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Frontiers of Medicine

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ISSN 2095-0225(Online)

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Front. Med.    2022, Vol. 16 Issue (4) : 551-573    https://doi.org/10.1007/s11684-022-0928-z
REVIEW
Bone metastasis of hepatocellular carcinoma: facts and hopes from clinical and translational perspectives
Zhao Huang1,2,3, Jingyuan Wen1,2,3, Yufei Wang1,2,3, Shenqi Han1,2,3, Zhen Li4, Xuemei Hu4, Dongling Zhu5, Zhenxiong Wang6, Junnan Liang1,2,3, Huifang Liang1,2,3, Xiao-ping Chen1,2,3,7(), Bixiang Zhang1,2,3,7()
1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2. Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan 430030, China
3. Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
4. Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
5. Department of Nuclear Medicine and PET, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
6. Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China
7. Key Laboratory of Organ Transplantation, Ministry of Education; Key Laboratory of Organ Transplantation, National Health Commission; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
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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     
Corresponding Author(s): Xiao-ping Chen,Bixiang Zhang   
About author:

Tongcan Cui and Yizhe Hou contributed equally to this work.
Just Accepted Date: 19 May 2022   Online First Date: 20 July 2022    Issue Date: 02 September 2022
 Cite this article:   
Zhao Huang,Jingyuan Wen,Yufei Wang, et al. Bone metastasis of hepatocellular carcinoma: facts and hopes from clinical and translational perspectives[J]. Front. Med., 2022, 16(4): 551-573.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0928-z
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I4/551
Period Center Diagnostic approaches Incidence of BM Rate of BM in EhMs
1962–1981 [16] Single Autopsy 16.10% (14/87) N.A.
1969–1978 [9] Single Autopsy 5.33% (12/225) 8.33% (12/144)
1969–1983 [4] Single Autopsy N.A. 20%
1978–1987 [11] Single BS, radiography, CT, and/or MRI 4.46% (12/269) N.A.
1983–1987 [10] Single Plain films, bone scans, or CT 5.06% (20/395) N.A.
1988–1997 [11] Single BS, radiography, CT, and/or MRI 12.87% (52/404) N.A.
1988–2012 [4] Single Autopsy N.A. 32.1%
1990–2005 [17] Single CT, MRI, BS, and/or PET with FDG 5.63% (56/995) 37.09% (56/151)
1990–2006 [18] Single Bone X-ray, BS, and CT or MRI 3.65% (87/2386) 25.44% (87/342)
1992–1997 [19] Single CT 10.17% (41/403) 27.70% (41/148)
2002–2014 [15] Single At least one imaging modality 23.59% (151/640) 32.90% (151/459)
2005–2015 [20] Single Symptoms, and CT or MRI 1.97% (20/1017) N.A.
2006–2009 [21] Single PET/CT N.A. 19.07% (49/257)
2009–2016 [5] Single Radiological images or pathological findings 9.71% (76/783) N.A.
2010–2013 [12] Multiple Unknown N.A. 22.93% (1008/4396)
2010–2014 [22] Multiple Unknown 4.29% (1567/36 507) N.A.
2010–2015 [13] Multiple Unknown N.A. 32.47% (1015/3126)
Tab.1  Reported incidences of HCC BM in various patient cohorts
Fig.1  Imaging techniques for the diagnosis of HCC BM. (A) X-ray images of metastatic HCC lesions in the right humerus (left image) and in the L1 vertebral body (right image). (B) Anterior and posterior positions of BS for a patient with multiple BM (left panel) and a patient with a bone lesion in the right scapula (right panel). (C) MRI of skeletal HCC lesions in the L1 vertebral body (upper row) and L3 vertebral body (lower row). (D) CT scans of BM in the right humerus (upper row) and the spine (lower row). (E) Whole-body 18F-FDG PET/CT images of BM in the fifth right rib (left panel) and right ilium (right panel). Arrows point to metastatic HCC bone lesions. Abbreviations: CT, computed tomography; BS, bone scintigraphy; MRI, magnetic resonance imaging; PET, positron emission tomography; BM, bone metastasis; LT, left; RT, right; AP, anteroposterior; TS, transverse section; T1WI, T1 weighted image; T2WI, T2 weighted image; STIR, short time inversion recovery; MIP, maximum intensity projection.
