C-C motif) ligand 2 engages CCR2⁺ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J Biol Chem 2009; 284( 42): 29087– 29096

[116] Zhao E, Wang L, Dai J, Kryczek I, Wei S, Vatan L, Altuwaijri S, Sparwasser T, Wang G, Keller ET, Zou W. Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer. OncoImmunology 2012; 1( 2): 152– 161

[117] Yoldi G, Pellegrini P, Trinidad EM, Cordero A, Gomez-Miragaya J, Serra-Musach J, Dougall WC, Muñoz P, Pujana MA, Planelles L, González-Suárez E. RANK signaling blockade reduces breast cancer recurrence by inducing tumor cell differentiation. Cancer Res 2016; 76( 19): 5857– 5869

[118] Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 2011; 470( 7335): 548– 553

[119] Ahern E, Smyth MJ, Dougall WC, Teng MWL. Roles of the RANKL-RANK axis in antitumour immunity—implications for therapy. Nat Rev Clin Oncol 2018; 15( 11): 676– 693

[120] Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, Kim JK, Patel LR, Ying C, Ziegler AM, Pienta MJ, Song J, Wang J, Loberg RD, Krebsbach PH, Pienta KJ, Taichman RS. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest 2011; 121( 4): 1298– 1312

[121] Okamoto K, Takayanagi H. Regulation of bone by the adaptive immune system in arthritis. Arthritis Res Ther 2011; 13( 3): 219

[122] Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015; 523( 7559): 221– 225

[123] Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001; 166( 1): 678– 689

[124] Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016; 7( 1): 12150

[125] Shurin MR, Naiditch H, Zhong H, Shurin GV. Regulatory dendritic cells: new targets for cancer immunotherapy. Cancer Biol Ther 2011; 11( 11): 988– 992

[126] Capietto AH, Faccio R. Immune regulation of bone metastasis. Bonekey Rep 2014; 3 : 600

[127] Sawant A, Hensel JA, Chanda D, Harris BA, Siegal GP, Maheshwari A, Ponnazhagan S. Depletion of plasmacytoid dendritic cells inhibits tumor growth and prevents bone metastasis of breast cancer cells. J Immunol 2012; 189( 9): 4258– 4265

[128] Esen E, Long F. Aerobic glycolysis in osteoblasts. Curr Osteoporos Rep 2014; 12( 4): 433– 438

[129] Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA 2010; 107( 5): 2037– 2042

[130] Park S, Chang CY, Safi R, Liu X, Baldi R, Jasper JS, Anderson GR, Liu T, Rathmell JC, Dewhirst MW, Wood KC, Locasale JW, McDonnell DP. ERRα-regulated lactate metabolism contributes to resistance to targeted therapies in breast cancer. Cell Rep 2016; 15( 2): 323– 335

[131] Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 2017; 25( 6): 1282– 1293.e7

[132] Ell B, Kang Y. SnapShot: bone metastasis. Cell 2012; 151( 3): 690– 690.e1

[133] Huang Z, Chu L, Liang J, Tan X, Wang Y, Wen J, Chen J, Wu Y, Liu S, Liao J, Hou R, Ding Z, Zhang Z, Liang H, Song S, Yang C, Zhang J, Guo T, Chen X, Zhang B. H19 promotes HCC bone metastasis through reducing osteoprotegerin expression in a protein phosphatase 1 catalytic subunit alpha/p38 mitogen-activated protein kinase-dependent manner and sponging microRNA 200b-3p. Hepatology. 2021; 74( 1): 214– 232

[134] Zhang S, Xu Y, Xie C, Ren L, Wu G, Yang M, Wu X, Tang M, Hu Y, Li Z, Yu R, Liao X, Mo S, Wu J, Li M, Song E, Qi Y, Song L, Li J. RNF219/α-catenin/LGALS3 axis promotes hepatocellular carcinoma bone metastasis and associated skeletal complications. Adv Sci (Weinh) 2021; 8( 4): 2001961

[135] Zhang L, Niu H, Ma J, Yuan BY, Chen YH, Zhuang Y, Chen GW, Zeng ZC, Xiang ZL. The molecular mechanism of lncRNA34a-mediated regulation of bone metastasis in hepatocellular carcinoma. Mol Cancer 2019; 18( 1): 120

