Skip to content
2000
image of Liver Cancer Bone Metastasis: Molecular Mechanisms and Therapeutic Insights

Abstract

Liver cancer is a highly aggressive malignancy, and bone metastasis is a severe complication that negatively affects prognosis and quality of life. However, the molecular mechanisms underlying liver cancer bone metastasis remain poorly understood. This review examined recent advances related to epithelial–mesenchymal transition (EMT), circulating tumor cells (CTCs), and liver cancer stem cells (LCSCs), with a focus on surface markers, interactions within bone marrow (BM) niche, and relevant signaling pathways. Liver cancer bone metastasis is driven by EMT activation, CTC dissemination, and LCSC colonization in BM niches. Surface markers such as CD133, CD44, CD90, CD13, EpCAM, and OV6 contribute to tumor heterogeneity, dormancy, and therapy resistance. Key processes such as BM homing, osteolysis, and immune labelpression are regulated through the osteoblast–osteoclast–cancer stem cell (OB–OC–CSC) axis and CXCL12–CXCR4 signaling. Dormancy-regulating molecules, including Annexin II, GAS6, osteopontin, TSP-1, tenascin C, and fibronectin, further determine CSCs' quiescence or reactivation. These insights highlighted the complexity of liver cancer bone metastasis, and suggested potential therapeutic strategies targeting EMT, LCSCs, and OB–OC–CSC crosstalk. Future studies are encouraged to validate marker functions in clinical cohorts, elucidate dormancy-exit mechanisms, and explore immunomodulatory interventions to overcome microenvironment-mediated resistance.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ctmc/10.2174/0115680266430839251017113122
2025-11-04
2025-12-16

  • From This Site

    /content/journals/ctmc/10.2174/0115680266430839251017113122
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Anwanwan D. Singh S.K. Singh S. Saikam V. Singh R. Challenges in liver cancer and possible treatment approaches. Biochim. Biophys. Acta Rev. Cancer 2020 1873 1 188314 10.1016/j.bbcan.2019.188314 31682895
    [Google Scholar]
  2. Yu S. Lv H. Zhang J. Zhang H. Ju W. Jiang Y. Lin L. Heparanase/Syndecan-1 axis regulates the grade of liver cancer and proliferative ability of hepatocellular carcinoma cells. Oncologie 2022 24 3 539 551 10.32604/oncologie.2022.024882
    [Google Scholar]
  3. Ye W. Wang J. Zheng J. Jiang M. Zhou Y. Wu Z. Association between higher expression of Vav1 in hepatocellular carcinoma and unfavourable clinicopathological features and prognosis. Protein Pept. Lett. 2024 31 9 706 713 10.2174/0109298665330781240830042601 39301900
    [Google Scholar]
  4. Paroli M. Perrone A. Bonavita M.S. Barnaba V. Immunology of hepatocellular carcinoma. Ital. J. Gastroenterol. 1991 23 8 494 497 1661196
    [Google Scholar]
  5. Gottwick C. Carambia A. Herkel J. Harnessing the liver to induce antigen-specific immune tolerance. Semin. Immunopathol. 2022 44 4 475 484 10.1007/s00281‑022‑00942‑8 35513495
    [Google Scholar]
  6. Kim E. Viatour P. Hepatocellular carcinoma: Old friends and new tricks. Exp. Mol. Med. 2020 52 12 1898 1907 10.1038/s12276‑020‑00527‑1 33268834
    [Google Scholar]
  7. Llovet J.M. Montal R. Villanueva A. Randomized trials and endpoints in advanced HCC: Role of PFS as a surrogate of survival. J. Hepatol. 2019 70 6 1262 1277 10.1016/j.jhep.2019.01.028 30943423