Period Treatment Prognosis 　　Independent risk factors
1978–1987 [11] RT, surgery, ethanol injection, and supportive care Median OS: 170 days 　　–
1981–1997 [48] Palliative RT Median OS from the diagnosis of spinal metastasis: 3 months 　　Responssive RT (complete 　　response, partial response) 　　and good performance 　　status (score < 2)
1988–1997 [11] RT, surgery, ethanol injection, and supportive care Median OS: 227 days 　　–
1991–2000 [25] RT OS rates at 1 and 2 years of 50% and 20%, respectively, with a median OS of 12 months from the time of HCC diagnosis; OS rates from the occurrence of BM at 1 and 2 years of 15% and 4%, respectively, with the median OS of 5 months 　　Tumor stage within the liver 　　and the presence of 　　metastases to organs
1992–2012 [49] RT Median OS from diagnosis of spinal metastases: 4.5 months; 1- and 2-year OS rates of 18.1% and 6.3%, respectively 　　Performance status (ECOG), 　　presence of uncontrolled 　　primary HCC, and presence 　　of extrahepatic metastases
1993–2013 [14] Sorafenib, RT, BP and surgery Median OS from the diagnosis of BM: 7 months 　　HCC etiology, performance 　　status (ECOG), BM 　　localized to the spine and 　　not receiving any BP 　　treatment
1997–2007 [44] RT Median OS after the diagnosis of BM: 7.4 months; 1-year and 2-year OS rates of 32.4% and 13.2%, respectively 　　Low KPS, high AFP levels, 　　uncontrolled intrahepatic 　　tumor, and receiving 　　treatment within the past 5 　　years
2000–2011 [50] RT Median OS: 7.0 months; OS rates at 1 and 2 years of 13.8% and 6.9%, respectively 　　–
2000–2018 [45] Surgery, RT, chemotherapy, and bone-modifying agents Median OS from the initiation of treatment: 7.4 ± 8.2 months (range 0.3–36 months) for all; 10.46 ± 8.05 months for surgical groups, and 5.19 ± 7.72 months for the conservative treatment groups 　　Patient’s general condition, 　　the serum albumin level, 　　and bone-modifying agent 　　treatment
2002–2009 [51] Irradiation/zoledronic acid Median OS from the initial date of therapy: 6.0 months (95% CI 0.0–12.7 months) for patients treated with zoledronic acid, and 4.2 months (95% CI 1.2–7.2 months) for patients treated with non-zoledronic acid; cumulative OS rates at 3 months of 74% and 44% and at 6 months of 79% and 37% 　　–
2002–2011 [52] SRS, cRT Median OS: 3 months in the cRT group and 7 months in the SRS group 　　Child–Pugh class and KPS
2002–2014 [15] Radiation, surgical resection, BPs, and sorafenib Median OS after the diagnosis of any type of metastasis: 5.6 months (95% CI 4.6–6.9) 　　AFP levels, Child–Pugh 　　score, and SREs
2005–2011 [53] EBRT Median OS after the first EBRT: 3.8 months 　　–
2006–2013 [54] Surgery, EBRT Median OS: 261 days (range 22–1359 days) after the diagnosis of metastasis, and 180 days (range 19–1351 days) after the initial operation 　　Tomita scoring system
2009–2014 [55] EBRT Median OS for the entire cohort: 8.0 months; 1-year and 2-year survival rates of 35.1% and 10.8%, respectively in patients receiving conventional fraction EBRT, and of 38.7% and 15.1%, respectively, in patients receiving hypofraction RT 　　KPS, TB, and intrahepatic 　　tumor control
2009–2016 [5] Sorafenib, sunitinib or lenvatinib RT, zoledronic acid and denosumab Median OS after the diagnosis of BM: 11.7 months (range 0.2–94.5 months) 　　Age over 75 years, HCV, 　　and Child–Pugh class B/C
2010–2014 [22] Surgery and other N/A Median OS from the time of diagnosis of HCC: 3.00 months (95% CI 2.77–3.24 months) 　　Unmarried, uninsured, high　　primary tumor stage, high 　　regional lymph node (N1), 　　lung metastases, poor tumor 　　differentiated grade, and 　　elevated AFP, without surgery
