IL‑6 plays a crucial role in epithelial‑mesenchymal transition and pro‑metastasis induced by sorafenib in liver cancer.

Interleukin‑6 (IL‑6) is involved in various biological responses, including tumor progression, metastasis and chemoresistance. However, the role and molecular mechanism of IL‑6 in the treatment of sorafenib in liver cancer remain unclear. In the present study, through western blot analysis, Transwell assay, flow cytometric assay, ELISA analysis and immunohistochemistry it was revealed that sorafenib promoted metastasis and induced epithelial‑mesenchymal transition (EMT) in liver cancer cells in vitro and in vivo, and significantly increased IL‑6 expression.

Effect of TALEN-mediated IL-6 knockout on cell proliferation, apoptosis, invasion and anti-cancer therapy in hepatocellular carcinoma (HCC-LM3) cells.

Purpose: To determine the exact effect of Interleukin-6 (IL-6) on tumor cell proliferation, apoptosis, invasion, and anti-cancer therapy in hepatocellular carcinoma (HCC).

Experimental Design: IL-6 was disrupted by transcription activator-like effector nucleases (TALEN) in HCCLM3 cells, and was used to evaluate the role of IL-6 on tumor cell proliferation, apoptosis, invasion and key signaling pathways involved in sorafenib and/or IFNα therapy.

Results: IL-6 has no direct effect on cell proliferation and invasion but promotes cell apoptosis and up-regulate IL-33 and VEGF-A expression.

Higher proliferation of peritumoral endothelial cells to IL-6/sIL-6R than tumoral endothelial cells in hepatocellular carcinoma.

Background: This study aimed to explore the responses to the interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) complex in peritumoral endothelial cells (PECs) and tumor endothelial cells (TECs), as well as determine the signaling pathways in the angiogenesis of hepatocellular carcinoma (HCC).

Methods: The expression of IL-6, IL-6R, gp130, CD68, HIF-1α, and microvessel density (MVD) were assessed with an orthotopic xenograft model in nude mice. ECs were incubated under hypoxic conditions to detect IL-6 and gp130.

Peritumoral Neuropilin-1 and VEGF receptor-2 expression increases time to recurrence in hepatocellular carcinoma patients undergoing curative hepatectomy.

Purpose: To determined Neuropilin-1 (NRP-1) and vascular endothelial growth factor receptor 2 (VEGFR-2) expression in the tumoral and peritumoral tissues of 214 treatment-naïve HCC patients and its correlation with overall survival (OS) and time to recurrence (TTR).

Experimental Design: NRP-1 and VEGFR-2 expression were examined by tissue microarray and peritumoral hypoxia by pimonidazole staining and angiogenesis by microvessel density (MVD). OS and TTR were evaluated by Kaplan-Meier analysis and log-rank test.

ZBTB20 is involved in liver regeneration after partial hepatectomy in mouse.

Background: A better understanding of the molecular mechanisms in liver regeneration holds promise for exploring the new potential therapy for liver failure. The present study was to investigate the role of zinc finger and BTB domain-containing protein 20 (ZBTB20), a potential factor associated with liver regeneration, in a model of 70% hepatectomy in mice.

Methods: Parameters for liver proliferation such as liver/body ratio and BrdU positivity were obtained via direct measurement and immunohistochemistry.

[Comprehensive measures for improving the radical resection rate and safety of Bismuth-Corlette type III hilar cholangiocarcinoma].

Objective: To investigate the comprehensive measures for improving radical resection rate and safety of Bismuth-Corlette type III hilar cholangiocarcinoma.

Methods: The clinical data of 15 patients with Bismuth-Corlette type III hilar cholangiocarcinoma who performed radical resection from June 2009 to December 2011 was analyzed retrospectively. There were 11 male and 4 female patients, aged from 45 to 74 years (mean 59 years).

Prognostic roles of cross-talk between peritumoral hepatocytes and stromal cells in hepatocellular carcinoma involving peritumoral VEGF-C, VEGFR-1 and VEGFR-3.

Background: Peritumoral liver tissue could play a potential role in hepatocellular carcinoma (HCC) progression and patient survival via angiogenesis- and lymphangiogensis-related factors. The prognostic role of these factors in hepatocytes and stromal cells in HCC patients after curative resection remains to be explored.

Methods: Tumor tissue and surrounding peritumoral tissue were obtained from 145 resected HCC patients without lymph node metastasis (LNM) and 37 resected HCC patients with LNM.

Antiangiogenic therapy promoted metastasis of hepatocellular carcinoma by suppressing host-derived interleukin-12b in mouse models.