[136] Huang J, Hu W, Lin X, Wang X, Jin K. FRZB up-regulated in hepatocellular carcinoma bone metastasis. Int J Clin Exp Pathol 2015; 8( 10): 13353– 13359

[137] Xiang ZL, Zeng ZC, Tang ZY, Fan J, He J, Zeng HY, Zhu XD. Potential prognostic biomarkers for bone metastasis from hepatocellular carcinoma. Oncologist 2011; 16( 7): 1028– 1039

[138] Jin K, Lan H, Wang X, Lv J. Genetic heterogeneity in hepatocellular carcinoma and paired bone metastasis revealed by next-generation sequencing. Int J Clin Exp Pathol 2017; 10( 10): 10495– 10504

[139] Xiang ZL, Zeng ZC, Fan J, Wu WZ, He J, Zeng HY, Tang ZY. A clinicopathological model to predict bone metastasis in hepatocellular carcinoma. J Cancer Res Clin Oncol 2011; 137( 12): 1791– 1797

[140] Hou R, Wang YW, Liang HF, Zhang ZG, Liu ZM, Zhang BH, Zhang BX, Chen XP. Animal and cellular models of hepatocellular carcinoma bone metastasis: establishment and characterisation. J Cancer Res Clin Oncol 2015; 141( 11): 1931– 1943

[141] Xiang ZL, Zeng ZC, Tang ZY, Fan J, Zhuang PY, Liang Y, Tan YS, He J. Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival. BMC Cancer 2009; 9( 1): 176

[142] Wang X, Lan H, Shen T, Gu P, Guo F, Lin X, Jin K. Perineural invasion: a potential reason of hepatocellular carcinoma bone metastasis. Int J Clin Exp Med 2015; 8( 4): 5839– 5846

[143] Xiang ZL, Zhao XM, Zhang L, Yang P, Fan J, Tang ZY, Zeng ZC. MicroRNA-34a expression levels in serum and intratumoral tissue can predict bone metastasis in patients with hepatocellular carcinoma. Oncotarget 2016; 7( 52): 87246– 87256

[144] Zhang L, Niu H, Yang P, Ma J, Yuan BY, Zeng ZC, Xiang ZL. Serum lnc34a is a potential prediction biomarker for bone metastasis in hepatocellular carcinoma patients. BMC Cancer 2021; 21( 1): 161

[145] Ma ZJ, Wang Y, Li HF, Liu MH, Bi FR, Ma L, Ma H, Yan HL. LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis. J Cancer 2020; 11( 17): 5118– 5128

[146] Liu J, Chen S, Wang W, Ning BF, Chen F, Shen W, Ding J, Chen W, Xie WF, Zhang X. Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-β pathways. Cancer Lett 2016; 379( 1): 49– 59

[147] Sun C, Hu A, Wang S, Tian B, Jiang L, Liang Y, Wang H, Dong J. ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells promotes spinal metastasis from hepatocellular carcinoma. Int J Oncol 2020; 57( 1): 249– 263

[148] Campbell JP, Merkel AR, Masood-Campbell SK, Elefteriou F, Sterling JA. Models of bone metastasis. J Vis Exp 2012; ( 67): e4260

[149] Shevrin DH, Kukreja SC, Ghosh L, Lad TE. Development of skeletal metastasis by human prostate cancer in athymic nude mice. Clin Exp Metastasis 1988; 6( 5): 401– 409

[150] Li M, Zhou M, Gong M, Ma J, Pei F, Beamer WG, Shultz LD, Hock JM, Yu X. A novel animal model for bone metastasis in human lung cancer. Oncol Lett 2012; 3( 4): 802– 806

[151] Tian Z, Wu L, Yu C, Chen Y, Xu Z, Bado I, Loredo A, Wang L, Wang H, Wu KL, Zhang W, Zhang XH, Xiao H. Harnessing the power of antibodies to fight bone metastasis. Sci Adv 2021; 7( 26): eabf2051

[152] Yu C, Wang H, Muscarella A, Goldstein A, Zeng HC, Bae Y, Lee BH, Zhang XH. Intra-iliac artery injection for efficient and selective modeling of microscopic bone metastasis. J Vis Exp 2016; ( 115): e53982

