Hepatocellular carcinoma (HCC) is one of the most common human malignant tumors worldwide; it is also hard to prevent its metastasis and recurrence by traditional treatments. Up to now, how to prevent and treat HCC is still a challenging problem in clinic. Cancer stem cells (CSCs) are cells within malignant tumor that possess the capacity to self-renew and differentiate to lead to the heterogeneous lineages of cancer cells that comprise the tumor, and are the root to cause metastasis, recurrence and bad prognosis of the cancer. Targeting CSCs is a novel therapeutic strategy for management and treatment of the cancer. In recent years, targeting intervention on liver cancer stem cells (LCSCs) gradually became a novel strategy for HCC treatment, and some exciting research results in the treatment of HCC were also achieved. In this review, we introduce the biological characteristics of LCSCs and highlight the therapeutic strategies for hepatocellular carcinoma by targeting intervention on LCSCs.
Animals ; Antineoplastic Agents ; therapeutic use ; Carcinoma, Hepatocellular ; therapy ; Humans ; Liver Neoplasms ; therapy ; Molecular Targeted Therapy ; Neoplastic Stem Cells ; metabolism ; pathology

OBJECTIVETo investigate clinicopathological features of combined hepatocellular-cholangiocarcinoma (C-HCC-CC) with neuroendocrine carcinoma (NEC) differentiation and to review the literature.

METHODSThe clinical data, histological manifestations and immunohistochemical staining results of two cases of C-HCC-CC were analyzed along with a review of the current literature.

RESULTSBoth patients were male with an average age of 57.5 years. Both patients were positive for hepatitis B virus antigen. The tumors of both cases demonstrated the following 3 unequivocal mixed elements: (1) polygonal epithelial tumor cells growing in nests or trabeculae with positive staining for Hepatocyte and AFP, diagnostic of hepatocellular carcinoma (HCC). Cytoplasmic bile production was present in the tumor cells in one case; (2) elliptic or short spindle-shape small blue tumor cells growing in nests or organoid pattern with Syn/CgA/CD56 positivity confirming the presence of neuroendocrine carcinoma (NEC) component; (3) oval tumor cells growing in nests or glandular forms with positivity of CK19 and CK7 confirming differentiation of cholangiocarcinoma (CC). In both cases, the tumors contained at least 20% of each of HCC, NEC and CC components.

CONCLUSIONC-HCC-CC with NEC is a rare form of primary malignancy of the liver with a poor prognosis.

Bile Duct Neoplasms ; Bile Ducts, Intrahepatic ; Bone Neoplasms ; secondary ; CD56 Antigen ; metabolism ; Carcinoma, Hepatocellular ; metabolism ; pathology ; therapy ; Carcinoma, Neuroendocrine ; metabolism ; pathology ; therapy ; Chemoembolization, Therapeutic ; Cholangiocarcinoma ; metabolism ; pathology ; therapy ; Chromogranin A ; metabolism ; Humans ; Immunohistochemistry ; Keratin-19 ; metabolism ; Keratin-7 ; metabolism ; Ki-67 Antigen ; metabolism ; Liver Neoplasms ; metabolism ; pathology ; therapy ; Male ; Middle Aged ; Mixed Tumor, Malignant ; metabolism ; pathology ; therapy ; Synaptophysin ; metabolism ; alpha-Fetoproteins ; metabolism

BACKGROUNDAccumulating evidence indicates that systemic inflammation response is associated with the prognosis of various cancers. The aim of this study was to investigate the neutrophil-lymphocyte ratio (NLR), which is one of the systemic inflammation markers, in the prognosis of hepatocellular carcinoma (HCC) after treatment of transcatheter arterial chemoembolization (TACE).

METHODSThe clinical data of 178 HCC patients who received TACE were retrospectively analyzed. The optimal NLR cutoff was determined according to the receiver operating characteristic (ROC) analysis. All patients were divided into NLR-normal group and NLR-elevated group according to the cutoff, and the clinical features of these two groups were comparatively analyzed. Meanwhile, the overall survival and disease free survival (DFS) were analyzed using the Kaplan-Meier method. The risk factors of postoperative survival were investigated using univariate and multivariate Cox regression analyses.

