Research progress in bone metastasis from hepatocellular carcinoma

doi:10.3877/cma.j.issn.2095-3232.2025.04.004

Abstract

Abstract:

The incidence of hepatocellular carcinoma (HCC) is high in China. The early diagnostic rate of bone metastasis from HCC is low, and clinical prognosis is poor. At present, no definite treatment consensus has been reached, which is one of the difficulties to be resolved for metastatic HCC. The pathogenesis of bone metastasis from HCC remains elusive, which is probably associated with exosomes, epithelial-mesenchymal transition (EMT) and bone microenvironment. Radiotherapy, local surgical resection and other treatments for metastatic lesions can prolong the survival time of patients. However, systematic treatment is still the main therapy for bone metastasis from HCC. Based on systematic treatments, individualized treatments for patients can improve the quality of life and prolong the survival time. In this article, clinical characteristics, mechanism of metastasis and treatment progress of bone metastasis from HCC were illustrated, aiming to provide evidence for clinical work.

Key words: Carcinoma, hepatocellular, Bone metastasis, Exosome, Eepithelial-mesenchymal transition, Radiotherapy, Systematic therapy

Chen Lo, Pengcheng Wei, Xin Sun, Zhao Li. Research progress in bone metastasis from hepatocellular carcinoma[J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2025, 14(04): 522-527.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhgzwkssxdzzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-3232.2025.04.004

