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
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.
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
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
Fig.5
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