2010–2014 [56] Zoledronic acid, palliative RT, curettage, and wide resection Median OS after BM diagnosis: 11 months (range 4–52); 1- and 2-year survival rates of 44.2% and 11.6%, respectively 　　Progression beyond the　　University of California San 　　Francisco criteria and the 　　treatment of the primary 　　tumors
2011–2016 [57] RT Median OS after RT: 13.6, 4.8, and 2.6 months for the low-, intermediate-, and high-risk groups, respectively 　　ECOG performance status, 　　controlled primary HCC, and 　　extrahepatic metastases other 　　than bone
2014–2017 [58] RT and other N/A Median OS from the start of the RT for BM: 6.5 months; 1- and 2-year survival rates after diagnosis of BM of 35.5% and 13.5%, respectively 　　Child–Pugh class A group, 　　increase in AFP beyond 30 ng/mL,　　and HCC size of 　　more than 5 cm
Abbreviations: RT, radiotherapy; OS, overall survival time; BM, bone metastases; ECOG, Eastern Cooperative Oncology Group; KPS, Karnofsky performance status; TB, total bilirubin; SRS, stereotactic radiosurgery; cRT, conventional radiation therapy; BP, bisphosphonate.
Tab.2  Prognosis and risk factors for HCC patients with BM
Fig.2  Outline of the multidisciplinary treatment options for patients with HCC and BM. Therapeutic strategies for HCC BM should be determined in accordance with the systematic evaluation of each patient’s general condition by a multidisciplinary team. BTAs are recommended to be started at the definite diagnosis of BM. Treatments for primary HCC, BM, and systematic symptoms are the three approaches for controlling disease progression and alleviating cancer-induced bone pain. Abbreviations: BM, bone metastases; BTAs, bone-targeting agents; EBRT, external beam radiotherapy; BPs, bisphosphonates; SRE, skeleton-related events.
Fig.3  Hypothetical bone metastatic cascade of HCC. On the basis of the academic advances in cancer BM, an integrated metastatic process was proposed for HCC bone lesion formation. (A) The malignant transformation of liver cells and microenvironment predispose HCC cells to metastasis by augmenting their mobility and inducing angiogenesis. HCC cells exploit the arterial bloodstream and vertebral venous system to spread to the bone cavity. The dysregulation and immunosuppressive status of the bone microenvironment benefit the settlement, proliferation, and further metastasis of disseminated tumor cells in the bone. Additionally, signals that induce the osteotropism of cancer cells are predelivered to the bone from the primary tumor site and prepare metastatic niches. Conversely, the bone microenvironment modulates the behavior of tumor cells at the primary site via the secretion of various bioactive substances. (B) The formation of a metastatic lesion in bone. The disseminated tumor cells first home to the bone cavity and adhere to bone stromal cells to settle inside the bone. Bone metastatic tumor cells either remain dormant or directly start to colonize and form micro-metastatic lesions. By interacting with various bone stromal cells, the migrated tumor cells finally thrive inside the bone and expand into a macrometastatic lesion.
Fig.4  Disturbed homeostasis of the bone microenvironment driven by tumor cells. Bone-metastasized tumor cells trigger the imbalances of immune-suppressive/immune-active and osteoclastic/osteoblastic activities to escape from immune elimination and initiate excessive bone reconstruction. Thriving tumor cells, the immune-privileged microenvironment, and uncoupled bone remodeling benefit each other through various bioactive molecules to perpetuate the destructive vicious cycle. Abbreviations: TAMs, tumor associated macrophages; Tregs, regulatory T cells; Th17, CD4+ T helper cells 17; MDSCs, myeloid-derived suppressor cells; DCs, dendritic cells; pDCs, plasmacytoid DCs; TI-DCs, tumor-infiltrating DCs; NK cells, natural killer cells; TIMs, tumor inflammatory macrophages.