https://zhgzwkssxdzzz.cma-cmc.com.cn/EN/Y2025/V14/I04/522

References 36

[1]	中华人民共和国国家卫生健康委员会医政司.原发性肝癌诊疗指南(2024年版)[J/OL].中华肝脏外科手术学电子杂志, 2024, 13(4): 407-449. DOI: 10.3877/cma.j.issn.2095-3232.2024.04.001.
[2]	Bhatia R, Ravulapati S, Befeler A, et al. Hepatocellular carcinoma with bone metastases: incidence, prognostic significance, and management-single-center experience[J]. J Gastrointest Cancer, 2017, 48(4): 321-325. DOI: 10.1007/s12029-017-9998-6.
[3]	Harding JJ, Abu-Zeinah G, Chou JF, et al. Frequency, morbidity, and mortality of bone metastases in advanced hepatocellular carcinoma[J]. J Natl Compr Canc Netw, 2018, 16(1): 50-58. DOI: 10.6004/jnccn.2017.7024.
[4]	Guo X, Xu Y, Wang X, et al. Advanced hepatocellular carcinoma with bone metastases: prevalence, associated factors, and survival estimation[J]. Med Sci Monit, 2019, 25: 1105-1112. DOI: 10.12659/MSM.913470.
[5]	Yuan X, Zhuang M, Zhu X, et al. Emerging perspectives of bone metastasis in hepatocellular carcinoma[J]. Front Oncol, 2022, 12: 943866. DOI: 10.3389/fonc.2022.943866.
[6]	Clézardin P, Coleman R, Puppo M, et al. Bone metastasis: mechanisms, therapies, and biomarkers[J]. Physiol Rev, 2021, 101(3): 797-855. DOI: 10.1152/physrev.00012.2019.
[7]	Lu Y, Hu JG, Lin XJ, et al. Bone metastases from hepatocellular carcinoma: clinical features and prognostic factors[J]. Hepatobiliary Pancreat Dis Int, 2017, 16(5): 499-505. DOI: 10.1016/S1499-3872(16)60173-X.
[8]	Fang JH, Zhang ZJ, Shang LR, et al. Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins[J]. Hepatology, 2018, 68(4): 1459-1475. DOI: 10.1002/hep.29920.
[9]	Zhou Y, Ren H, Dai B, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts[J]. J Exp Clin Cancer Res, 2018, 37(1): 324. DOI: 10.1186/s13046-018-0965-2.
[10]	Giannelli G, Koudelkova P, Dituri F, et al. Role of epithelial to mesenchymal transition in hepatocellular carcinoma[J]. J Hepatol, 2016, 65(4): 798-808. DOI: 10.1016/j.jhep.2016.05.007.
[11]	Zhou P, Liu Y, Wu G, et al. LincRNA PRNCR1 activates the Wnt/β-catenin pathway to drive the deterioration of hepatocellular carcinoma via regulating miR-411-3p/ZEB1 axis[J]. Biotechnol Genet Eng Rev, 2024, 40(4): 4809-4824. DOI: 10.1080/02648725.2023.2216966.
[12]	Ning J, Ye Y, Bu D, et al. Imbalance of TGF-β1/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness[J]. Mol Ther, 2021, 29(6): 2067-2087. DOI: 10.1016/j.ymthe.2021.02.016.
[13]	Man J, Zhou W, Zuo S, et al. TANGO1 interacts with NRTN to promote hepatocellular carcinoma progression by regulating the PI3K/AKT/mTOR signaling pathway[J]. Biochem Pharmacol, 2023, 213: 115615. DOI: 10.1016/j.bcp.2023.115615.
[14]	党东民, 董栋, 罗小虎, 等. 骨组织微环境PTEN和AKT状态与肝癌骨转移预后的相关性研究[J]. 中华转移性肿瘤杂志, 2018, 1(2): 46-51. DOI:10.3760/cma.j.issn.2096-5400.2018.02.010.
[15]	Zhang L, Niu H, Ma J, et al. The molecular mechanism of LncRNA34a-mediated regulation of bone metastasis in hepatocellular carcinoma[J]. Mol Cancer, 2019, 18(1): 120. DOI: 10.1186/s12943-019-1044-9.
[16]	Ono T, Hayashi M, Sasaki F, et al. RANKL biology: bone metabolism, the immune system, and beyond[J]. Inflamm Regen, 2020, 40: 2. DOI: 10.1186/s41232-019-0111-3.
[17]	Sasaki A, Ishikawa K, Haraguchi N, et al. Receptor activator of nuclear factor-κB ligand (RANKL) expression in hepatocellular carcinoma with bone metastasis[J]. Ann Surg Oncol, 2007, 14(3): 1191-1199. DOI: 10.1245/s10434-006-9277-4.
[18]	Jin J, Chung JO, Chung MY, et al. Clinical characteristics, causes and survival in 115 cancer patients with parathyroid hormone related protein-mediated hypercalcemia[J]. J Bone Metab, 2017, 24(4): 249-255. DOI: 10.11005/jbm.2017.24.4.249.
[19]	Kim JM, Jeong D, Kang HK, et al. Osteoclast precursors display dynamic metabolic shifts toward accelerated glucose metabolism at an early stage of RANKL-stimulated osteoclast differentiation[J]. Cell Physiol Biochem, 2007, 20(6): 935-946. DOI: 10.1159/000110454.
[20]	Tiedemann K, Hussein O, Komarova SV. Role of altered metabolic microenvironment in osteolytic metastasis[J]. Front Cell Dev Biol, 2020, 8: 435. DOI: 10.3389/fcell.2020.00435.
[21]	Kezic A, Popovic L, Lalic K. mTOR inhibitor therapy and metabolic consequences: where do we stand?[J]. Oxid Med Cell Longev, 2018, 2018: 2640342. DOI: 10.1155/2018/2640342.
[22]	Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging[J]. CA Cancer J Clin, 2017, 67(2): 93-99. DOI: 10.3322/caac.21388.
[23]	Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update[J]. J Hepatol, 2022, 76(3): 681-693. DOI: 10.1016/j.jhep.2021.11.018.
[24]	Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382(20): 1894-1905. DOI: 10.1056/NEJMoa1915745.
[25]	Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study[J]. Lancet Oncol, 2021, 22(7): 977-990. DOI: 10.1016/S1470-2045(21)00252-7.
[26]	Long X, Zhang L, Wang WQ, et al. Response of scalp and skull metastasis to anti-PD-1 antibody combined with regorafenib treatment in a sorafenib-resistant hepatocellular carcinoma patient and a literature review[J]. Onco Targets Ther, 2022, 15: 703-716. DOI: 10.2147/OTT.S365652.
[27]	Saâda-Bouzid E, Defaucheux C, Karabajakian A, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma[J]. Ann Oncol, 2017, 28(7): 1605-1611. DOI: 10.1093/annonc/mdx178.
[28]	Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade[J]. N Engl J Med, 2018, 378(2): 158-168. DOI: 10.1056/NEJMra1703481.
[29]	Llovet JM, Kudo M, Cheng AL, et al. Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): phase 3 LEAP-002 study[J]. J Clin Oncol, 2019, 37(15_suppl): TPS4152. DOI: 10.1200/jco.2019.37.15_suppl.tps4152.
[30]	Kelley RK, Greten TF. Hepatocellular carcinoma - origins and outcomes[J]. N Engl J Med, 2021, 385(3): 280-282. DOI: 10.1056/NEJMcibr2106594.
[31]	Southcott D, Awan A, Ghate K, et al. Practical update for the use of bone-targeted agents in patients with bone metastases from metastatic breast cancer or castration-resistant prostate cancer[J]. Curr Oncol, 2020, 27(4): 220-224. DOI: 10.3747/co.27.6631.
[32]	Mao K, Yan Y, Zhang J, et al. The impact of liver resection on survival outcomes of hepatocellular carcinoma patients with extrahepatic metastases: a propensity score matching study[J]. Cancer Med, 2018, 7(9): 4475-4484. DOI: 10.1002/cam4.1738.
[33]	Lee JI, Kim JK, Kim DY, et al. Prognosis of hepatocellular carcinoma patients with extrahepatic metastasis and the controllability of intrahepatic lesions[J]. Clin Exp Metastasis, 2014, 31(4): 475-482. DOI: 10.1007/s10585-014-9641-x.
[34]	李照, 高杰, 孙馨, 等. 肝癌肝移植术后骨转移患者的手术治疗[J]. 中华普通外科杂志, 2013, 28(3): 193-195. DOI: 10.3760/cma.j.issn.1007-631X.2013.03.008.
[35]	Elazab S, Elkalla H, Zahi M. Palliative radiotherapy to asymptomatic bone metastasis: is it beneficial or not? Single institution experience[J]. Middle East J Cancer, 2021, 12(3): 422-428. DOI: 10.30476/mejc.2021.84106.1201.
[36]	Chen L, Wang Z, Song S, et al. The efficacy of radiotherapy in the treatment of hepatocellular carcinoma with distant organ metastasis[J]. J Oncol, 2021, 2021: 5190611. DOI: 10.1155/2021/5190611.

Please choose a citation manager

Content to export