[153] Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordón-Cardo C, Guise TA, Massagué J. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003; 3( 6): 537– 549

[154] Lelekakis M, Moseley JM, Martin TJ, Hards D, Williams E, Ho P, Lowen D, Javni J, Miller FR, Slavin J, Anderson RL. A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis 1999; 17( 2): 163– 170

[155] Broutier L, Mastrogiovanni G, Verstegen MM, Francies HE, Gavarró LM, Bradshaw CR, Allen GE, Arnes-Benito R, Sidorova O, Gaspersz MP, Georgakopoulos N, Koo BK, Dietmann S, Davies SE, Praseedom RK, Lieshout R, IJzermans JNM, Wigmore SJ, Saeb-Parsy K, Garnett MJ, van der Laan LJ, Huch M. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat Med 2017; 23( 12): 1424– 1435

[156] Lee S, Burner DN, Mendoza TR, Muldong MT, Arreola C, Wu CN, Cacalano NA, Kulidjian AA, Kane CJ, Jamieson CAM. Establishment and analysis of three-dimensional (3D) organoids derived from patient prostate cancer bone metastasis specimens and their xenografts. J Vis Exp 2020; ( 156): e60367

[157] Nemeth JA, Harb JF, Barroso U Jr, He Z, Grignon DJ, Cher ML. Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. Cancer Res 1999; 59( 8): 1987– 1993

[158] Kuperwasser C, Dessain S, Bierbaum BE, Garnet D, Sperandio K, Gauvin GP, Naber SP, Weinberg RA, Rosenblatt M. A mouse model of human breast cancer metastasis to human bone. Cancer Res 2005; 65( 14): 6130– 6138

[159] Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 2012; 12( 11): 786– 798

[160] Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol 2007; 7( 2): 118– 130

[161] Li YH, Lv MF, Lu MS, Bi JP. Bone marrow mesenchymal stem cell-derived exosomal miR-338-3p represses progression of hepatocellular carcinoma by targeting ETS1. J Biol Regul Homeost Agents 2021; 35( 2): 617– 627

[162] Baccin C, Al-Sabah J, Velten L, Helbling PM, Grünschläger F, Hernández-Malmierca P, Nombela-Arrieta C, Steinmetz LM, Trumpp A, Haas S. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat Cell Biol 2020; 22( 1): 38– 48

[163] Adjei IM, Sharma B, Peetla C, Labhasetwar V. Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer. J Control Release 2016; 232 : 83– 92

[164] Mu CF, Shen J, Liang J, Zheng HS, Xiong Y, Wei YH, Li F. Targeted drug delivery for tumor therapy inside the bone marrow. Biomaterials 2018; 155 : 191– 202

[165] Mbese Z, Aderibigbe BA. Bisphosphonate-based conjugates and derivatives as potential therapeutic agents in osteoporosis, bone cancer and metastatic bone cancer. Int J Mol Sci 2021; 22( 13): 6869

[166] Sun W, Ge K, Jin Y, Han Y, Zhang H, Zhou G, Yang X, Liu D, Liu H, Liang XJ, Zhang J. Bone-targeted nanoplatform combining zoledronate and photothermal therapy to treat breast cancer bone metastasis. ACS Nano 2019; 13( 7): 7556– 7567

[167] Herrmann IK, Wood MJA, Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol 2021; 16( 7): 748– 759

[168] Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJ, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D. Tumour exosome integrins determine organotropic metastasis. Nature 2015; 527( 7578): 329– 335

Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 81372327, 81572427, and 81874189); the State Key Project on Infection Disease of China (No. 2018ZX10723204-003-003); the National Key Research and Development Program of China (No. 2018YFA0208904); the Major Technological Innovation Projects of Hubei Province (No. 2018ACA137); the Fundamental Research Funds for the Central Universities, HUST (No. 5001540059).

Compliance with ethics guidelines

Zhao Huang, Jingyuan Wen, Yufei Wang, Shenqi Han, Zhen Li, Xuemei Hu, Dongling Zhu, Zhenxiong Wang, Junnan Liang, Huifang Liang, Xiao-ping Chen, and Bixiang Zhang declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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