RESULTSThe optimal NLR cutoff was defined at 1.85 and 42 (23.6%) patients had an elevated NLR (NLR>1.85). The median survival time was 9.5 months (range 1-99 months). The clinical data between the two groups were comparable, except for a-fetoprotein. Follow-up results showed that the median survival of patients with normal NLR was 17.5 months (range: 1-99 months) compared with 8 months (range: 8-68 months) of patients with elevated NLR. The 1, 3 and 5-year overall survival of patients in the NLR-normal group and NLR-elevated group were 57.3%, 44.1%, and 27.2% and 42.1%, 19.6%, and 9.5% respectively (χ(2) = 194.2, P < 0.001). Similarly, the disease free survival also has a significant difference (χ(2) = 39.3, P < 0.001). Multivariate Cox regression analysis showed that a high NLR was an independent factor affecting the survival rate of HCC after TACE (P = 0.04).

CONCLUSIONPreoperative NLR was an important prognostic factor to predict the prognosis of patients with intermediate HCC treated with TACE.

Adult ; Aged ; Carcinoma, Hepatocellular ; pathology ; therapy ; Chemoembolization, Therapeutic ; Female ; Humans ; Liver Neoplasms ; pathology ; therapy ; Lymphocytes ; metabolism ; physiology ; Male ; Middle Aged ; Neutrophils ; metabolism ; physiology

OBJECTIVETo investigate the inhibition effect of Salvia chinensis extraction (SJC) on growth of H22 bearing tumor, and to analyze the mechanism about the anti-tumor effect.

METHODWith hepatoma H22 bearing mice, ICR mice were inoculated with H22 cells by subcutaneous injection. On day 2 after inoculation, the ICR mice were randomize into 5 groups, they were the control group, the high, middle, low dosages of SJC, and the positive-control group. Administrated 10 days, the inhibition rate of tumor in the treatment groups were analyzed at 11th day. Meanwhile, Immunostaining with antibodies against CD105 and VEGF were used to investigate the tumor-related angiogenesis. In addition, the effect of SJC on angiogenesis of tumor were investigated on chick embry chorioallantoic membrane (CAM) inoculated H22 cells.

RESULTIn contrast to model group, the inhibition rate of the high, middle, and low dosages of SJC were 26.44% (P < 0.05), 42.28% (P < 0.01) and 32.59% (P < 0.05), respectively, and SJC could significantly reduced the express of VEGF and microvessel density (MVD) (P < 0.01). Injection with 6.25 g x L(-1) doses of SJC could significantly inhibited the angiogenesis of tumor, the inhibition rate of tumor-related angiogenesis was 50.67% (P < 0.01).

CONCLUSIONSJC showed anticancer effect, and maybe it is related to down-regulation VEGF and reducing MVD, then inhibiting the tumor-related angiogenesis.

Animals ; Carcinoma, Hepatocellular ; drug therapy ; metabolism ; pathology ; Cell Line, Tumor ; Male ; Mice ; Mice, Inbred ICR ; Neovascularization, Pathologic ; drug therapy ; metabolism ; pathology ; Plant Extracts ; therapeutic use ; Salvia ; chemistry

OBJECTIVETo study the changes in hypoxia-inducible factor (HIF1α, HIF2α) in the residual tumor cells in nude mice bearing hepatocellular carcinoma (HCC) following treatment with high-intensity focused ultrasound (HIFU).

METHODSThirty nude mice bearing human HCC received treatment with HIFU. At 1, 3, and 5 days and 1 and 2 weeks after the treatment, the mice were examined for pathological changes of the residual tumor with HE staining; SP immunohistochemistry, Western blotting and real-time quantitative PCR were used to detect the protein and mRNA expressions of HIF1α and HIF2α in the tumor.

RESULTSHE staining revealed the presence of residual tumor cells and large necrotic areas after the treatment. Immunohistochemistry showed a gradual increment of HIF1α protein and mRNA expressions after the treatment, reaching the peak level at 3 days (P<0.05) followed by progressive reduction at 5 days and 1 and 2 weeks. HIF2α expressions at either the protein or mRNA levels exhibited no significant changes within 3 days after the treatment (P>0.05) but increased significantly at 5 days and 1 and 2 weeks (P<0.05).

