Browsing by Subject "Carcinoma, Hepatocellular"

Now showing 1 - 6 of 6
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    The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-02) Jinjuvadia, Raxitkumar; Patel, Suhag; Liangpunsakul, Suthat; Department of Medicine, IU School of Medicine
    BACKGROUND: The metabolic syndrome (MetS) and/or its individual components have been linked to the development of cancer. Recent studies have suggested a similar link to hepatocellular carcinoma (HCC). The aim of this study was to evaluate the direction and magnitude of the association between the MetS and HCC. METHODS: Two reviewers independently conducted a systemic search to identify the available evidence from databases from January 1980 to June 2012. Search terms included "Metabolic syndrome," "insulin resistance syndrome," "metabolic abnormalities" combined with "hepatocellular carcinoma," and "liver cancer." No language restriction was applied to the search. Only studies reporting an effect measure for the association between MetS and HCC were eligible for inclusion. Publication bias was assessed using the Begg and Egger tests, with a visual inspection of funnel plot. All analyses were performed using Comprehensive Meta-analysis version 2 software. RESULTS: Four studies (3 cohort and 1 case control) with a total of 829,651 participants were included in the analysis. The age range of participants was between 30 and 84 years. The combined analysis showed an overall 81% increased risk of HCC in cases with MetS (relative risk, 1.81; 95% confidence interval, 1.37-2.41). After excluding the single case-control study from analysis, the overall risk ratio remained statistically significant (relative risk, 1.49; 95% confidence interval, 1.27-1.74). Funnel plot inspection, Begg and Egger tests showed no evidence of publication bias for combined analysis. CONCLUSIONS: Though studies are scarce, currently available epidemiologic data are suggestive of significantly higher risk of HCC among patients with MetS.
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    Decreased PCSK9 expression in human hepatocellular carcinoma
    (Springer (Biomed Central Ltd.), 2015-12-16) Bhat, Mamatha; Skill, Nicolas; Marcus, Victoria; Deschenes, Marc; Tan, Xianming; Bouteaud, Jeanne; Negi, Sarita; Awan, Zuhier; Aikin, Reid; Kwan, Janet; Amre, Ramila; Tabaries, Sebastien; Hassanain, Mazen; Seidah, Nabil G.; Maluccio, Mary; Siegel, Peter; Metrakos, Peter; Department of Surgery, IU School of Medicine
    BACKGROUND: The management of hepatocellular carcinoma (HCC) is limited by the lack of adequate screening biomarkers and chemotherapy. In response, there has been much interest in tumor metabolism as a therapeutic target. PCSK9 stimulates internalization of the LDL-receptor, decreases cholesterol uptake into hepatocytes and affects liver regeneration. Thus, we investigated whether PCSK9 expression is altered in HCC, influencing its ability to harness cholesterol metabolism. METHODS: Thirty-nine patients undergoing partial hepatectomy or liver transplantation for HCC were consented for use of HCC tissue to construct a tissue microarray (TMA). The TMA was immunostained for PCSK9. Imagescope software was used to objectively determine staining, and assess for pathological and clinical correlations. PCSK9 and LDL receptor mRNA levels in flash-frozen HCC and adjacent liver tissue were determined by quantitative RT-PCR. Serum PCSK9 levels were determined by ELISA. RESULTS: By immunohistochemistry, there was significantly lower expression of PCSK9 in HCC as compared to adjacent cirrhosis (p-value < 0.0001, wilcoxon signed-rank test). Significantly greater staining of PCSK9 was present in cirrhosis compared to HCC (p value <0.0001), and positivity (percentage of positive cells) was significantly greater in cirrhosis compared to HCC (p-value < 0.0001). Conversely, significantly higher expression of LDL-R was present in HCC as compared to the adjacent cirrhosis (p-value < 0.0001). There was no significant correlation of PCSK9 staining with grade of tumor, but there were significant correlations between PCSK9 staining and stage of fibrosis, according to spearman correlation test. PCSK9 mRNA levels were relatively less abundant within HCC compared to adjacent liver tissue (p-value =0.08) and normal control tissue (p-value =0.02). In contrast, serum PCSK9 levels were significantly increased among patients with HCC compared to those with chronic liver disease without HCC (p-value =0.029). LDL receptor mRNA was consistantly greater in HCC when compared to normal control tissue (p-value = 0.06) and, in general, was significantly greater in HCC when compared to adjacent liver (p-value = 0.04). CONCLUSIONS: The decreased expression of PCSK9 and conversely increased LDL-R expression in HCC suggests that HCC modulates its local microenvironment to enable a constant energy supply. Larger-scale studies should be conducted to determine whether PCSK9 could be a therapeutic target for HCC.
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    Detection of Hepatocellular Carcinoma in Hepatitis C Patients: Biomarker Discovery by LC-MS
    (Elsevier, 2014-09-01) Bowers, Jeremiah; Hughes, Emma; Skill, Nicholas; Maluccio, Mary; Raftery, Daniel; Department of Surgery, IU School of Medicine
    Hepatocellular carcinoma (HCC) accounts for most cases of liver cancer worldwide; contraction of hepatitis C (HCV) is considered a major risk factor for liver cancer even when individuals have not developed formal cirrhosis. Global, untargeted metabolic profiling methods were applied to serum samples from patients with either HCV alone or HCC (with underlying HCV). The main objective of the study was to identify metabolite based biomarkers associated with cancer risk, with the long term goal of ultimately improving early detection and prognosis. Serum global metabolite profiles from patients with HCC (n=37) and HCV (n=21) were obtained using high performance liquid chromatography-mass spectrometry (HPLC-MS) methods. The selection of statistically significant metabolites for partial least-squares discriminant analysis (PLS-DA) model creation based on biological and statistical significance was contrasted to that of a traditional approach utilizing p-values alone. A PLS-DA model created using the former approach resulted in a model with 92% sensitivity, 95% specificity, and an AUROC of 0.93. A series of PLS-DA models iteratively utilizing three to seven metabolites that were altered significantly (p<0.05) and sufficiently (FC≤0.7 or FC≥1.3) showed the best performance using p-values alone, the PLS-DA model was capable of generating 73% sensitivity, 95% specificity, and an AUROC of 0.92. Metabolic profiles derived from LC-MS readily distinguish patients with HCC and HCV from those with HCV only. Differences in the metabolic profiles between highrisk individuals and HCC indicate the possibility of identifying the early development of liver cancer in at risk patients. The use of biological significance as a selection process prior to PLSDA modeling may offer improved probabilities for translation of newly discovered biomarkers to clinical application.
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    GDNF secreted from adipose-derived stem cells stimulates VEGF-independent angiogenesis
    (Impact Journals, LLC, 2016-06-14) Zhong, Zhaohui; Gu, Huiying; Peng, Jirun; Wang, Wenzheng; Johnstone, Brian H.; March, Keith L.; Farlow, Martin R.; Du, Yansheng; Department of Neurology, School of Medicine
    Adipose tissue stroma contains a population of mesenchymal stem cells (MSC) promote new blood vessel formation and stabilization. These adipose-derived stem cells (ASC) promote de novo formation of vascular structures in vitro. We investigated the angiogenic factors secreted by ASC and discovered that glial-derived neurotrophic factor (GDNF) is a key mediator for endothelial cell network formation. It was found that both GDNF alone or present in ASC-conditioned medium (ASC-CM) stimulated capillary network formation by using human umbilical vein endothelial cells (HUVECs) and such an effect was totally independent of vascular endothelial growth factor (VEGF) activity. Additionally, we showed stimulation of capillary network formation by GDNF, but not VEGF, could be blocked by the Ret (rearranged during transfection) receptor antagonist RPI-1, a GDNF signaling inhibitor. Furthermore, GDNF were found to be overexpressed in cancer cells that were resistant to the anti-angiogenic treatment using the VEGF antibody. Cancer cells in the liver hepatocellular carcinoma (HCC), a non-nervous related cancer, highly overexpressed GDNF as compared to normal liver cells. Our data strongly suggest that, in addition to VEGF, GDNF secreted by ASC and HCC cells, may be another important factor promoting pathological neovascularization. Thus, GDNF may be a potential therapeutic target for HCC and obesity treatments.
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    Inflammatory Chemokines MIP-1δ and MIP-3α Are Involved in the Migration of Multipotent Mesenchymal Stromal Cells Induced by Hepatoma Cells
    (Mary Ann Liebert, Inc., 2015-05-15) Lejmi, Esma; Perriraz, Nadja; Clement, Sophie; Morel, Philippe; Baertschiger, Reto; Christofilopoulos, Panayiotis; Meier, Raphael; Bosco, Domenico; Gonelle-Gispert, Carmen; Buhler, Leo H.; Department of Surgery, IU School of Medicine
    In vivo, bone marrow-derived multipotent mesenchymal stromal cells (MSC) have been identified at sites of tumors, suggesting that specific signals mobilize and activate MSC to migrate to areas surrounding tumors. The signals and migratory mechanisms that guide MSC are not well understood. Here, we investigated the migration of human MSC induced by conditioned medium of Huh-7 hepatoma cells (Huh-7 CM). Using a transwell migration system, we showed that human MSC migration was increased in the presence of Huh-7 CM. Using a human cytokine antibody array, we detected increased levels of MIP-1δ and MIP-3α in Huh-7 CM. Recombinant chemokines MIP-1δ and MIP-3α induced MSC migration. Anti-MIP-1δ and anti-MIP-3α antibodies added to Huh-7 CM decreased MSC migration, further suggesting that MIP-1δ and MIP-3α were implicated in the Huh-7 CM-induced MSC migration. By real-time polymerase chain reaction, we observed an absence of chemokine receptors CCR2 and CXCR2 and low expression of CCR1, CCR5, and CCR6 in MSC. Expression of these chemokine receptors was not regulated by Huh-7 CM. Furthermore, matrix metalloproteinase 1 (MMP-1) expression was strongly increased in MSC after incubation with Huh-7 CM, suggesting that MSC migration depends on MMP-1 activity. The signaling pathway MAPK/ERK was activated by Huh-7 CM but its inhibition by PD98059 did not impair Huh-7 CM-induced MSC migration. Further, long-term incubation of MSC with MIP-1δ increased α-smooth muscle actin expression, suggesting its implication in the Huh-7 CM-induced evolvement of MSC into myofibroblasts. In conclusion, we report that two inflammatory cytokines, MIP-1δ and MIP-3α, are able to increase MSC migration in vitro. These cytokines might be responsible for migration and evolvement of MSC into myofibroblasts around tumors.
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    Phase I Study of Lenalidomide and Sorafenib in Patients With Advanced Hepatocellular Carcinoma
    (Alphamed Press, 2016-06) Shahda, Safi; Loehrer, Patrick J.; Clark, Romnee S.; Spittler, A. John; Althouse, Sandra K.; Chiorean, E. Gabriella; Department of Medicine, IU School of Medicine
    LESSONS LEARNED: Combination therapies in patients with hepatocellular carcinoma can be associated with overlapping toxicity and are therefore poorly tolerated.Using sorafenib at the maximum tolerated dose can lead to a higher incidence of toxicities. Consequently, combination studies might evaluate sorafenib at alternative schedules or doses to improve tolerance, recognizing this could affect sorafenib efficacy.Although this combination was poorly tolerated, it does not exclude further evaluation of new-generation immunomodulator drugs or immune checkpoint inhibitors in the hope of optimizing tolerance and safety. BACKGROUND: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), and to date, no combination therapy has demonstrated superior survival compared with sorafenib alone. The immunosuppressive microenvironment in HCC is a negative predictor for survival. Lenalidomide is an immunomodulator and antiangiogenic agent, with limited single-agent efficacy in HCC. Based on these data, we designed a phase I study of sorafenib plus lenalidomide to determine the safety and preliminary antitumor activity of this combination. METHODS: This was an open-label, phase I study with a 3+3 dose escalation/de-escalation design. The starting dose of sorafenib was 400 mg p.o. b.i.d. and of lenalidomide was 15 mg p.o. daily with a planned dose escalation by 5 mg per cohort up to 25 mg daily. Dose de-escalation was planned to a sorafenib dose of 400 mg p.o. daily combined with two doses of lenalidomide: 10 mg p.o. daily for a 28-day cycle (cohort 1) and 10 mg p.o. daily for a 21- or 28-day cycle (cohort 2). Patients with cirrhosis, a Child-Pugh score of A-B7, and no previous systemic therapy were eligible. RESULTS: Five patients were enrolled. Their median age was 56 years (range 39-61), and the ECOG status was 0-2. Four patients were treated at dose level (DL) 1. Because of the poor tolerance to the combination associated with grade 2 toxicities, one more patient was treated at DL -1. No dose-limiting toxicity was observed as specified per protocol. The most common toxicities were nausea, anorexia, pruritus, elevated liver enzymes, and elevated bilirubin. Three patients experienced one or more of the following grade 3 toxicities: fatigue (DL 1), increased bilirubin (DL 1), skin desquamation (DL -1), and elevated transaminase levels (DL 1). The median duration of therapy was 1 cycle (range 1-3). All patients discontinued the study, 4 because of progressive disease and 1 by patient preference. The best confirmed response was progressive disease. The median progression-free survival was 1.0 month (95% confidence interval 0.9-2.8), and the median overall survival was 5.9 months (95% confidence interval 3.68-23.4). CONCLUSION: In our small study, the combination of lenalidomide and sorafenib was poorly tolerated and showed no clinical activity. Although the study was closed early because of toxicity concerns, future studies assessing combinations of sorafenib with new-generation immunomodulator drugs or other immunomodulatory agents, should consider lower starting doses of sorafenib to avoid excessive toxicity.