    [Google Scholar]
  8. Liu C. Shi J. Lin B. Zhou M. Shan D. Nie J. Wang Y. Zhang Y. Han P. Zheng T. SHR6390 combined with cabozantinib inhibits tumor progression in the hepatocellular carcinoma mouse model. Curr. Gene Ther. 2024 24 5 453 464 10.2174/1566523222666220825110147 36017825
    [Google Scholar]
  9. Chang X. Wang J. Ni, C Value of Mir-1271 and GPC3 in prognosis evaluation of liver cancer patients after liver transarterial chemoembolization. Oncologie 2021 23 1 119 130 10.32604/oncologie.2021.014152
    [Google Scholar]
  10. Hau H.M. Schmelzle M. Benzing C. Ascherl R. Tautenhahn H.M. Gäbelein G. Eichfeld U. Bartels M. Pulmonary metastasectomy for metastasized hepatocellular carcinoma after liver resection and liver transplantation: A single center experience. Z. Gastroenterol. 2016 54 1 31 39 10.1055/s‑0041‑104025 26619391
    [Google Scholar]
  11. Uka K. Aikata H. Takaki S. Shirakawa H. Jeong S.C. 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 10.3748/wjg.v13.i3.414 17230611
    [Google Scholar]
  12. Coleman R.E. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin. Cancer Res. 2006 12 20 6243s 6249s 10.1158/1078‑0432.CCR‑06‑0931 17062708
    [Google Scholar]
  13. 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 10.1007/s10555‑013‑9454‑4 24357055
    [Google Scholar]
  14. Weilbaecher K.N. Guise T.A. McCauley L.K. Cancer to bone: A fatal attraction. Nat. Rev. Cancer 2011 11 6 411 425 10.1038/nrc3055 21593787
    [Google Scholar]
  15. Crane G.M. Jeffery E. Morrison S.J. Adult haematopoietic stem cell niches. Nat. Rev. Immunol. 2017 17 9 573 590 10.1038/nri.2017.53 28604734
    [Google Scholar]
  16. Wang H. Tian L. Liu J. Goldstein A. Bado I. Zhang W. Arenkiel B.R. Li Z. Yang M. Du S. Zhao H. Rowley D.R. Wong S.T.C. Gugala Z. Zhang X.H.F. The osteogenic niche is a calcium reservoir of bone micrometastases and confers unexpected therapeutic vulnerability. Cancer Cell 2018 34 5 823 839.e7 10.1016/j.ccell.2018.10.002 30423299
    [Google Scholar]
  17. Esposito M. Mondal N. Greco T.M. Wei Y. Spadazzi C. Lin S.C. Zheng H. Cheung C. Magnani J.L. Lin S.H. Cristea I.M. Sackstein R. Kang Y. Bone vascular niche E-selectin induces mesenchymal–epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat. Cell Biol. 2019 21 5 627 639 10.1038/s41556‑019‑0309‑2 30988423
    [Google Scholar]
  18. Chaffer C.L. San Juan B.P. Lim E. Weinberg R.A. EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 2016 35 4 645 654 10.1007/s10555‑016‑9648‑7 27878502
    [Google Scholar]
  19. Harding J.J. Abu-Zeinah G. Chou J.F. Owen D.H. Ly M. Lowery M.A. Capanu M. Do R. Kemeny N.E. O’Reilly E.M. Saltz L.B. Abou-Alfa G.K. Frequency, morbidity, and mortality of bone metastases in advanced hepatocellular carcinoma. J. Natl. Compr. Canc. Netw. 2018 16 1 50 58 10.6004/jnccn.2017.7024 29295881
    [Google Scholar]
  20. Coleman R.E. Croucher P.I. Padhani A.R. Clézardin P. Chow E. Fallon M. Guise T. Colangeli S. Capanna R. Costa L. Bone metastases. Nat. Rev. Dis. Primers 2020 6 1 83 10.1038/s41572‑020‑00216‑3 33060614
    [Google Scholar]
  21. 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 10.1097/00042737‑200109000‑00015 11564960
    [Google Scholar]
  22. Santini D. Pantano F. Riccardi F. Di Costanzo G.G. Addeo R. Guida F.M. Ceruso M.S. 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 V.O. Infante G. Aieta M. Trogu A. Gadaleta C.D. Brunetti A.E. 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 10.1371/journal.pone.0105268 25170882
    [Google Scholar]
  23. 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 10.1093/jjco/hyz028 30957835
    [Google Scholar]
  24. Seong J. Koom W.S. Park H.C. Radiotherapy for painful bone metastases from hepatocellular carcinoma. Liver Int. 2005 25 2 261 265 10.1111/j.1478‑3231.2005.01094.x 15780048
    [Google Scholar]
  25. Goblirsch M.J. Zwolak P.P. Clohisy D.R. Biology of bone cancer pain. Clin. Cancer Res. 2006 12 20 6231s 6235s 10.1158/1078‑0432.CCR‑06‑0682 17062706
    [Google Scholar]
  26. El-Serag H.B. Rudolph K.L. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 2007 132 7 2557 2576 10.1053/j.gastro.2007.04.061 17570226
    [Google Scholar]
  27. Bakhoum S.F. Ngo B. Laughney A.M. Cavallo J.A. Murphy C.J. Ly P. Shah P. Sriram R.K. Watkins T.B.K. Taunk N.K. Duran M. Pauli C. Shaw C. Chadalavada K. Rajasekhar V.K. Genovese G. Venkatesan S. Birkbak N.J. McGranahan N. Lundquist M. LaPlant Q. Healey J.H. Elemento O. Chung C.H. Lee N.Y. Imielenski M. Nanjangud G. Pe’er D. Cleveland D.W. Powell S.N. Lammerding J. Swanton C. Cantley L.C. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 2018 553 7689 467 472 10.1038/nature25432 29342134
    [Google Scholar]
  28. Kong D. Banerjee S. Ahmad A. Li Y. Wang Z. Sethi S. Sarkar F.H. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One 2010 5 8 e12445 10.1371/journal.pone.0012445 20805998
    [Google Scholar]
  29. Dongre A. Weinberg R.A. New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 2019 20 2 69 84 10.1038/s41580‑018‑0080‑4 30459476
    [Google Scholar]
  30. Iguchi H. Yokota M. Fukutomi M. Uchimura K. Yonemasu H. Hachitanda Y. Nakao Y. Tanaka Y. Sumii T. Funakoshi A. A possible role of VEGF in osteolytic bone metastasis of hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 2002 21 3 309 313 12385570
    [Google Scholar]
  31. Kingsley L.A. Fournier P.G.J. Chirgwin J.M. Guise T.A. Molecular biology of bone metastasis. Mol. Cancer Ther. 2007 6 10 2609 2617 10.1158/1535‑7163.MCT‑07‑0234 17938257
    [Google Scholar]
  32. Renzulli M. Mottola M. Coppola F. Cocozza M.A. Malavasi S. Cattabriga A. Vara G. Ravaioli M. Cescon M. Vasuri F. Golfieri R. Bevilacqua A. Automatically extracted machine learning features from preoperative CT to early predict microvascular invasion in HCC: The role of the zone of transition (ZOT). Cancers (Basel) 2022 14 7 1816 10.3390/cancers14071816 35406589
    [Google Scholar]
  33. Luzzi K.J. MacDonald I.C. Schmidt E.E. Kerkvliet N. Morris V.L. Chambers A.F. Groom A.C. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am. J. Pathol. 1998 153 3 865 873 10.1016/S0002‑9440(10)65628‑3 9736035
    [Google Scholar]
  34. Amado V. González-Rubio S. Zamora J. Alejandre R. Espejo-Cruz M.L. Linares C. Sánchez-Frías M. García-Jurado G. Montero J.L. Ciria R. Rodríguez-Perálvarez M. Ferrín G. De la Mata M. Clearance of circulating tumor cells in patients with hepatocellular carcinoma undergoing surgical resection or liver transplantation. Cancers (Basel) 2021 13 10 2476 10.3390/cancers13102476 34069569
    [Google Scholar]
  35. Xu X.L. Xing B.C. Han H.B. Zhao W. Hu M.H. Xu Z.L. Li J.Y. Xie Y. Gu J. Wang Y. Zhang Z.Q. The properties of tumor-initiating cells from a hepatocellular carcinoma patient’s primary and recurrent tumor. Carcinogenesis 2010 31 2 167 174 10.1093/carcin/bgp232 19897602
    [Google Scholar]
  36. Meacham C.E. Morrison S.J. Tumour heterogeneity and cancer cell plasticity. Nature 2013 501 7467 328 337 10.1038/nature12624 24048065
    [Google Scholar]
  37. Suetsugu A. Nagaki M. Aoki H. Motohashi T. Kunisada T. Moriwaki H. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem. Biophys. Res. Commun. 2006 351 4 820 824 10.1016/j.bbrc.2006.10.128 17097610
    [Google Scholar]
  38. Ahuja N. Colorectal cancer stem cells--hype or real?: Comment on “Combined CD133+/CD44+ expression as a prognostic indicator of disease-free survival in patients with colorectal cancer”. Arch. Surg. 2012 147 1 24 25 10.1001/archsurg.2011.1218 22250107
    [Google Scholar]
  39. Yin S. Li J. Hu C. Chen X. Yao M. Yan M. Jiang G. Ge C. Xie H. Wan D. Yang S. Zheng S. Gu J. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int. J. Cancer 2007 120 7 1444 1450 10.1002/ijc.22476 17205516
    [Google Scholar]
  40. Davies O.G. Cooper P.R. Shelton R.M. Smith A.J. Scheven B.A. Isolation of adipose and bone marrow mesenchymal stem cells using CD29 and CD90 modifies their capacity for osteogenic and adipogenic differentiation. J. Tissue Eng. 2015 6 2041731415592356 10.1177/2041731415592356 26380065
    [Google Scholar]
  41. Yang Z.F. Ngai P. Ho D.W. Yu W.C. Ng M.N.P. Lau C.K. Li M.L.Y. Tam K.H. Lam C.T. Poon R.T.P. Fan S.T. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 2008 47 3 919 928 10.1002/hep.22082 18275073
    [Google Scholar]
  42. Ponta H. Sherman L. Herrlich P.A. CD44: From adhesion molecules to signalling regulators. Nat. Rev. Mol. Cell Biol. 2003 4 1 33 45 10.1038/nrm1004 12511867
    [Google Scholar]
  43. Zhu Z. Hao X. Yan M. Yao M. Ge C. Gu J. Li, J. Cancer stem/progenitor cells are highly enriched in CD133 + CD44 + population in hepatocellular carcinoma. Int. J. Cancer 2010 126 9 2067 2078 10.1002/ijc.24868 19711346
    [Google Scholar]
  44. Haraguchi N. Ishii H. Mimori K. Tanaka F. Ohkuma M. Kim H.M. Akita H. Takiuchi D. Hatano H. Nagano H. Barnard G.F. Doki Y. Mori M. CD13 is a therapeutic target in human liver cancer stem cells. J. Clin. Invest. 2010 120 9 3326 3339 10.1172/JCI42550 20697159
    [Google Scholar]
  45. Yamashita T. Forgues M. Wang W. Kim J.W. Ye Q. Jia H. Budhu A. Zanetti K.A. Chen Y. Qin L.X. Tang Z.Y. Wang X.W. EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008 68 5 1451 1461 10.1158/0008‑5472.CAN‑07‑6013 18316609
    [Google Scholar]
  46. Yang W. Yan H.X. Chen L. Liu Q. He Y.Q. Yu L.X. Zhang S.H. Huang D.D. Tang L. Kong X.N. Chen C. Liu S.Q. Wu M.C. Wang H.Y. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008 68 11 4287 4295 10.1158/0008‑5472.CAN‑07‑6691 18519688
    [Google Scholar]
  47. Deng T. Zhao J. Tong Y. Chen Z. He B. Li J. Chen B. Li R. Deng L. Yu H. Zhang B. Zhang T. Shi Z. Gao B. Jiang J. Shan Y. Yu Z. Jin Y. Wang Y. Xia J. Chen G. Crosstalk between endothelial progenitor cells and HCC through periostin/CCL2/CD36 labelports formation of the pro-metastatic microenvironment in HCC. Oncogene 2024 43 13 944 961 10.1038/s41388‑024‑02960‑2 38351345
    [Google Scholar]
  48. Massagué J. Obenauf A.C. Metastatic colonization by circulating tumour cells. Nature 2016 529 7586 298 306 10.1038/nature17038 26791720
    [Google Scholar]
  49. Nolan E. Kang Y. Malanchi I. Mechanisms of organ-specific metastasis of breast cancer. Cold Spring Harb. Perspect. Med. 2023 13 11 a041326 10.1101/cshperspect.a041326 36987584
    [Google Scholar]
  50. Gu Y. Liu Y. Fu L. Zhai L. Zhu J. Han Y. Jiang Y. Zhang Y. Zhang P. Jiang Z. Zhang X. Cao X. Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG. Nat. Med. 2019 25 2 312 322 10.1038/s41591‑018‑0309‑y 30643287
    [Google Scholar]
  51. Kaplan R.N. Riba R.D. Zacharoulis S. Bramley A.H. Vincent L. Costa C. MacDonald D.D. Jin D.K. Shido K. Kerns S.A. Zhu Z. Hicklin D. Wu Y. Port J.L. Altorki N. Port E.R. Ruggero D. Shmelkov S.V. Jensen K.K. Rafii S. Lyden D. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005 438 7069 820 827 10.1038/nature04186 16341007
    [Google Scholar]
  52. Liu Y. Cao X. Characteristics and significance of the pre-metastatic niche. Cancer Cell 2016 30 5 668 681 10.1016/j.ccell.2016.09.011 27846389
    [Google Scholar]
  53. Clézardin P. Coleman R. Puppo M. Ottewell P. Bonnelye E. Paycha F. Confavreux C.B. Holen I. Bone metastasis: Mechanisms, therapies, and biomarkers. Physiol. Rev. 2021 101 3 797 855 10.1152/physrev.00012.2019 33356915
    [Google Scholar]
  54. Truskowski K. Amend S.R. Pienta K.J. Dormant cancer cells: Programmed quiescence, senescence, or both? Cancer Metastasis Rev. 2023 42 1 37 47 10.1007/s10555‑022‑10073‑z 36598661
    [Google Scholar]
  55. Pantel K. Alix-Panabières C. Bone marrow as a reservoir for disseminated tumor cells: A special source for liquid biopsy in cancer patients. Bonekey Rep. 2014 3 584 10.1038/bonekey.2014.79 25419458
    [Google Scholar]
  56. Croucher P.I. McDonald M.M. Martin T.J. Bone metastasis: The importance of the neighbourhood. Nat. Rev. Cancer 2016 16 6 373 386 10.1038/nrc.2016.44 27220481
    [Google Scholar]
  57. Mundy G.R. Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2002 2 8 584 593 10.1038/nrc867 12154351
    [Google Scholar]
  58. Xiang Z. Zeng Z. Tang Z. Fan J. Zhuang P. Liang Y. Tan Y. 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 10.1186/1471‑2407‑9‑176 19508713
    [Google Scholar]
  59. Chen J. Feng W. Sun M. Huang W. Wang G. Chen X. Yin Y. Chen X. Zhang B. Nie Y. Fan D. Wu K. Xia L. TGF-β1-Induced SOX18 elevation promotes hepatocellular carcinoma progression and metastasis through transcriptionally upregulating PD-L1 and CXCL12. Gastroenterology 2024 167 2 264 280 10.1053/j.gastro.2024.02.025 38417530
    [Google Scholar]
  60. Sun Y.X. Wang J. Shelburne C.E. Lopatin D.E. Chinnaiyan A.M. Rubin M.A. Pienta K.J. Taichman R.S. Expression of CXCR4 and CXCL12 (SDF‐1) in human prostate cancers (PCa) in vivo. J. Cell. Biochem. 2003 89 3 462 473 10.1002/jcb.10522 12761880
    [Google Scholar]
  61. Bertolini G. D’Amico L. Moro M. Landoni E. Perego P. Miceli R. Gatti L. Andriani F. Wong D. Caserini R. Tortoreto M. Milione M. Ferracini R. Mariani L. Pastorino U. Roato I. Sozzi G. Roz L. Microenvironment-modulated metastatic CD133+/CXCR4+/EpCAM− lung cancer–initiating cells sustain tumor dissemination and correlate with poor prognosis. Cancer Res. 2015 75 17 3636 3649 10.1158/0008‑5472.CAN‑14‑3781 26141860
    [Google Scholar]
  62. Hoggatt J. Singh P. Tate T.A. Chou B.K. Datari S.R. Fukuda S. Liu L. Kharchenko P.V. Schajnovitz A. Baryawno N. Mercier F.E. Boyer J. Gardner J. Morrow D.M. Scadden D.T. Pelus L.M. Rapid mobilization reveals a highly engraftable hematopoietic stem cell. Cell 2018 172 1-2 191 204.e10 10.1016/j.cell.2017.11.003 29224778
    [Google Scholar]
  63. Darash-Yahana M. Pikarsky E. Abramovitch R. Zeira E. Pal B. Karplus R. Beider K. Avniel S. Kasem S. Galun E. Peled A. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J. 2004 18 11 1240 1242 10.1096/fj.03‑0935fje 15180966
    [Google Scholar]
  64. Liu C. Hu A. Chen H. Liang J. Gu M. Xiong Y. Mu C.F. The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone. Acta Pharm. Sin. B 2022 12 1 364 377 10.1016/j.apsb.2021.06.012 35127392
    [Google Scholar]
  65. Cackowski F.C. Taichman R.S. Parallels between hematopoietic stem cell and prostate cancer disseminated tumor cell regulation. Bone 2019 119 82 86 10.1016/j.bone.2018.02.025 29496517
    [Google Scholar]
  66. Ema H. Suda T. Two anatomically distinct niches regulate stem cell activity. Blood 2012 120 11 2174 2181 10.1182/blood‑2012‑04‑424507 22786878
    [Google Scholar]
  67. Sasaki A. Ishikawa K. Haraguchi N. Inoue H. Ishio T. Shibata K. Ohta M. Kitano S. Mori M. Receptor activator of nuclear factor-kappaB ligand (RANKL) expression in hepatocellular carcinoma with bone metastasis. Ann. Surg. Oncol. 2007 14 3 1191 1199 10.1245/s10434‑006‑9277‑4 17195907
    [Google Scholar]
  68. Ariyoshi W. Takahashi T. Kanno T. Ichimiya H. Takano H. Koseki T. Nishihara T. Mechanisms involved in enhancement of osteoclast formation and function by low molecular weight hyaluronic acid. J. Biol. Chem. 2005 280 19 18967 18972 10.1074/jbc.M412740200 15757905
    [Google Scholar]
  69. Abraham B.K. Fritz P. McClellan M. Hauptvogel P. Athelogou M. Brauch H. Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin. Cancer Res. 2005 11 3 1154 1159 10.1158/1078‑0432.1154.11.3 15709183
    [Google Scholar]
  70. Jung Y. Wang J. Song J. Shiozawa Y. Wang J. Havens A. Wang Z. Sun Y.X. Emerson S.G. Krebsbach P.H. Taichman R.S. Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood 2007 110 1 82 90 10.1182/blood‑2006‑05‑021352 17360942
    [Google Scholar]
  71. Abudourousuli A. Chen S. Hu Y. Qian W. Liao X. Xu Y. Song L. Zhang S. Li J. NKX2-8/PTHrP Axis-Mediated Osteoclastogenesis and Bone Metastasis in Breast Cancer. Front. Oncol. 2022 12 907000 10.3389/fonc.2022.907000 35707355
    [Google Scholar]
  72. Roskams T. Willems M. Campos R.V. Drucker D.J. Yap S.H. Desmet V.J. Parathyroid hormone‐related peptide expression in primary and metastatic liver tumours. Histopathology 1993 23 6 519 525 10.1111/j.1365‑2559.1993.tb01237.x 8314235
    [Google Scholar]
  73. Dunn L.K. Mohammad K.S. Fournier P.G.J. McKenna C.R. Davis H.W. Niewolna M. Peng X.H. Chirgwin J.M. Guise T.A. Hypoxia and TGF-beta drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment. PLoS One 2009 4 9 e6896 10.1371/journal.pone.0006896 19727403