Antiangiogenic therapy, specially sorafenib, has become the standard of care for patients with advanced hepatocellular carcinoma (HCC), however, the improvement in survival time is not satisfactory. Previous studies have found that, in some circumstances, antiangiogenic therapy promoted tumor metastasis and the mechanistic studies were mainly focus on cancer-cell-autonomous manners. In two experimental metastasis models with tail-vein injection with hepatoma cells and an orthotopic HCC mouse model, we found that pretreatment with two vascular endothelial growth factor receptor (VEGFR) inhibitors, sunitinib and sorafenib, facilitated tumor cell survival in blood stream and promoted lung metastasis from tumors that were subsequently incubated after drug discontinuation, indicating that host response joined into the pro-metastatic effects.

Direct transformation of lung microenvironment by interferon-α treatment counteracts growth of lung metastasis of hepatocellular carcinoma.

Background: Interferon (IFN)-α is effective in inhibiting tumor growth and metastasis of hepatocellular carcinoma (HCC). However, the biologic mechanisms of IFN-α treatment in lung metastasis are not yet clear.

Methods: The effect of IFN-α treatment was studied by using an orthotopic xenograft model and measuring tumor size and lung metastasis.

Xanthogranulomatous cholecystitis: a clinicopathological study of its association with gallbladder carcinoma.

Objectives: To determine the distribution of macrophages (MΦ) in both xanthogranulomatous cholecystitis (XGC) and gallbladder carcinoma (GBC) and to analyze the association between XGC and GBC.

Methods: From January 2009 to June 2011, 110 patients with gallbladder diseases, including 35 with GBC, 45 with XGC and 30 with chronic cholecystitis (CC), were enrolled. Immunohistochemistry stain and real-time polymerase chain reaction using oncogenes (BCL-2, c-Myc) and anti-oncogene genes (p53, p21) were performed, serum expressions of tumor marker (CA19-9, CA724 and CA242) were also conducted.

Diagnostic and prognostic role of laparoscopic staging for gallbladder carcinoma.

Background: The aim of this study was to evaluate the diagnostic and prognostic role of staging laparoscopy in gallbladder carcinoma (GBC).

Methods: From January 2007 through December 2010, 79 GBC patients without evidence of metastatic disease on preoperative imaging underwent staging laparoscopy. Peritoneal and liver metastases were assessed by a single surgeon in a systematic manner.

Up-regulation of platelet-derived growth factor-A is responsible for the failure of re-initiated interferon alpha treatment in hepatocellular carcinoma.

Background: Postoperative interferon-α(IFN-α) treatment delays hepatocellular carcinoma(HCC) recurrence and prolongs patient survival, and may thus be an effective form of adjuvant therapy. However, clinical observations found that HCC recurs in some patients within 8 months of IFN-α treatment being discontinued. We investigated whether HCC regrowth appears after IFN-α is discontinued, whether re-initiated IFN-α is effective, and the underlying mechanisms of IFN-α treatment.

Sorafenib down-regulates expression of HTATIP2 to promote invasiveness and metastasis of orthotopic hepatocellular carcinoma tumors in mice.

Background & Aims: Antiangiogenic agents can sometimes promote tumor invasiveness and metastasis, but little is known about the effects of the antiangiogenic drug sorafenib on progression of hepatocellular carcinoma (HCC).

Methods: Sorafenib was administered orally (30 mg · kg(-1) · day(-1)) to mice with orthotopic tumors grown from HCC-LM3, SMMC7721, or HepG2 cells. We analyzed survival times of mice, along with tumor growth, metastasis within liver and to lung, and induction of the epithelial-mesenchymal transition.

Antiangiogenic effects of pazopanib in xenograft hepatocellular carcinoma models: evaluation by quantitative contrast-enhanced ultrasonography.

Background: Antiangiogenesis is a promising therapy for advanced hepatocellular carcinoma (HCC), but the effects are difficult to be evaluated. Pazopanib (GW786034B) is a pan-vascular endothelial growth factor receptor inhibitor, the antitumor effects or antiangiogenic effects haven't been investigated in HCC.

Methods: In vitro direct effects of pazopanib on human HCC cell lines and endothelial cells were evaluated.

[Somatostatin enhanced anti-tumor effect of doxorubicin on gallbladder cancer cells through the regulation of intracellular drug concentration].

Objective: To investigate the possible mechanisms by which Somatostatin (SST) enhances the anti-tumor effect of doxorubicin (DOX) on gallbladder cancer cells.

Methods: GBC-SD cells were grouped into 4 groups: SST-treated group, DOX-treated group, SST+DOX co-treated group and control group. The concentrations of SST and DOX were 75 µg/ml and 5 µg/ml based on our previous studies.

Evaluation of two modified ECF regimens in the treatment of advanced gallbladder cancer.

Gallbladder cancer is a rare disease and it is associated with a poor clinical outcome and survival. A standard therapy for it has not been established yet. The aim of this study is to evaluate efficacy and safety of two modified ECF regimens in advanced gallbladder cancer patients.

Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects.

Purpose: To investigate the role of macrophages in tumor progression under sorafenib treatment and to explore whether combination of drugs that deplete macrophages improved the antitumor effect of sorafenib.