Gene Subject Expression pattern Biological function/molecular mechanism Potential application
CTGF [137,139] Primary tumor Highly expressed in patients with HCC and BM – Risk factor of BM
IL-11 [137,139] Primary tumor Highly expressed in patients with HCC and BM – Risk factor of BM
MMP-1 [137,140] Peritumor/HCC cell lines Highly expressed in patients with HCC and BM/in osteotropic cells lines – Risk factor of BM
CXCR4 [139,141] Primary tumor Highly expressed in patients with HCC and BM – Risk factor of BM
FRZB [136] BM Highly expressed in bone metastatic lesions – –
PNI [142] BM High density in bone metastatic lesions – –
RNF219 [134] Primary tumor/BM/HCC cell lines Highly expressed in patients with HCC and BM/in bone metastatic lesions/in osteotropic cell lines Promotes osteoclastogenesis by upregulating LGALS3 in a YAP1/β-catenin complex-dependent manner Therapeutic target
LGALS3 [134] Primary tumor/BM/HCC cell lines Highly expressed in patients with HCC and BM/in bone metastatic lesions/in osteotropic cell lines Promotes osteoclastogenesis and aggravate SREs Therapeutic target
miR-34a [143] Serum/primary tumor Low expression in the serum and in the primary tumor of patients with HCC and BM Promotes the migration and invasion of HCC cells by upregulating SMAD4 to further activate TGFβ signaling and upregulate its downstream effectors Risk factor of BM and therapeutic target
lnc34a [144] Serum/primary tumor Highly expressed in the serum and primary tumor of patients and HCC and BM Suppresses miR-34a expression epigenetically through DNMT3A/PHB2 and HDAC1 and sponging miR-34a Risk factor of BM
lncZEB1-AS1 [145] Primary tumor Highly expressed in patients with HCC and BM Promotes the migration and invasion of HCC cells by sponging miR-302b to activate PI3K/AKT signaling and increase EGFR expression Therapeutic target
H19 [133] Primary tumor/BM/HCC cell lines Highly expressed in patients with HCC and BM/in bone metastatic lesions/in osteotropic cell lines Promotes the migration and invasion of HCC cells by sponging miR-200b-3p and inducing osteoclastogenesis through the PPP1CA/p38MAPK axis Therapeutic target
CCL2 [146] CAFs Highly expressed in CAFs in primary site Promotes the migration of HCC cells by activating hedgehog signaling Therapeutic target
CCL5 [146] CAFs Highly expressed in CAFs in primary site Promotes the migration of HCC cells by activating hedgehog signaling Therapeutic target
CCL7 [146] CAFs Highly expressed in CAFs in primary site Promotes the invasion of HCC cells by activating TGFβ signaling Therapeutic target
CXCL16 [146] CAFs Highly expressed in CAFs in primary site Promotes the invasion of HCC cells by activating TGFβ signaling Therapeutic target
MAPK14 [147] BMECs Excessive activation in BMECs Upregulates ADAM17 expression Therapeutic target
ADAM17 [147] BMECs Highly expressed in BMECs Promotes the secretion of CX3CL1 Therapeutic target
CX3CL1 [147] HCC/BMECs Highly expressed in bone metastatic lesions/in BMECs Promotes the migration and invasion of HCC cells by activating PIK3CA/AKT1 and RHOA/ROCK2 signaling Therapeutic target
CX3CL1R [147] HCC Highly expressed in bone metastatic lesions Promotes the migration and invasion of HCC cells by activating PIK3CA/AKT1 and RHOA/ROCK2 signaling Therapeutic target
Tab.3  Biomarkers for the prediction of diagnosis and prognosis of HCC BM
Fig.5  Molecular mechanism of HCC BM. Elevated expression levels of H19, lnc34a, lncZEB1, and RNF219 in HCC cells contribute to strengthened bone metastatic ability by enhancing the migration, invasion, and metastasis ability of HCC cells and inducing osteolytic activities in bone. CCL2, CCL5, CCL7, and CXCL16 secreted by CAFs in primary sites activate Hh and TGFβ signaling in HCC cells to facilitate their metastatic capacities. High levels of IL11, CTGF, and MMP-1 have been found in primary HCCs with bone lesions and predict bone metastatic events. Various cytokines released from bone remodeling and bone stromal cells, such as BMECs, support the outgrowth of disseminated HCC cells in bone. Abbreviations: CAFs, cancer-associated fibroblasts; BMEC, bone marrow endothelial cells; OC, osteoclasts.
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