    [Google Scholar]
  74. Tanaka M. Siemann D.W. Gas6/Axl signaling pathway in the tumor immune microenvironment. Cancers (Basel) 2020 12 7 1850 10.3390/cancers12071850 32660000
    [Google Scholar]
  75. Ilg M.M. Lapthorn A.R. Harding S.L. Minhas T. Koduri G. Bustin S.A. Cellek S. Development of a phenotypic screening assay to measure activation of cancer-associated fibroblasts. Front. Pharmacol. 2025 16 1526495 10.3389/fphar.2025.1526495 40017592
    [Google Scholar]
  76. Nowosad A. Marine J.C. Karras P. Perivascular niches: critical hubs in cancer evolution. Trends Cancer 2023 9 11 897 910 10.1016/j.trecan.2023.06.010 37453870
    [Google Scholar]
  77. Vives M. Ginestà M.M. Gracova K. Graupera M. Casanovas O. Capellà G. Serrano T. Laquente B. Viñals F. Metronomic chemotherapy following the maximum tolerated dose is an effective anti‐tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells. Int. J. Cancer 2013 133 10 2464 2472 10.1002/ijc.28259 23649709
    [Google Scholar]
  78. Halper J. Basic components of connective tissues and extracellular matrix: Fibronectin, fibrinogen, laminin, elastin, fibrillins, fibulins, matrilins, tenascins and thrombospondins. Adv. Exp. Med. Biol. 2021 1348 105 126 10.1007/978‑3‑030‑80614‑9_4 34807416
    [Google Scholar]
  79. Jiang X. Liang L. Chen G. Liu C. Modulation of immune components on stem cell and dormancy in cancer. Cells 2021 10 11 2826 10.3390/cells10112826 34831048
    [Google Scholar]
  80. Kudo A. Kii I. Periostin function in communication with extracellular matrices. J. Cell Commun. Signal. 2018 12 1 301 308 10.1007/s12079‑017‑0422‑6 29086200
    [Google Scholar]
  81. Nashchekina Y. Nikonov P. Prasolov N. Sulatsky M. Chabina A. Nashchekin A. The structural interactions of molecular and fibrillar collagen type I with fibronectin and its role in the regulation of mesenchymal stem cell morphology and functional activity. Int. J. Mol. Sci. 2022 23 20 12577 10.3390/ijms232012577 36293432
    [Google Scholar]
  82. Fox D.B. Garcia N.M.G. McKinney B.J. Lupo R. Noteware L.C. Newcomb R. Liu J. Locasale J.W. Hirschey M.D. Alvarez J.V. NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism. Nat. Metab. 2020 2 4 318 334 10.1038/s42255‑020‑0191‑z 32691018
    [Google Scholar]
  83. Robertson H. Dinkova-Kostova A.T. Hayes J.D. NRF2 and the ambiguous consequences of its activation during initiation and the subsequent stages of tumourigenesis. Cancers (Basel) 2020 12 12 3609 10.3390/cancers12123609 33276631
    [Google Scholar]
  84. Hampsch R.A. Wells J.D. Traphagen N.A. McCleery C.F. Fields J.L. Shee K. Dillon L.M. Pooler D.B. Lewis L.D. Demidenko E. Huang Y.H. Marotti J.D. Goen A.E. Kinlaw W.B. Miller T.W. AMPK Activation by Metformin Promotes Survival of Dormant ER+ Breast Cancer Cells. Clin. Cancer Res. 2020 26 14 3707 3719 10.1158/1078‑0432.CCR‑20‑0269 32321715
    [Google Scholar]
  85. Lutz S. Berk L. Chang E. Chow E. Hahn C. Hoskin P. Howell D. Konski A. Kachnic L. Lo S. Sahgal A. Silverman L. von Gunten C. Mendel E. Vassil A. Bruner D.W. Hartsell W. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int. J. Radiat. Oncol. Biol. Phys. 2011 79 4 965 976 10.1016/j.ijrobp.2010.11.026 21277118