Experimental Design: Tumor growth, lung metastasis, and tumor angiogenesis were observed in HCCLM3-R and SMMC7721, two human hepatocellular carcinoma xenograft nude mouse models, when treated with sorafenib (30 mg/kg daily, n = 6 per group) or a vehicle as control. Macrophage infiltration was measured in the peripheral blood and in sorafenib-treated tumor by immunohistochemistry and flow cytometry with F4/80 antibody and CD11b antibody.

High expression of macrophage colony-stimulating factor-1 receptor in peritumoral liver tissue is associated with poor outcome in hepatocellular carcinoma after curative resection.

Background: Macrophage colony-stimulating factor 1 receptor (CSF-1R) expression in hepatocellular carcinoma (HCC) and its prognostic values are unclear. This study evaluated the prognostic values of the intratumoral and peritumoral expression of CSF-1R in HCC patients after curative resection.

Methods: Tissue microarrays containing material from cohort 1 (105 patients) and cohort 2 (32 patients) were constructed.

Expression and prognostic significance of placental growth factor in hepatocellular carcinoma and peritumoral liver tissue.

Vascular endothelial growth factor-targeted therapy is a promising treatment for hepatocellular carcinoma (HCC), but its clinical benefit is often accompanied by acquired resistance. In animal studies, antiplacental growth factor therapy is effective with less resistance. The role of placental growth factor (PlGF) in the progression of HCC is not clear.

Bevacizumab enhances chemosensitivity of hepatocellular carcinoma to adriamycin related to inhibition of survivin expression.

Purpose: In recent years, anti-angiogenesis drugs have shown promising clinical effects against many tumors, particularly in combination with chemotherapy. Although the combination has become a standard of care for many tumors, the mechanisms of the chemosensitizing activity of anti-angiogenic drugs are not fully understood. Here, we sought to determine if anti-angiogenesis drug bevacizumab could enhance the chemosensitivity of HCC by inhibition of survivin.

Long-term interferon-α treatment suppresses tumor growth but promotes metastasis capacity in hepatocellular carcinoma.

Purpose: To elucidate the effect of IFN-α treatment on tumor growth and metastasis of hepatocellular carcinoma (HCC).

Methods: IFN-α administration was conducted in nude mice using an orthotopic implantation model of human HCC, and the key molecular markers in the IFN-α treatment was detected by immunohistochemistry staining and PCR array.

Results: Up to 12 weeks of IFN-α treatment significantly suppressed tumor growth of HCC, but relatively increased the number of circulating tumor cells, which might be due to the enhanced tumor hypoxia as well as up-regulation of metastasis-related genes, such as HIF-1α, c-met, u-PA, PDGF-A, and IL-8.

Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells.

Purpose: Increasing evidence indicates that tumor-derived endothelial cells (TEC) possess a distinct and unique phenotype compared with endothelial cells (NEC) from adjacent normal tissue and may be able to acquire resistance to drugs. The aim of this study was to investigate the angiogenesis activity and response to drug treatment of TECs and NECs derived from human hepatocellular carcinoma (HCC).

Experimental Design: TECs or NECs were isolated from HCC or adjacent normal liver tissue using anti-CD105 antibody coupled to magnetic beads.

Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival.

Background: The chemokine and bone marrow-homing receptor CXCR4 is implicated in metastases of various cancers. This study was conducted to analyze the association of CXCR4 expression with hepatocellular carcinoma (HCC) bone metastasis and patient survival.

Methods: Tumor tissue from HCC patients with (n = 43) and without (n = 138) bone metastasis was subjected to immunohistochemical staining for CXCR4 using tissue microarrays.

Protein expression profiling of vascular endothelial growth factor and its receptors identifies subclasses of hepatocellular carcinoma and predicts survival.

Purpose: To examine expression profile and prognostic significance of vascular endothelial growth factor (VEGF) and its receptors in hepatocellular carcinoma (HCC) and peritumoral tissue.

Methods: Expression of VEGF-A, VEGF-C, and VEGF receptor 1(VEGFR-1), VEGFR-2, and VEGFR-3 in tumor and peritumoral liver tissue was studied by immunohistochemistry in a tissue microarray from 107 patients with HCC. Unsupervised hierarchical cluster analyses were conducted to identify relevant clusters.

High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma.

Purpose: To investigate prognostic values of the intratumoral and peritumoral expression of macrophage colony-stimulating factors (M-CSF) in hepatocellular carcinoma (HCC) patients after curative resection.

Patients And Methods: Expression of M-CSF and density of macrophages (M Phi) were assessed by immunohistochemistry in tissue microarrays containing paired tumor and peritumoral liver tissue from 105 patients who had undergone hepatectomy for histologically proven HCC. Prognostic value of these and other clinicopathologic factors was evaluated.