CONCLUSIONThe changes of HIF1α and HIF2α in the residual tumor after HIFU treatment in nude mice bearing HCC can be associated with tumor cell apoptosis and angiogenesis after the treatment.

Animals ; Carcinoma, Hepatocellular ; metabolism ; pathology ; therapy ; Hep G2 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Liver Neoplasms ; metabolism ; pathology ; therapy ; Mice ; Neoplasm, Residual ; metabolism ; pathology ; Ultrasonic Therapy ; methods

OBJECTIVETo screen out the HAb18G/CD147 binding peptides and find out an antagonist against hepatoma invasion.

METHODSHAb18G/CD147 was purified by affinity chromatographic method and the antigen binding peptides acquired by bio-panning a phage-displayed 12-peptide library. After obtaining the sequence of the selected phage-displayed peptides, all the 9 peptides were synthesized by solid-phase method and identified by mass spectrograph. The peptides' anti-metastatic function was tested by Boyden Chamber assay.

RESULTSThe purified HAb18G/CD147, identified by Western blot (molecular weight about 65 kd) could be used to bio-pan the phage-displayed peptide library. After 3 rounds of bio-panning, 9 positive phage clones were selected and sequenced. The synthesized peptides had uneven inhibitory activities and three of them were able to markedly inhibit the hepatoma cell invasion (P < 0.01). The most effective peptide decreased by 90.1% of hepatoma cells migrating through the Boyden Chamber membrane as compared with the control.

CONCLUSIONBio-panning the phage-displayed peptide library can be used successfully to screen out the antigen binding peptides. Hepatoma metastatic potential can be inhibited by peptide antagonist which could be a good foundation of developing peptide therapeutic agent against hepatoma metastasis.

Animals ; Antibodies, Monoclonal ; therapeutic use ; Basigin ; metabolism ; Carcinoma, Hepatocellular ; drug therapy ; pathology ; Humans ; Liver Neoplasms ; drug therapy ; pathology ; Mice ; Neoplasm Invasiveness ; Peptide Library ; Peptides ; therapeutic use

OBJECTIVETo study the effect of transcatheter arterial chemoembolization (TACE) combined with beta-ultrasound guided portal vein embolization (PVE) through fine-needle liver puncture for hepatocellular carcinoma.

METHODS209 patients with primary hepatocellular carcinoma were divided into TACE group (104 patients) and TACE + PVE group (105 patients).

RESULTSThe response rates (CR + PR) were 37.5% in TACE group and 57.2% in TACE + PVE group (P < 0.01). Tumor thrombi became lessened or resolved in the portal vein with incidences of 22.2% in TACE group and 68.8% in TACE + PVE group (P < 0.01). The 1-, 2- and 3-year survival rates were 65.1%, 36.3% and 20.5% in TACE group and 95.6%, 59.6% and 39.1% in TACE + PVE group (P < 0.05).

CONCLUSIONThe effect of TACE combined with PVE is much more effective than TACE alone for hepatocellular carcinoma. Beta-ultrasound guided portal vein embolization through fine-needle liver puncture is effective, easy, safe and should be widely practiced.

Adult ; Aged ; Arteries ; Carcinoma, Hepatocellular ; drug therapy ; metabolism ; pathology ; therapy ; Catheterization ; Chemoembolization, Therapeutic ; adverse effects ; methods ; Female ; Follow-Up Studies ; Humans ; Liver Neoplasms ; drug therapy ; metabolism ; pathology ; therapy ; Male ; Middle Aged ; Portal Vein ; Treatment Outcome ; alpha-Fetoproteins ; metabolism