    [Google Scholar]
  86. He J. Zeng Z.C. Tang Z.Y. Fan J. Zhou J. Zeng M.S. Wang J.H. Sun J. Chen B. Yang P. Pan B.S. Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma receiving external beam radiotherapy. Cancer 2009 115 12 2710 2720 10.1002/cncr.24300 19382203
    [Google Scholar]
  87. Nakamura N. Igaki H. Yamashita H. Shiraishi K. Tago M. Sasano N. Shiina S. Omata M. Makuuchi M. Ohtomo K. Nakagawa K. A retrospective study of radiotherapy for spinal bone metastases from hepatocellular carcinoma (HCC). Jpn. J. Clin. Oncol. 2007 37 1 38 43 10.1093/jjco/hyl128 17142252
    [Google Scholar]
  88. Costa S. Reagan M.R. Therapeutic irradiation: Consequences for bone and bone marrow adipose tissue. Front. Endocrinol. (Lausanne) 2019 10 587 10.3389/fendo.2019.00587 31555210
    [Google Scholar]
  89. Pacheco R. Stock H. Effects of radiation on bone. Curr. Osteoporos. Rep. 2013 11 4 299 304 10.1007/s11914‑013‑0174‑z 24057133
    [Google Scholar]
  90. Hayashi K. Tsuchiya H. The role of surgery in the treatment of metastatic bone tumor. Int. J. Clin. Oncol. 2022 27 8 1238 1246 10.1007/s10147‑022‑02144‑6 35226235
    [Google Scholar]
  91. Lian Q. Liu C. Chen F. Wang B. Wang M. Qiao S. Guan Z. Jiang S. Wang Z. Orthopedic therapeutic surgery for bone metastasis of liver cancer: Clinical efficacy and prognostic factors. Front. Surg. 2022 9 957674 10.3389/fsurg.2022.957674 36386547
    [Google Scholar]
  92. van der Linden E. Kroft L.J.M. Dijkstra P.D.S. 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 10.1016/j.jvir.2007.02.018 17538136
    [Google Scholar]
  93. Cai Z. 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 10.12659/MSM.889742 24699431
    [Google Scholar]
  94. 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 10.1097/BRS.0b013e3182983bf8 23632333
    [Google Scholar]
  95. 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 10.1007/s00268‑018‑4861‑x 30465085
    [Google Scholar]
  96. 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. The effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway. J. Gastroenterol. Hepatol. 2015 30 3 619 627 10.1111/jgh.12715 25167891
    [Google Scholar]
  97. 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 10.1111/j.1872‑034X.2010.00729.x 21040275
    [Google Scholar]
  98. 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 10.1007/s00280‑009‑1122‑6 19760218
    [Google Scholar]
  99. 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 10.1007/s10147‑018‑1277‑4 29654428
    [Google Scholar]
  100. Body J.J. Lipton A. Gralow J. Steger G.G. 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 10.1359/jbmr.090810 19653815
    [Google Scholar]
/content/journals/ctmc/10.2174/0115680266430839251017113122
Loading
Liver Cancer Bone Metastasis: Molecular Mechanisms and Therapeutic Insights
Bentham Science Publishers ; https://doi.org/10.2174/0115680266430839251017113122
/content/journals/ctmc/10.2174/0115680266430839251017113122
/content/journals/ctmc/10.2174/0115680266430839251017113122
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Review Article
Keywords: Therapeutics ; Cancer stem cell dormancy ; Liver cancer stem cells ; Pre-metastatic niche ; Liver cancer ; Bone metastasis

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test