Hepatocellular carcinoma (HCC) is a major health problem worldwide, and it has a poor prognosis. Extrahepatic metastasis from HCC is not unusual, with direct invasion representing the main spreading mode. Sites that are frequently involved are the lung, bone, and lymph nodes. There are few reports of HCC invading the distant gastrointestinal tract, especially hematogenously. Herein we report a case of sigmoid colon metastasis from HCC. The patient was diagnosed with HCC and treated with transcatheter arterial chemoembolization (TACE). Eighteen months after TACE the patient presented with abdominal pain on the left lower quadrant, and a CT scan showed an enhanced mass on the sigmoid colon. Immunohistochemical staining revealed that a tumor cell was positive for polyclonal carcinoembryonic antigen and weakly positive for hepatocyte antigen, supporting the diagnosis of HCC metastasis. The patient underwent anterior resection for the metastatic HCC.
Carcinoembryonic Antigen/metabolism ; Carcinoma, Hepatocellular/*diagnosis/pathology/*secondary ; Chemoembolization, Therapeutic ; Humans ; Liver Neoplasms/*pathology/therapy ; Male ; Middle Aged ; Sigmoid Neoplasms/*diagnosis/*secondary/ultrasonography ; Tomography, X-Ray Computed

OBJECTIVE: To investigate the antitumor activity of decoction and study its liver and kidney toxicity and its effect on the immune system in a tumor-bearing mouse model. METHODS: Hepatoma H22 tumor-bearing mouse models were randomized into model group, cyclophosphamide (CTX) group, and low-, moderate-, and high-dose decoction groups (JW-L, JW-M, and JW-H groups, respectively). The antitumor activity of decoction was assessed by calculating the tumor inhibition rate and pathological observation of the tumor tissues. Immunohistochemistry was used to detect the expressions of Bax, Bcl-2, Bax/Bcl-2 and caspase-3 in the tumors. The liver and kidney toxicity of decoction was analyzed by evaluating the biochemical indicators of liver and kidney functions. The immune function of the tumor-bearing mice were assessed by calculating the immune organ index, testing peripheral blood routines, and detection of serum IL-2 and TNF-α levels using enzyme-linked immunosorbent assay. RESULTS: Compared with that in the model group, the tumor mass in CTX, JW-M and JW-H groups were all significantly reduced ( < 0.05) with cell rupture and necrosis in the tumors. Immunohistochemistry revealed obviously up-regulated expressions of Bax and caspase-3 and down- regulated expression of Bcl-2 protein with an increased Bax/Bcl-2 ratio in CTX, JW-M and JW-H groups. Treatment with decoction significantly reduced Cr, BUN, AST and ALT levels, improved the immune organ index, increased peripheral blood leukocytes, erythrocytes and hemoglobin levels, and up-regulated the levels of TNF-α and IL-2 in the tumor-bearing mice. These changes were especially significant in JW-H group when compared with the parameters in the model group ( < 0.01). CONCLUSIONS decoction has a strong anti-tumor activity and can improve the liver and kidney functions of tumor-bearing mice. Its anti-tumor effect may be attributed to the up-regulation of Bax, caspase-3, TNF-α and IL-2 levels and the down-regulation of Bcl-2 expression as well as the enhancement of the non-specific immune function.
Animals ; Antineoplastic Agents, Phytogenic ; pharmacology ; Carcinoma, Hepatocellular ; drug therapy ; immunology ; metabolism ; pathology ; Drugs, Chinese Herbal ; pharmacology ; Kidney ; drug effects ; Liver ; drug effects ; pathology ; Liver Neoplasms ; drug therapy ; immunology ; metabolism ; pathology ; Mice ; Necrosis ; Neoplasm Proteins ; metabolism ; Random Allocation ; Up-Regulation

The development of hepatocellular carcinoma (HCC) is a complex process, and HCC arises from the accumulation of multiple genetic alterations leading to changes in the genomic landscape. Current advances in genomic technologies have revolutionized the search for genetic alterations in cancer genomes. Recent studies in which all coding exons in HCC were sequenced have shed new light on the genomic landscape of this malignant disease. Catalogues of these somatic mutations and systematic analysis of catalogued mutations will lead us to uncover candidate HCC driver genes, although further functional validation is needed to determine whether these genes play a causal role in the development of HCC. This review provides an overview of previously known oncogenes and new oncogene candidates in HCC that were uncovered from recent exome or whole-genome sequencing studies. This knowledge provides direction for future personalized treatment approaches for patients with HCC.
Carcinoma, Hepatocellular/*pathology/therapy ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Liver Neoplasms/*pathology/therapy ; Mutation ; Oxidative Stress ; Precision Medicine ; Telomerase/metabolism ; Transcription Factors/genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism