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He K, Liu X, Yang Z. Development and Validation of a Vascular Endothelial Growth Factor A-associated Prognostic Model for Unresectable Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:139-156. [PMID: 36777498 PMCID: PMC9910209 DOI: 10.2147/jhc.s399299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 01/26/2023] [Indexed: 02/05/2023] Open
Abstract
Purpose High serum vascular endothelial growth factor (VEGF) levels have been identified as an independent risk factor for hepatocellular carcinoma (HCC). We aimed to construct a VEGF-included prognostic model to accurately perform individualized predictions of survival probability for patients with unresectable HCC. Patients and Methods From October 2018 to March 2021, 182 consecutive newly diagnosed patients with unresectable HCC were retrospectively enrolled. Baseline serum VEGF-A and other characteristics were collected for all patients. Univariate Cox regression analysis and LASSO regression model were applied to develop the prognostic model, enhanced bootstrap method with 100 replicates was performed to validate its discrimination and calibration. We compared the final model with China Liver Cancer (CNLC) stage, American Joint Committee on Cancer (AJCC) stage, Barcelona Clinic Liver Cancer (BCLC) stage, and the model without the "VEGF". Finally, the established model was stratified by age. Results The VEGF-associated prognostic model we established has high accuracy with an overall C-index of 0.7892 after correction for optimistic estimates. The area under the curve (AUC) of the time-dependent receiver operating characteristic (ROC) curves at 6-month, 1-year, and 2-year after correction were 0.843, 0.860, 0.833, respectively, and the calibration of the model was 0.1153, 0.1514, and 0.1711, respectively. The final model showed significant improvement in predicting OS when compared to the other models according to Harrell's C-index, The AUC of the time-dependent ROC, area under the decision curve analysis (AUDC), integrated discrimination improvement (IDI), and continuous net reclassification index (NRI). Conclusion The VEGF-associated prognostic model may help to predict the survival probabilities of HCC patients with favorable performance and discrimination. However, further validation is required since we only verified this model using internal but not external data.
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Affiliation(s)
- Kun He
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Xinyu Liu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Zelong Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China,Correspondence: Zelong Yang, Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, No. 15, Changle West Road, Xi’an, People’s Republic of China, Tel +86 17795714179, Email
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He K, Yang Z, Liu X, Yang Y, Song W, Wang S, Chen Y. Identification of Potential Predictors of Prognosis and Sorafenib-Associated Survival Benefits in Patients with Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization. Curr Oncol 2022; 30:476-491. [PMID: 36661687 PMCID: PMC9857819 DOI: 10.3390/curroncol30010038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/22/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Some studies have shown that sorafenib could significantly prolong the overall survival of patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization (TACE). However, other studies revealed that patients had no access to sorafenib-related survival benefits after TACE. To identify the predictive biomarkers of therapeutic efficacy of sorafenib, we explored the potential predictive value of vascular endothelial growth factor (VEGF) and other clinical variables for survival benefits from sorafenib in patients treated with TACE previously. The results demonstrated that patients with tumor size > 7 cm or total bilirubin ≤ 17.3 μmol/L showed significant survival benefits from sorafenib after TACE treatment compared with those with tumor size ≤ 7 cm or total bilirubin > 17.3 μmol/L. Meanwhile, patients with VEGF > 131.09 pg/mL may obtain sorafenib-associated survival benefits after TACE when compared to those with VEGF ≤ 131.09 pg/mL, which needs further confirmation. The abovementioned results are helpful to confirm the specific population who are sensitive to targeted therapy. (1) Background: VEGF plays a crucial role in modulating proliferation and metastasis in HCC. We aimed to explore the relationship between VEGF and the prognosis, as well as the mortality risk of HCC patients who received TACE, and whether it and other variables could be considered as potential biomarkers for predicting the benefits from sorafenib. (2) Method: A total of 230 consecutive newly diagnosed patients with unresectable HCC treated with either TACE or TACE−sorafenib were collected retrospectively. Cox regression analyses were performed to evaluate the prognostic value of VEGF. Furthermore, restricted cubic splines were fitted to assess the nonlinear associations between VEGF and OS, and the threshold effect analysis was subsequently performed. Lastly, the potential factors for predicting the survival benefits from sorafenib after the TACE procedure were identified using the Cox proportional hazard model with an interaction term. (3) Results: VEGF was recognized as an independent prognostic factor for OS in the TACE alone cohort (HR = 3.237, p = 0.013). A nonlinear relationship was observed between VEGF and OS in HCC patients with TACE administration after adjustment for confounders (p for nonlinearity = 0.030); the mortality risk increased with increasing the baseline VEGF before the inflection point, and the HR for death was 1.008. There was no significant interaction between the VEGF levels and treatment modality (p for interaction = 0.233), and further studies are needed to identify its predictive value on the efficacy of sorafenib. Patients with tumor size > 7 cm or total bilirubin ≤ 17.3 μmol/L derived significant sorafenib-related benefits in OS when compared to those with tumor size ≤ 7 cm or total bilirubin > 17.3 μmol/L (p for interaction = 0.004 and 0.031, respectively). (4) Conclusions: Within a certain concentration range, elevated baseline VEGF meant an increased risk of death in HCC patients treated with TACE. Significant improvements in OS associated with sorafenib were observed in patients with higher tumor size and lower total bilirubin after TACE treatment.
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Affiliation(s)
| | | | | | | | | | | | - Yong Chen
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
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3
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Yang Y, Cao Y. The impact of VEGF on cancer metastasis and systemic disease. Semin Cancer Biol 2022; 86:251-261. [PMID: 35307547 DOI: 10.1016/j.semcancer.2022.03.011] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/08/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023]
Abstract
Metastasis is the leading cause of cancer-associated mortality and the underlying mechanisms of cancer metastasis remain elusive. Both blood and lymphatic vasculatures are essential structures for mediating distal metastasis. The vasculature plays multiple functions, including accelerating tumor growth, sustaining the tumor microenvironment, supplying growth and invasive signals, promoting metastasis, and causing cancer-associated systemic disease. VEGF is one of the key angiogenic factors in tumors and participates in the initial stage of tumor development, progression and metastasis. Consequently, VEGF and its receptor-mediated signaling pathways have become one of the most important therapeutic targets for treating various cancers. Today, anti-VEGF-based antiangiogenic drugs (AADs) are widely used in the clinic for treating different types of cancer in human patients. Despite nearly 20-year clinical experience with AADs, the impact of these drugs on cancer metastasis and systemic disease remains largely unknown. In this review article, we focus our discussion on tumor VEGF in cancer metastasis and systemic disease and mechanisms underlying AADs in clinical benefits.
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Affiliation(s)
- Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institute, 171 77 Stockholm, Sweden.
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4
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Hong T, Tsai H, Lin Y, Chen C, Chuang C, Wu I, Chang T, Han M, Lin S, Chen S, Wang H, Chen P, Hsieh M, Chiang H, Liu C, Kuo H. Efficacy of Local‐regional Treatment Plus Sorafenib in Intermediate‐stage Hepatocellular Carcinoma Patients Refractory to Transarterial Chemoembolization. ADVANCES IN DIGESTIVE MEDICINE 2022. [DOI: 10.1002/aid2.13317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Tzu‐Chun Hong
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Hong‐Ming Tsai
- Department of Diagnostic Radiology National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Yih‐Jyh Lin
- Department of Surgery National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Chiung‐Yu Chen
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Chiao‐Hsiung Chuang
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - I‐Chin Wu
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Ting‐Tsung Chang
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Meng‐Zhi Han
- Department of Internal Medicine An Nan Hospital, China Medical University Tainan Taiwan
| | - Sheng‐Hsiang Lin
- Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Shang‐Hung Chen
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
- National Institute of Cancer Research, National Health Research Institutes Tainan Taiwan
| | - Hao‐Chen Wang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Po‐Jun Chen
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Ming‐Tsung Hsieh
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Hsueh‐chien Chiang
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Chieh‐Yen Liu
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
| | - Hsin‐Yu Kuo
- Department of Internal Medicine National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Tainan Taiwan
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HORIKIRIZONO H, ISHIGAKI K, IIZUKA K, TAMURA K, SAKURAI N, TERAI K, HEISHIMA T, YOSHIDA O, ASANO K. Serum vascular endothelial growth factor in dogs with various proliferative diseases. J Vet Med Sci 2022; 84:720-725. [PMID: 35370210 PMCID: PMC9177393 DOI: 10.1292/jvms.21-0509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Angiogenesis plays an important role in the proliferation and metastasis mechanisms of malignant tumors. Vascular endothelial growth factor (VEGF), a group of cytokines that contribute to
angiogenesis and vasculogenesis. This study aimed to investigate the serum VEGF-A concentrations in dogs with various proliferative diseases. A total of 202 dogs that were
histopathologically diagnosed with proliferative diseases were included in the study. Serum VEGF-A concentrations were measured using enzyme-linked immunosorbent assay. Median serum VEGF-A
concentrations in dogs were as follows: healthy dogs, 4 pg/ml [0–21 pg/ml]; hepatocellular carcinoma, 30 pg/ml [0–158 pg/ml, P=<0.001]; hepatocellular adenoma, 32 pg/ml
[0–49 pg/ml, P=0.003]; hepatic nodular hyperplasia, 18 pg/ml [0–51 pg/ml, P=0.595]; adrenal pheochromocytoma, 32 pg/ml [0–187 pg/ml,
P=<0.001]; adrenocortical carcinoma, 32 pg/ml [3–161 pg/ml, P=0.002]; adrenocortical adenoma, 27 pg/ml [0–106 pg/ml, P=0.005];
colorectal adenocarcinoma, 36 pg/ml [0–75 pg/ml, P=0.002]; colorectal adenoma, 43 pg/ml [0–48 pg/ml, P=0.144]; inflammatory colorectal polyps, 37 pg/ml
[0–111 pg/ml, P=<0.001]; pulmonary adenocarcinoma, 35 pg/ml [4–107 pg/ml, P=0.002]; pulmonary histiocytic sarcoma, 35 pg/ml [0–131 pg/ml,
P=0.016]; and follicular thyroid carcinoma, 35 pg/ml [0–106 pg/ml, P=0.009]. The serum VEGF-A concentrations were significantly higher in dogs with
neoplastic lesions compared to healthy dogs, except for colorectal adenoma. High serum VEGF-A concentrations were observed in dogs with proliferative diseases. The present study suggests
that angiogenesis-inhibiting therapy, which targets VEGF-A, may be useful for canine neoplastic diseases.
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Affiliation(s)
- Hiro HORIKIRIZONO
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University
| | - Kumiko ISHIGAKI
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University
| | - Keigo IIZUKA
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University
| | - Kei TAMURA
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University
| | - Naoki SAKURAI
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University
| | - Kazuyuki TERAI
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University
| | - Tatsuya HEISHIMA
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University
| | - Orie YOSHIDA
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University
| | - Kazushi ASANO
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University
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Wilk SS, Zabielska-Koczywąs KA. Molecular Mechanisms of Canine Osteosarcoma Metastasis. Int J Mol Sci 2021; 22:3639. [PMID: 33807419 PMCID: PMC8036641 DOI: 10.3390/ijms22073639] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/24/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma (OSA) represents the most common bone tumor in dogs. The malignancy is highly aggressive, and most of the dogs die due to metastasis, especially to the lungs. The metastatic process is complex and consists of several main steps. Assessment of the molecular mechanisms of metastasis requires in vitro and especially in vivo studies for a full evaluation of the process. The molecular and biological resemblance of canine OSA to its human counterpart enables the utilization of dogs as a spontaneous model of this disease in humans. The aim of the present review article is to summarize the knowledge of genes and proteins, including p63, signal transducer and activator of transcription 3 (STAT3), Snail2, ezrin, phosphorylated ezrin-radixin-moesin (p-ERM), hepatocyte growth factor-scatter factor (HGF-SF), epidermal growth factor receptor (EGFR), miR-9, and miR-34a, that are proven, by in vitro and/or in vivo studies, to be potentially involved in the metastatic cascade of canine OSA. The determination of molecular targets of metastatic disease may enhance the development of new therapeutic strategies.
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Affiliation(s)
| | - Katarzyna A. Zabielska-Koczywąs
- Department of Small Animal Diseases and Clinic, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland;
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7
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Zhou L, Pan LC, Zheng YG, Zhang XX, Liu ZJ, Meng X, Shi HD, Du GS, He Q. Reduction of FoxP3 + Tregs by an immunosuppressive protocol of rapamycin plus Thymalfasin and Huaier extract predicts positive survival benefits in a rat model of hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:472. [PMID: 32395516 PMCID: PMC7210174 DOI: 10.21037/atm.2020.03.129] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Investigate immunoregulation and anti-tumor immunity of FoxP3+Tregs after treatment with rapamycin (RAPA/SRL) plus thymalfasin (Zadaxin) and Huaier extract (PS-T) in a hepatocellular carcinoma (HCC) rat model simulating HCC relapse after liver transplant (LT). Methods We successfully established a rat model simulating HCC relapse after LT using an optimized chemical induction method with TACROLIMUS, methylprednisolone, and diethylnitrosamine as identified by visible liver nodules and hematoxylin-eosin staining. The model rats were then treated with RAPA, Zadaxin, and PS-T. Immune status changes were analyzed by flow cytometry, and protein expression of Akt and mTOR was determined by western blotting. Cytokines were measured by ELISAs. Results Combined therapy by RAPA plus Zadaxin and PS-T obviously alleviated hepatic pathological changes and significantly decreased the levels of FoxP3+Tregs in peripheral blood, the spleen, and the liver (P<0.05) and expression of mTOR protein (P<0.01) in the liver, obviously improved survival time (P=0.02). Moreover, the levels of CD8+T cells were increased significantly to almost normal levels (P<0.05) in comparison with no SRL monotherapy protocols. Inhibitory cytokines were also decreased in accordance with FoxP3+Tregs. Significant decreases of IL-10 and TGF-β were observed after SRL-based therapy (P<0.01) in comparison with the other groups. Serum alpha fetoprotein (AFP) and vascular endothelial growth factor (VEGF) levels were also decreased significantly (P<0.05). FoxP3+Tregs showed a negative correlation with CD8+ and CD4+/CD8+T cells and a positive correlation with AFP, and VEGF (P<0.05). Conclusions SRL-based therapy reduces FoxP3+Tregs to decrease secreted inhibitory cytokines which may enhancement the viability and number of CD8+T cells to exert anti-tumor effects that are mainly mediated through the AKT-mTOR signaling pathway.
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Affiliation(s)
- Lin Zhou
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, China.,Department of (Second) Hepatobiliary Surgery, the 1 Medical Center of Chinese PLA General Hospital, Beijing 100853, China.,Departmentof Hepatobiliary Surgery, the 8 Medical center of Chinese PLA General Hospital, Beijing 100091, China
| | - Li-Chao Pan
- Department of (Second) Hepatobiliary Surgery, the 1 Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Yong-Gen Zheng
- Departmentof Hepatobiliary Surgery, the 8 Medical center of Chinese PLA General Hospital, Beijing 100091, China
| | - Xin-Xue Zhang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, China
| | - Zhi-Jia Liu
- Departmentof Hepatobiliary Surgery, the 8 Medical center of Chinese PLA General Hospital, Beijing 100091, China
| | - Xuan Meng
- Department of (Second) Hepatobiliary Surgery, the 1 Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Hai-Da Shi
- Department of (Second) Hepatobiliary Surgery, the 1 Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Guo-Sheng Du
- Departmentof Hepatobiliary Surgery, the 8 Medical center of Chinese PLA General Hospital, Beijing 100091, China
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, China
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Lacin S, Yalcin S. The Prognostic Value of Circulating VEGF-A Level in Patients With Hepatocellular Cancer. Technol Cancer Res Treat 2020; 19:1533033820971677. [PMID: 33234055 PMCID: PMC7705781 DOI: 10.1177/1533033820971677] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Neovascularization plays a crucial pathogenic role in tumor development and
vascular endothelial growth factor (VEGF-A) is a key signaling element that
drives angiogenesis, thereby facilitating hepatocellular cancer (HCC) growth
and metastasis. We aimed to define the relationship between serum VEGF-A
levels and clinical outcomes in a cohort of Turkish patients with HCC. Methods: We enrolled and prospectively followed 84 patients with HCC in our study.
Serum VEGF-A levels were measured and we assessed the association between
VEGF-A levels and clinical features. Results: Forty-eight patients had cirrhosis while 35 patients were noncirrhotic. Serum
VEGF-A levels were significantly lower in HCC patients with cirrhosis
compared to non-cirrhotic HCC patients (p = 0.03).In terms of viral
hepatitis subtype, 36 (%42.8) of patients were hepatitis B virus (HBV)
positive and 8 (%9.5) of patients were hepatitis C virus (HCV) positive.
Patients with serum VEGF-A levels ≥100 pg/mL had significantly lower OS
rates than patients with serum VEGF-A level <100 pg/mL (p = 0.01). The OS
rates were 5.8 and 14.2 months, respectively (p = 0.02). The median OS was
7.38 months (95% CI: 5.89-13.79 months). We observed a significant
relationship between serum VEGF-A level and tumor size. Patients with tumor
size ≤ 5cm had lower VEGF-A levels than patients with VEGF-A levels <5
cm. The VEGF-A levels were 132.7 and 342.1 pg/mL, respectively (p <
0.001). The median follow-up was 32 months. Conclusions: Serum VEGF-A level, a biological marker of angiogenesis, is an independent
predictor of survival in patients with HCC. Serum VEGF-A levels may be
utilized to predict response to treatment targeting serum VEGF-A in patients
with HCC.
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Affiliation(s)
- Sahin Lacin
- Department of Medical Oncology, Faculty of Medicine, 64173Yeditepe University, İstanbul, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, 64005Hacettepe University, Hacettepe Cancer Institute, Ankara, Turkey
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Park CS, Eom DW, Ahn Y, Jang HJ, Hwang S, Lee SG. Can heme oxygenase-1 be a prognostic factor in patients with hepatocellular carcinoma? Medicine (Baltimore) 2019; 98:e16084. [PMID: 31261522 PMCID: PMC6617477 DOI: 10.1097/md.0000000000016084] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Heme oxygenase-1 (HO-1) is an important catalytic enzyme in heme degradation, which increases during stressful conditions. It plays a major role in antioxidative and antiapoptotic processes and is associated with tumor growth and metastasis.This study aimed to evaluate the degree of HO-1 expressions in hepatocellular carcinoma (HCC) surgical specimens and the correlation between HO-1 expression and patient prognosis. Formalin-fixed, paraffin-embedded HCC tissue samples (n = 96) were included in the analysis, and the expression of HO-1 was evaluated by immunohistochemical staining. We reviewed clinical features of patients and evaluated the prognostic role of HO-1 in patient survival and recurrence.Positive HO-1 expression was identified in 43 cases (44.8%) and was frequently found in patients with advanced histology (Edmondson-Steiner [E-S] grade 2, 3, 4), α-fetoprotein (AFP) level of more than 200 IU/mL, and the presence of microvascular and capsular invasion (P < .05). In the univariate analysis, the overall survival (OS) and disease-free survival (DFS) of patients with HO-1-positive HCC were not statistically different from those with HO-1-negative HCC. Moreover, HO-1 expression was not associated with patient survival and recurrence based on the multivariate analysis. In the subgroup analysis of patients without preoperative transarterial chemoembolization (TACE) (n = 61), HO-1 was not also associated with tumor recurrence (P = .681).The clinical implication of HO-1 activity is controversial in various malignancies. However, HO-1 expression did not seem to influence the prognosis of HCC patients.
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Affiliation(s)
- Cheon-Soo Park
- Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea
| | - Dae-Woon Eom
- Department of Pathology, Gangneung Asan Hospital, University of Ulsan College of Medicine
| | - Yongchel Ahn
- Department of Hematology and Oncology, Gangneung Asan Hospital, University of Ulsan College of Medicine
| | - Hyuk Jai Jang
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung
| | - Shin Hwang
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung-Gyu Lee
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Abstract
Ramucirumab is a fully humanized monoclonal antibody directed selectively at VEGFR-2 - a key player in the VEGF orchestra and angiogenic process. It has demonstrated clinical efficacy and a favorable safety profile in the treatment of a number of malignancies including gastric, lung, urothelial, colorectal and, most recently, advanced liver cancer. This article describes the recent Phase III trial results of ramucirumab in patients with hepatocellular carcinoma, including safety data and patient-reported outcomes, with particular emphasis on efficacy data in the patient population with baseline α-fetoprotein levels ≥400 ng/ml, traditionally considered a poor prognostic group.
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Affiliation(s)
- Fiona Turkes
- Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Ian Chau
- Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UK
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Update in global trends and aetiology of hepatocellular carcinoma. Contemp Oncol (Pozn) 2018; 22:141-150. [PMID: 30455585 PMCID: PMC6238087 DOI: 10.5114/wo.2018.78941] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 08/25/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver responsible for an increasing number of cancer-related deaths, especially in developing economies of Asia and Africa. A plethora of risk factors have been described in the literature. Some of the important ones include chronic viral hepatitis, liver cirrhosis, environmental toxins such as aflatoxin, non-alcoholic fatty liver disease, lifestyle factors like alcohol consumption, smoking, and dietary factors, metabolic diseases like diabetes mellitus and obesity, and genetic and hereditary disorders. The development of HCC is complex involving sustained inflammatory damage leading to hepatocyte necrosis, regeneration, and fibrotic deposition. It also poses multiple challenges in diagnosis and treatment despite advances in diagnostic, surgical, and other therapeutic advancements. This is a narrative review of findings of multiple studies that were retrieved from electronic databases like PubMed, MEDLINE, Embase, Google Scholar, Scopus, and Cochrane. We summarise the current knowledge regarding the epidemiology and various risk factors for the development of HCC with a brief note on various prevention strategies.
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Abstract
Background/Aims To date, numerous studies have demonstrated that several angiogenesis regulators circulate in the blood and may function as endocrine factors in cancer patients. This review aims to give a comprehensive insight into the possible clinical value of circulating angiogenesis regulators, mainly basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF), angiogenin, pleiotrophin, thrombospondin (TSP) and endostatin (ES) in cancer patients. Methods A computerized (MEDLINE) and a manual search based on the reference lists of the publications were performed to identify articles published on this topic. Results In a detailed literature search, approximately 100 publications were found up to the end of 1999. Circulating angiogenic factors such as bFGF, VEGF, HGF and angiogenin have been evaluated not only as diagnostic and/or prognostic factors but also as predictive factors in cancer patients. On the other hand, little is known about the clinical significance of negative regulators. Neither the source nor the mechanism of protein externalization has been clarified in detail. Conclusions Although there are no known factors with established clinical utility, circulating angiogenesis regulators may be useful in several situations. They could be used to determine the risk of developing cancer, to screen for early detection, to distinguish benign from malignant disease, and to distinguish between different types of malignancies. In patients with established malignancies such factors might be used to determine prognosis, to predict the response to therapy, and to monitor the clinical course. Further investigations are warranted to assess the specific utility of each factor.
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Affiliation(s)
- K Kuroi
- Department of Surgery, Tokyo Metropolitan Komagome Hospital, Japan.
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Rohr-Udilova N, Klinglmüller F, Seif M, Hayden H, Bilban M, Pinter M, Stolze K, Sieghart W, Peck-Radosavljevic M, Trauner M. Oxidative stress mediates an increased formation of vascular endothelial growth factor in human hepatocarcinoma cells exposed to erlotinib. Oncotarget 2017; 8:57109-57120. [PMID: 28915658 PMCID: PMC5593629 DOI: 10.18632/oncotarget.19055] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 06/19/2017] [Indexed: 02/05/2023] Open
Abstract
The tyrosine kinase inhibitor erlotinib targets the receptor of epidermal growth factor (EGFR) involved in development of hepatocellular carcinoma (HCC). Although inefficient in established HCC, erlotinib has been recently proposed for HCC chemoprevention. Since Cyp3A4 and Cyp1A2 enzymes metabolize erlotinib in the liver, the insights into the mechanisms of erlotinib effects on liver cells with maintained drug metabolizing activity are needed. We applied erlotinib to both commercially available (SNU398, Huh7) and established in Austria HCC cell lines (HCC-1.2, HCC-3). Cyp3A4 and Cyp1A2, microarray gene expression, cell viability, LDH release, DHFC fluorescence were assessed. VEGF expression was analysed by real-time RT-PCR and ELISA. Higher cumulative expression of erlotinib metabolizing enzymes was observed in HCC-1.2 and HCC-3 cells. Gene expression microarray analysis showed upregulation of VEGF signalling by erlotinib. VEGF was increased up to 134 ± 14% (n = 5, p = 0.002) in HCC-1.2, HCC-3 and Huh7 cells. Interventions by Cyp1A2 and Mek2siRNA, MEK inhibitor UO126, diphenylene iodonium, as well as a combination of N-acetylcysteine with selenium all inhibited VEGF upregulation caused by erlotinib. Thus, erlotinib increases VEGF production by mechanisms involving Cyp1A2, oxidative stress and MEK1/2. VEGF may favour angiogenesis and growth of early HCC tumours limiting the therapeutic and chemopreventive effects of erlotinib.
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Affiliation(s)
- Nataliya Rohr-Udilova
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria
| | - Florian Klinglmüller
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, A-1090 Vienna, Austria
| | - Martha Seif
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria
| | - Hubert Hayden
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria
| | - Martin Bilban
- Clinical Institute for Laboratory Medicine, Medical University of Vienna, A-1090 Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria
| | - Klaus Stolze
- Institute of Animal Nutrition and Functional Plant Compounds, Department for Farm Animals and Veterinary Public Health, University of Veterinary Medicine, A-1220 Vienna, Austria
| | - Wolfgang Sieghart
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria
| | - Markus Peck-Radosavljevic
- Clinic Klagenfurth, Division of Gastroenterology and Hepatology, 9020 Klagenfurt am Wörthersee, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria
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14
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Cash E, Sephton SE, Chagpar AB, Spiegel D, Rebholz WN, Zimmaro LA, Tillie JM, Dhabhar FS. Circadian disruption and biomarkers of tumor progression in breast cancer patients awaiting surgery. Brain Behav Immun 2015; 48:102-14. [PMID: 25728235 DOI: 10.1016/j.bbi.2015.02.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 02/09/2015] [Accepted: 02/20/2015] [Indexed: 02/08/2023] Open
Abstract
Psychological distress, which can begin with cancer diagnosis and continue with treatment, is linked with circadian and endocrine disruption. In turn, circadian/endocrine factors are potent modulators of cancer progression. We hypothesized that circadian rest-activity rhythm disruption, distress, and diurnal cortisol rhythms would be associated with biomarkers of tumor progression in the peripheral blood of women awaiting breast cancer surgery. Breast cancer patients (n=43) provided actigraphic data on rest-activity rhythm, cancer-specific distress (IES, POMS), saliva samples for assessment of diurnal cortisol rhythm, cortisol awakening response (CAR), and diurnal mean. Ten potential markers of tumor progression were quantified in serum samples and grouped by exploratory factor analysis. Analyses yielded three factors, which appear to include biomarkers reflecting different aspects of tumor progression. Elevated factor scores indicate both high levels and strong clustering among serum signals. Factor 1 included VEGF, MMP-9, and TGF-β; suggesting tumor invasion/immunosuppression. Factor 2 included IL-1β, TNF-α, IL-6R, MCP-1; suggesting inflammation/chemotaxis. Factor 3 included IL-6, IL-12, IFN-γ; suggesting inflammation/TH1-type immunity. Hierarchical regressions adjusting age, stage and socioeconomic status examined associations of circadian, distress, and endocrine variables with these three factor scores. Patients with poor circadian coordination as measured by rest-activity rhythms had higher Factor 1 scores (R(2)=.160, p=.038). Patients with elevated CAR also had higher Factor 1 scores (R(2)=.293, p=.020). These relationships appeared to be driven largely by VEGF concentrations. Distress was not related to tumor-relevant biomarkers, and no other significant relationships emerged. Women with strong circadian activity rhythms showed less evidence of tumor promotion and/or progression as indicated by peripheral blood biomarkers. The study was not equipped to discern the cause of these associations. Circadian/endocrine aberrations may be a manifestation of systemic effects of aggressive tumors. Alternatively, these results raise the possibility that, among patients with active breast tumors, disruption of circadian activity rhythms and elevated CAR may facilitate tumor promotion and progression.
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Affiliation(s)
- E Cash
- Department of Surgery, Division of Otolaryngology-HNS, University of Louisville School of Medicine, Louisville, KY, United States; Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, United States; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
| | - S E Sephton
- Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, United States; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States.
| | - A B Chagpar
- The Breast Center - Smilow Cancer Hospital at Yale-New Haven, Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
| | - D Spiegel
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, United States
| | - W N Rebholz
- Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, United States
| | - L A Zimmaro
- Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, United States
| | - J M Tillie
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
| | - F S Dhabhar
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, United States; Institute for Immunity, Transplantation, and Infection, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, United States.
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15
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SHI SHANSHAN, YUAN CHENXING, ZHUANG KAIZAN, LIANG GUIKAI, YAO ZHANGTING, WANG DUODUO, WENG QINJIE, CAO JI, LUO PEIHUA, ZHU HONG, DING LING, MA SHENGLIN. Resistance of SMMC-7721 hepatoma cells to etoposide in hypoxia is reversed by VEGF inhibitor. Mol Med Rep 2015; 11:3842-7. [DOI: 10.3892/mmr.2015.3217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Accepted: 10/24/2014] [Indexed: 11/06/2022] Open
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16
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Muto J, Shirabe K, Sugimachi K, Maehara Y. Review of angiogenesis in hepatocellular carcinoma. Hepatol Res 2015; 45:1-9. [PMID: 24533487 DOI: 10.1111/hepr.12310] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 01/27/2014] [Accepted: 02/03/2014] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular tumor, and its vascularity is unique and greatly different from peripheral parenchyma of liver. Afferent and efferent vessels of HCC lesions come to differ as the lesion develops. The characteristic of the flow regulates the common style of metastasis. The portal tract of the HCC lesion is the first site of the intrahepatic metastasis, because cancer cells roll into the portal vein via efferent flow. On microscopic observation, HCC displays marked vascular abnormalities, arteriogenesis and capillarization. Arteriogenesis is defined as the growth of functional collateral arteries covered with smooth muscle cells from pre-existing arteries. Sinusoidal capillarization involves the transformation of fenestrated hepatic sinusoids into continuous capillaries. Several angiogenic factors have been reported, and some of them are studied as prognostic factors or target molecules of chemotherapeutic reagents. However, the mechanism of neovascularization during HCC development is still unclear. This review discusses the characteristics of angiogenesis in HCC and known angiogenic factors of HCC.
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Affiliation(s)
- Jun Muto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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17
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Zhang W, Kim R, Quintini C, Hashimoto K, Fujiki M, Diago T, Eghtesad B, Miller C, Fung J, Tan A, Menon KVN, Aucejo F. Prognostic role of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma undergoing liver transplantation. Liver Transpl 2015; 21:101-11. [PMID: 25283528 DOI: 10.1002/lt.24013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 09/04/2014] [Accepted: 09/29/2014] [Indexed: 12/21/2022]
Abstract
Vascular endothelial growth factor (VEGF) is pivotal in the development of hepatocellular carcinoma (HCC). Studies have demonstrated the prognostic value of circulating VEGF levels in patients undergoing liver resection or locoregional therapy (LRT) for HCC. We investigated the significance of preoperative plasma VEGF levels in patients with HCC undergoing liver transplantation (LT) at a Western transplant center. Pre-LT plasma VEGF levels were measured with an enzyme-linked immunoassay for 164 patients with HCC undergoing LT. The preoperative plasma VEGF level was correlated with clinicopathological variables and overall and recurrence-free post-LT survival. A higher pre-LT plasma VEGF level was significantly associated with pre-LT LRT (P = 0.01), multiple tumors (P = 0.02), a total tumor diameter ≥ 5 cm (P = 0.01), bilobar tumor distribution (P = 0.03), tumor vascular invasion (VI; P < 0.001), and HCC beyond the Milan criteria (P < 0.001). Patients with a plasma VEGF level > 44 pg/mL had significantly worse overall and disease-free survival than those with VEGF levels ≤ 44 pg/mL (P = 0.04 and P = 0.02, respectively). In a multivariate analysis, a plasma VEGF level > 44 pg/mL was independently associated with tumor VI (P < 0.001) and recurrence-free survival (hazard ratio = 2.12, 95% confidence interval = 1.08-4.14, P = 0.03). In conclusion, in patients with chronic end-stage liver disease and HCC, a pre-LT plasma VEGF level > 44 pg/mL may be a predictor of tumor VI and recurrence-free post-LT survival.
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Affiliation(s)
- Wei Zhang
- Hepatobiliary & Liver Transplant Surgery; Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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Talaat RM, Salem TA, El-Masry S, Imbarek A, Mokhles M, Abdel-Aziz A. Circulating pro- and anti-angiogenic mediators in patients infected with hepatitis C at different stages of hepatocellular carcinoma. J Med Virol 2014; 86:1120-9. [DOI: 10.1002/jmv.23932] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2014] [Indexed: 12/12/2022]
Affiliation(s)
- Roba M. Talaat
- Molecular Biology Department; Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University; Sadat City Egypt
| | - Tarek A. Salem
- Molecular Biology Department; Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University; Sadat City Egypt
| | - Samir El-Masry
- Molecular Biology Department; Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University; Sadat City Egypt
| | - Arafat Imbarek
- Molecular Biology Department; Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University; Sadat City Egypt
| | - Mohamed Mokhles
- Medical Biochemistry Department; Medical Division, National Research Center (NRC); Sadat City Egypt
| | - Amal Abdel-Aziz
- Molecular Biology Department; Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University; Sadat City Egypt
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19
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Ranieri G, Marech I, Lorusso V, Goffredo V, Paradiso A, Ribatti D, Gadaleta CD. Molecular targeting agents associated with transarterial chemoembolization or radiofrequency ablation in hepatocarcinoma treatment. World J Gastroenterol 2014; 20:486-497. [PMID: 24574717 PMCID: PMC3923023 DOI: 10.3748/wjg.v20.i2.486] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer in the world. According to Barcelona Clinic Liver Cancer modified criteria, patients with early stage disease are candidate to radiofrequency ablation (RFA), while patients with intermediate stage HCC are usually treated by transarterial chemoembolization (TACE). TACE and RFA induce a transient devascularisation effect followed by strong neo-angiogenic stimulus. In fact, after these procedures, it has been demonstrated an up-regulation of pro-angiogenic and growth factors such as vascular endothelial growth factor-A, which might contribute to accelerated progression in patients with incomplete response. Several studies have demonstrated that MAP-kinase and AKT pathways, in addition to neo-angiogenesis, have an important role in the development of HCC. In advanced HCC, anti-angiogenic therapy and tyrosine kinases inhibitors showed potential clinical benefit. Actually, a number of clinical studies are ongoing testing these agents in combination with TACE or RFA. In this paper, we have reviewed the most recent preclinical and clinical results of such trials.
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20
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Finegold MJ, López-Terrada DH. Hepatic Tumors in Childhood. PATHOLOGY OF PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2014:547-614. [DOI: 10.1007/978-3-642-54053-0_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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21
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Liu Y, Sogawa K, Sunaga M, Umemura H, Satoh M, Kazami T, Yoshikawa M, Tomonaga T, Yokosuka O, Nomura F. Increased concentrations of apo A-I and apo A-II fragments in the serum of patients with hepatocellular carcinoma by magnetic beads-assisted MALDI-TOF mass spectrometry. Am J Clin Pathol 2014; 141:52-61. [PMID: 24343737 DOI: 10.1309/ajcpblfbnap6n2un] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Recent advances in sophisticated technologies in proteomics should provide promising ways to discover novel markers for hepatocellular carcinoma (HCC) in the early diagnosis. METHODS Serum peptide and protein profiling was conducted by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Profiling was carried out in a training set of 16 patients with HCC and a testing set of 15 patients with cirrhosis without HCC. All the patients were hepatitis C virus positive. Candidate peaks were processed to partial purification, followed by protein identification by amino acid sequence analysis. Immunoprecipitation was conducted to confirm the protein identity. RESULTS Partial purification and protein identification revealed that one peak that was up-regulated in HCC sera both in the training and the testing sets was a fragment of apolipoprotein A-I (apo A-I). Immunoprecipitation confirmed this result. CONCLUSIONS MALDI-TOF MS analysis revealed that apo A-I is a potential novel serum marker of HCC. Combination of these pretreatments and the current magnet bead-assisted MALDI-TOF MS will further enhance the efficiency of biomarker discovery for HCC.
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Affiliation(s)
- Yang Liu
- Departments of Medicine and Clinical Oncology, Chiba University, Chiba, Japan
- Basic Medicine College, Beihua University, Jilin City, China
| | - Kazuyuki Sogawa
- Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan
- Clinical Proteomics Center, Chiba University Hospital, Chiba
| | - Masahiko Sunaga
- Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroshi Umemura
- Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Mamoru Satoh
- Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan
- Clinical Proteomics Center, Chiba University Hospital, Chiba
| | - Takahiro Kazami
- Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masaharu Yoshikawa
- Departments of Medicine and Clinical Oncology, Chiba University, Chiba, Japan
| | - Takeshi Tomonaga
- Clinical Proteomics Center, Chiba University Hospital, Chiba
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Osaka, Japan
| | - Osamu Yokosuka
- Departments of Medicine and Clinical Oncology, Chiba University, Chiba, Japan
| | - Fumio Nomura
- Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan
- Clinical Proteomics Center, Chiba University Hospital, Chiba
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22
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Diaz-Sanchez A, Matilla A, Nuñez O, Lorente R, Fernandez A, Rincón D, Campos R, Bañares R, Clemente G. Serum angiopoietin-2 level as a predictor of tumor invasiveness in patients with hepatocellular carcinoma. Scand J Gastroenterol 2013; 48:334-43. [PMID: 23249262 DOI: 10.3109/00365521.2012.746391] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Because hepatocellular carcinoma (HCC) has important angiogenic activity, the expression of angiopoietin-2 (Ang-2) may have a pathogenic role. The information about the influence of serum Ang-2 (sAng-2) in patients with HCC is scarce. AIMS The aim was to assess the association between sAng-2 levels and characteristics of tumor and liver disease in patients with HCC. METHODS sAng-2 concentrations in peripheral (sAng-2-P) and hepatic (sAng-2-H) veins were analyzed by ELISA in 33 patients with chronic liver disease who underwent a splanchnic hemodynamic study. Thirty-two patients received treatment for HCC. RESULTS The median age was 61 years and 79% were male. Hepatitis C infection (70%) was the main etiology. Most patients were Child-Pugh grade A (72.7%). sAng-2-P and sAng-2-H were well correlated (r = 0.95; p < 0.0001). A significant association was found between sAng-2-H and lobar tumor extension, vascular thrombosis, BCLC staging, infiltrating pattern, abnormal alpha-fetoprotein level, fulfillment of the Milan criteria, and performance of nonsystemic treatment. sAng-2-H also showed a significant correlation with the MELD score (r = 0.49; p = 0.007), albumin (r = -0.63; p < 0.001), and HVPG (r = 0.44; p = 0.02). Eleven patients received treatment with radiofrequency ablation and eight with transarterial chemoembolization. HCC treatment did not influence the sAng-2 concentration while the necrosis response to treatment was not influenced by previous sAng-2 levels. CONCLUSIONS Ang-2 seems to play an important role in the angiogenic processes of HCC and its serum levels are associated with tumor characteristics and invasive behavior. Our results suggest that Ang-2 is not related with treatment response and its level is not modified by treatment.
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Affiliation(s)
- Antonio Diaz-Sanchez
- Gastroenterology Unit, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain.
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23
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Lin CC, Yin MC. Clinical significance of circulating IL-10 and fibronectin levels in hepatocellular carcinoma patients with HBV infection. Biomedicine (Taipei) 2012. [DOI: 10.1016/j.biomed.2012.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
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24
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Rohr-Udilova N, Sieghart W, Eferl R, Stoiber D, Björkhem-Bergman L, Eriksson LC, Stolze K, Hayden H, Keppler B, Sagmeister S, Grasl-Kraupp B, Schulte-Hermann R, Peck-Radosavljevic M. Antagonistic effects of selenium and lipid peroxides on growth control in early hepatocellular carcinoma. Hepatology 2012; 55:1112-21. [PMID: 22105228 DOI: 10.1002/hep.24808] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
UNLABELLED Activation of the activator protein 1 (AP-1) transcription factor as well as increased serum levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-8 predict poor prognosis of patients with hepatocellular carcinomas (HCCs). Moreover, HCC patients display reduced selenium levels, which may cause lipid peroxidation and oxidative stress because selenium is an essential component of antioxidative glutathione peroxidases (GPx). We hypothesized that selenium-lipid peroxide antagonism controls the above prognostic markers and tumor growth. (1) In human HCC cell lines (HCC-1.2, HCC-3, and SNU398) linoleic acid peroxide (LOOH) and other prooxidants enhanced the expression of VEGF and IL-8. LOOH up-regulated AP-1 activation. Selenium inhibited these effects. This inhibition was mediated by glutathione peroxidase 4 (GPx4), which preferentially degrades lipid peroxides. Selenium enhanced GPx4 expression and total GPx activity, while knock-down of GPx4 by small interfering RNA (siRNA) increased VEGF, and IL-8 expression. (2) These results were confirmed in a rat hepatocarcinogenesis model. Selenium treatment during tumor promotion increased hepatic GPx4 expression and reduced the expression of VEGF and of the AP-1 component c-fos as well as nodule growth. (3) In HCC patients, increased levels of LOOH-related antibodies (LOOH-Ab) were found, suggesting enhanced LOOH formation. LOOH-Ab correlated with serum VEGF and IL-8 and with AP-1 activation in HCC tissue. In contrast, selenium inversely correlated with VEGF, IL-8, and HCC size (the latter only for tumors smaller than 3 cm). CONCLUSION Reduced selenium levels result in accumulation of lipid peroxides. This leads to enhanced AP-1 activation and consequently to elevated expression of VEGF and IL-8, which accelerate the growth of HCC. Selenium supplementation could be considered for investigation as a strategy for chemoprevention or additional therapy of early HCC in patients with low selenium levels.
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Affiliation(s)
- Nataliya Rohr-Udilova
- Division of Gastroenterology and Hepatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria
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25
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Lin ZY, Chuang YH, Chuang WL. Cancer-associated fibroblasts up-regulate CCL2, CCL26, IL6 and LOXL2 genes related to promotion of cancer progression in hepatocellular carcinoma cells. Biomed Pharmacother 2012; 66:525-9. [PMID: 22739041 DOI: 10.1016/j.biopha.2012.02.001] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 02/29/2012] [Indexed: 12/13/2022] Open
Abstract
Impact of different cancer-associated fibroblast (CAF) cell lines on proliferation, migration, invasion and differential expressions of genes in different hepatocellular carcinoma (HCC) cell lines was investigated. Two human CAF cell lines (F26/KMUH, F28/KMUH) and two human HCC cell lines (HCC24/KMUH, HCC38/KMUH) were studied. Influence of F28/KMUH cells on expressions of genes in HCC38/KMUH cells was detected by microarray to select genes for further analysis. Both CAF cell lines promoted proliferation (all P<0.05), migration (all P<0.05) and Matrigel invasion (all P<0.0001) of both HCC cell lines. F26/KMUH cells showed stronger promoted effects on, firstly, proliferation of HCC24/KMUH cells (P=0.0064) and, secondly, migration of both HCC cell lines than F28/KMUH cells did (all P<0.002). Ten up-regulated genes (APLN, CCL2, CCL26, CXCR4, IL6, MUC1, LOXL2, PDGFA, PGK1, VEGFA) related to proliferation, migration, invasion and angiogenesis of HCC detected by microarray were selected for quantitative reverse transcriptase-polymerase chain reaction analysis. Both CAF cell lines had same tendency of effects on differential expressions of genes in same HCC cell line, but expressions of genes between different HCC cell lines were not consistent. Only CCL2, CCL26, IL6 and LOXL2 genes were consistently up-regulated in both HCC cell lines. In conclusion, the effects of CAFs to promote proliferation, migration and invasion of HCC cells are influenced by the characteristics of both CAFs and HCC cells. Up-regulations of CCL2, CCL26, IL6 and LOXL2 genes in cancer cells are part of the common effects of CAFs on HCC cells.
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Affiliation(s)
- Zu-Yau Lin
- Cancer Center and Division of Hepatobiliary Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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26
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Kaseb AO, Morris JS, Hassan MM, Abbruzzese JL. Reply to A. Goyal et al. J Clin Oncol 2012. [DOI: 10.1200/jco.2011.40.9375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Ahmed O. Kaseb
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Manal M. Hassan
- The University of Texas MD Anderson Cancer Center, Houston, TX
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Frenette C, Gish R. Targeted systemic therapies for hepatocellular carcinoma: Clinical perspectives, challenges and implications. World J Gastroenterol 2012; 18:498-506. [PMID: 22363115 PMCID: PMC3280394 DOI: 10.3748/wjg.v18.i6.498] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 06/06/2011] [Accepted: 06/13/2011] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a lethal disease in most patients, due to its aggressive course and a lack of effective systemic therapies for advanced disease. Surgical resection and liver transplantation remain the only curative options for a small subset of patients. Few patients with HCC are diagnosed early enough to be eligible for curative treatment. Angiogenesis inhibition is a natural therapeutic target for all solid tumors, but particularly for the highly vascularized HCC tumors. With the approval of the targeted agent sorafenib, there are now additional options for patients with HCC. Although sorafenib does produce some improvement in survival in HCC patients, the responses are not durable. In addition, there are significant dermatologic, gastrointestinal, and metabolic toxicities, and, as importantly, there is still limited knowledge of its usefulness in special subpopulations with HCC. Other angiogenesis inhibitors are in development to treat HCC both in the first-line setting and for use following sorafenib failure; the furthest in development is brivanib, a dual fibroblast growth factor pathway and vascular endothelial growth factor receptor inhibitor. Additional agents with antiangiogenic properties also in phase II and III development for the treatment of patients with HCC include bevacizumab, ramucirumab, ABT-869, everolimus and ARQ 197.
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28
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Perdomo AB, Ciccosanti F, Iacono OL, Angeletti C, Corazzari M, Daniele N, Testa A, Pisa R, Ippolito G, Antonucci G, Fimia GM, Piacentini M. Liver protein profiling in chronic hepatitis C: identification of potential predictive markers for interferon therapy outcome. J Proteome Res 2011; 11:717-27. [PMID: 22098443 DOI: 10.1021/pr2006445] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The current anti-hepatitis C virus (HCV) therapy, based on pegylated-interferon alpha and ribavirin, has limited success rate and is accompanied by several side effects. The aim of this study was to identify protein profiles in pretreatment liver biopsies of HCV patients correlating with the outcome of antiviral therapy. Cytosolic or membrane/organelle-enriched protein extracts from liver biopsies of eight HCV patients were analyzed by two-dimensional fluorescence difference gel electrophoresis and mass spectrometry. Overall, this analysis identified 21 proteins whose expression levels correlate with therapy response. These factors are involved in interferon-mediated antiviral activity, stress response, and energy metabolism. Moreover, we found that post-translational modifications of dihydroxyacetone kinase were also associated with therapy outcome. Differential expression of the five best performing markers (STAT1, Mx1, DD4, DAK, and PD-ECGF) was confirmed by immunoblotting assays in an independent group of HCV patients. Finally, we showed that a prediction model based on the expression levels of these markers classifies responder and nonresponder patients with an accuracy of 85.7%. These results provide evidence that the analysis of pretreatment liver protein profiles is valuable for discriminating between responder and nonresponder HCV patients, and may contribute to reduce the number of nonresponder patients exposed to therapy-associated risks.
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Serial serum VEGF-A, angiopoietin-2, and endostatin measurements in cirrhotic patients with hepatocellular carcinoma treated by transcatheter arterial chemoembolization. Kaohsiung J Med Sci 2011; 27:314-22. [PMID: 21802642 DOI: 10.1016/j.kjms.2011.03.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Accepted: 12/24/2010] [Indexed: 12/15/2022] Open
Abstract
Vascular endothelial growth factor (VEGF), angiopoietin-2, and endostatin have been reported to be related with angiogenesis of hepatocellular carcinoma (HCC). The potential feasibility of serial serum VEGF-A, angiopoietin-2, and endostatin measurements in cirrhotic patients with HCC treated by transcatheter arterial chemoembolization (TACE) was investigated. VEGF-A, angiopoietin-2, and endostatin serum level were determined by enzyme-linked immunosorbent assay 1 day before and 7 days after TACE in 40 patients. Then they were followed up for 3 months. The results showed that TACE could cause significant increase of VEGF-A (p < 0.01) and angiopoietin-2 (p = 0.01); whereas there was no significant change of endostatin (p > 0.1). Twenty-five patients with rapid growth of HCC within 3 months after TACE had higher proportion of American Joint Committee on Cancer HCC staging >II and higher increase of VEGF-A after TACE than 15 patients without rapid growth (all p < 0.05). Stepwise logistic regression analysis revealed that VEGF-A >16.7 pg/mL 7 days after TACE selected by receiver operating characteristic curve analysis (p < 0.05) was the only independent predictor for rapid growth of HCC (odds ratio 6.33, 95% confidence interval: upper 26, lower 1.54, p < 0.05; sensitivity 76%, specificity 66.7%, accuracy 72.5%, positive predictive level 79.2%, negative predictive level 62.5%, p < 0.01). In conclusion, significant increases of serum level VEGF-A and angiopoietin-2 after TACE have been demonstrated from this study. Therefore, serial VEGF-A level 1 day before and 7 days after TACE may be used to predict rapid HCC growth.
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Vanpouille-Box C, Lacoeuille F, Roux J, Aubé C, Garcion E, Lepareur N, Oberti F, Bouchet F, Noiret N, Garin E, Benoît JP, Couturier O, Hindré F. Lipid nanocapsules loaded with rhenium-188 reduce tumor progression in a rat hepatocellular carcinoma model. PLoS One 2011; 6:e16926. [PMID: 21408224 PMCID: PMC3049769 DOI: 10.1371/journal.pone.0016926] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Accepted: 01/07/2011] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC(188)Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC(188)Re-SSS in a chemically induced hepatocellular carcinoma rat model. METHODOLOGY/PRINCIPAL FINDINGS Animals were treated with an injection of LNC(188)Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n = 12; 120 MBq, n = 11) were compared with sham (n = 12), blank LNC (n = 7) and (188)Re-perrhenate (n = 4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC(188)Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC(188)Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process. CONCLUSIONS/SIGNIFICANCE Overall, these results demonstrate that internal radiation with LNC(188)Re-SSS is a promising new strategy for hepatocellular carcinoma treatment.
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Affiliation(s)
| | - Franck Lacoeuille
- LUNAM Université, Université d'Angers, INSERM U646, Angers, France
- Nuclear Medicine Department, Angers CHU, Angers, France
| | - Jérôme Roux
- LUNAM Université, Université d'Angers, SCAHU, UFR Medicine, Angers, France
| | - Christophe Aubé
- Radiology Department, Angers CHU, Angers, France
- LUNAM Université, Université d'Angers, Laboratory HIFI, UPRES EA3589, Angers, France
| | - Emmanuel Garcion
- LUNAM Université, Université d'Angers, INSERM U646, Angers, France
| | - Nicolas Lepareur
- Medical Imaging Department, CRLCC Eugene Marquis, Rennes, France
- European University of Brittany, Rennes, France
| | - Frédéric Oberti
- LUNAM Université, Université d'Angers, Laboratory HIFI, UPRES EA3589, Angers, France
| | | | - Nicolas Noiret
- European University of Brittany, Rennes, France
- UMR CNRS 6226, ENSCR, Rennes, France
| | - Etienne Garin
- Medical Imaging Department, CRLCC Eugene Marquis, Rennes, France
- European University of Brittany, Rennes, France
| | | | - Olivier Couturier
- LUNAM Université, Université d'Angers, INSERM U646, Angers, France
- Nuclear Medicine Department, Angers CHU, Angers, France
| | - François Hindré
- LUNAM Université, Université d'Angers, INSERM U646, Angers, France
- * E-mail:
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Giacalone A, Montalto G, Giannitrapani L, Balasus D, Terranova A, Cervello M, Soresi M, Marasà L. Association Between Single Nucleotide Polymorphisms in the Cyclooxygenase-2, Tumor Necrosis Factor-α, and Vascular Endothelial Growth Factor-A Genes, and Susceptibility to Hepatocellular Carcinoma. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2011; 15:193-6. [PMID: 21319995 DOI: 10.1089/omi.2010.0095] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Antonio Giacalone
- Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Palermo, Italy
| | - Giuseppe Montalto
- Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Palermo, Italy
| | - Lydia Giannitrapani
- Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Palermo, Italy
| | - Daniele Balasus
- Department of Human Pathology, A.R.N.A.S. Civic Hospital, Palermo, Italy
| | - Angela Terranova
- Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Palermo, Italy
| | - Melchiorre Cervello
- Institute of Biomedicine and Molecular Immunology, National Research Council, Palermo, Italy
| | - Maurizio Soresi
- Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Palermo, Italy
| | - Lorenzo Marasà
- Department of Human Pathology, A.R.N.A.S. Civic Hospital, Palermo, Italy
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Abstract
Hepatocellular carcinoma (HCC) is a fatal disease that represents the fifth most common human cancer. Although remarkable progress has been achieved in HCC treatment in China, the overall incidence and mortality rates of HCC show no obvious changes. Pharmacological treatment can not improve the prognosis of patients with unresectable HCC. This emphasizes the need to identify new targets for early diagnosis, chemoprevention, and treatment of the disease. An effort to understand the molecular mechanisms responsible for tumor initiation and progression has led to the identification of several potential molecular targets for HCC. The majority of these targets are involved in receptor tyrosine kinase-activated pathways, such as the Raf/MEK/ERK, PI-3K/Akt/mTOR, and Jak/Stat pathways. Sorafenib is a multikinase inhibitor that has attracted wide attention. This review describes the potential targets for HCC and recent progress in targeted therapy of the disease.
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Talaat RM. Soluble angiogenesis factors in sera of Egyptian patients with hepatitis C virus infection: correlation with disease severity. Viral Immunol 2010; 23:151-7. [PMID: 20373995 DOI: 10.1089/vim.2009.0089] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) infection causes chronic hepatitis, which gradually progresses to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC). Angiogenesis plays a major role in chronic inflammation and may have prognostic value in disease progression. This study was designed to evaluate vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and tumor necrosis factor-alpha (TNF-alpha) as prognostic factors of disease progression in Egyptian patients with different stages of HCV-related cirrhosis and HCC. VEGF, PDGF, and TNF-alpha were measured using enzyme-linked immunosorbent assay (ELISA) in 82 HCV-infected patients (20 mild, 20 moderate, and 20 severe cirrhosis patients, and 22 HCC patients), and 20 healthy controls. Our results showed comparable increases in VEGF and PDGF levels in those with increasing clinical stages of disease, with maximal production seen in HCC patients. A gradual elevation of TNF-alpha levels was seen also in HCV-infected patients at different stages of disease and HCC. A statistically significantly positive correlation between serum levels of VEGF, PDGF, and TNF-alpha, and grade of disease was recorded. Thus assessment of these parameters in those with different stages of disease may be helpful in choosing the best treatment strategy, and indicate that anti-angiogenic therapy may be useful.
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Affiliation(s)
- Roba M Talaat
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), Menofia University, Sadat City, Egypt.
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Huynh H. Molecularly targeted therapy in hepatocellular carcinoma. Biochem Pharmacol 2010; 80:550-60. [PMID: 20371362 DOI: 10.1016/j.bcp.2010.03.034] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2010] [Revised: 03/16/2010] [Accepted: 03/29/2010] [Indexed: 01/02/2023]
Abstract
With an annual incidence of over 660,000 deaths, hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally. This disease is often diagnosed at an advanced stage, when potentially curative therapies are not feasible. HCC is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Given the clear need, clinical development of novel therapeutic agents in HCC has begun in earnest. Our recent knowledge of the molecular mechanisms responsible of tumor initiation and progression has identified several potential molecular targets in HCC. These targets are the receptor tyrosine kinase-activated pathways, which include the Raf/MEK/ERK, PI-3K/Akt/mTOR, and Jak/Stat. Sorafenib is the multikinase inhibitor that has shown modest survival benefits in advanced HCC in two randomized controlled trials, supporting the use of molecularly targeted therapies in treatment of HCC. A number of strategies including monoclonal antibodies and tyrosine kinase inhibitors such as erlotinib, sunitinib, vandetanib, cediranib, brivanib, foretinib, and dovitinib have been developed and tested in various phases of clinical trials. The successful development of these novel targeted agents in the future will be dependent on the selection of patient populations that are most likely to derive clinical benefit, optimization of the dose used and schedules, and investigation of combined therapies. This review describes evolving molecular targeted agents, their common adverse side effects, and its potential use in management of HCC.
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Affiliation(s)
- Hung Huynh
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, Level 6, Lab 1, 11 Hospital Drive, Singapore 169610, Singapore.
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Lai XD, Chen XH, Xu HB, Liu YR, Ma NF. Correlations of EIF-5A2 protein expression with VEGF expression and microvessel density in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2010; 18:137-142. [DOI: 10.11569/wcjd.v18.i2.137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlations of eukaryotic initiation factor-5A2 (EIF-5A2) expression with vascular endothelial growth factor (VEGF) expression, microvessel density (MVD) and clinicopathological parameters in hepatocellular carcinoma (HCC).
METHODS: Immunohistochemistry was used to determine the expression of EIF-5A2, VEGF and CD34 in 49 HCC tissues and 6 normal liver tissues. The MVD was calculated by counting CD34-labeled vessels. The correlations of EIF-5A2 expression with VEGF expression, MVD and clinicopathological parameters in HCC were then analyzed.
RESULTS: The positive rates of EIF-5A2, VEGF and CD34 expression in 49 HCC tissues were 87.7%, 89.7% and 100%, respectively. In contrast, EIF-5A2 and CD34 expression was not detected and VEGF was weakly detected in normal liver tissues. EIF-5A2 expression was positively correlated with VEGF expression and MVD (r = 0.416 and 0.321, respectively; both P < 0.05) in HCC. There were no significant differences in EIF-5A2 expression, VEGF expression and MVD between HCC tissues containing a single tumor focus and multiple tumor foci. No differences were found in the expression of EIF-5A2 and VEGF among HCCs of different diameters though a significant difference was noted in MVD. The levels of EIF-5A2 and VEGF expression and MVD were significantly higher in HCC patients with portal vein tumor thrombosis than in those without portal vein tumor thrombosis (all P < 0.05). Significant differences were also noted in EIF-5A2 and VEGF expression and MVD between HCC with an integral capsule and that without an integral capsule (all P < 0.05).
CONCLUSION: EIF-5A2 is highly expressed in HCC tissues. EIF-5A2 expression is positively correlated with VEGF expression and MVD in HCC. The overexpression of EIF-5A2 may play an important role in portal vein encroachment and metastasis of HCC.
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AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J Hepatol 2010; 52:79-87. [PMID: 19910069 DOI: 10.1016/j.jhep.2009.10.008] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2009] [Revised: 07/17/2009] [Accepted: 08/25/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a particularly vascularized solid tumor where the Raf/MEK/ERK pathway is activated; suggesting that inhibition of this pathway may have therapeutic potential. METHODS We treated patient-derived HCC xenografts with (i) sorafenib, (ii) AZD6244 (ARRY-142886), and (iii) sorafenib plus AZD6244. Western blotting was employed to determine pharmacodynamic changes in biomarkers relevant to both angiogenesis and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry. RESULTS We report here that sorafenib treatment resulted in suppression of tumor growth, reduction in cell proliferation, induction of apoptosis and inhibition of mTOR targets. Sorafenib-induced elevation of the insulin-like growth factor receptor 1 (IGF-1R), phospho-c-Raf Ser338, phospho-MEK Ser217/221 and phospho-ERK Thr202/Tyr204 was attenuated by co-treating cells with anti-human IGF-1R antibody or over-expression of activated mutant p70S6K. Pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the anti-tumor effect of sorafenib in both orthotopic and ectopic models of HCC. Such inhibition led to a further increase in pro-apoptotic Bim, apoptosis and a profound inhibition of cell proliferation. CONCLUSION Our findings underscore the potential of a combined therapeutic approach with sorafenib and MEK inhibitors in the treatment of HCC.
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Kaseb AO, Hanbali A, Cotant M, Hassan MM, Wollner I, Philip PA. Vascular endothelial growth factor in the management of hepatocellular carcinoma: a review of literature. Cancer 2009; 115:4895-906. [PMID: 19637355 DOI: 10.1002/cncr.24537] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The importance of tumor angiogenesis in tumor biology is now widely accepted. Hepatocellular carcinoma (HCC) is a highly vascular tumor, and angiogenesis is believed to play a considerable role in its development and progression. The authors reviewed the role of circulating vascular endothelial growth factor (VEGF) in screening for HCC and in risk stratification and treatment monitoring. They searched the world medical literature by accessing MEDLINE and PubMed for articles on: 1) the utility of circulating VEGF for HCC screening in patients with cirrhosis; 2) the role of circulating VEGF as a predictor of the invasive potential of HCC; and 3) monitoring anti-HCC treatment effects by serial measurements of circulating VEGF. They found evidence to support a potential role for VEGF in screening and surveillance of HCC. They also found support for developing the use of VEGF in the monitoring of treatment outcomes. Several studies suggested that the circulating VEGF level may be an independent prognostic marker in HCC. Further studies are needed to determine the utility of circulating VEGF in screening of patients with cirrhosis and to determine its potential role as a prognostic and predictive biomarker in patients with HCC. Cancer 2009. (c) 2009 American Cancer Society.
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Affiliation(s)
- Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
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Gusani NJ, Jiang Y, Kimchi ET, Staveley-OʼCarroll KF, Cheng H, Ajani JA. New Pharmacological Developments in the Treatment of Hepatocellular Cancer. Drugs 2009; 69:2533-40. [DOI: 10.2165/11530870-000000000-00000] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Ma LH, Zhou J, Wang ZX, Hu DW, Shi LM, Ao YZ, Zhang HF. Use of preoperative serum VEGF and CRP levels for prediction of postoperative early recurrence in patients with hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2009; 17:3460-3464. [DOI: 10.11569/wcjd.v17.i33.3460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlations between liver cancer recurrence and preoperative serum vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) levels in patient with hepatocellular carcinoma.
METHODS: The levels of serum VEGF and CRP in 32 liver cancer patients, 30 patients with benign liver diseases and 20 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA) and single immunodiffusion, respectively.
RESULTS: The levels of serum VEGF and CRP in hepatocellular carcinoma patients were significantly higher than those in patients with benign liver diseases and healthy controls (VEGF: 432.32 ± 340.57 ng/L vs 158.54 ± 120.58 ng/L and 124.03 ± 51.65 ng/L; CRP: 9.80 ± 0.86 mg/L vs 6.48 ± 0.98 mg/L and 6.12 ± 0.80 mg/L, all P < 0.01). The sensitivity and specificity of preoperative serum VEGF and CRP levels for prediction of postoperative early recurrence in patients with hepatocellular carcinoma were 77.27% and 59.09% as well as 30% and 60%, respectively.
CONCLUSION: Preoperative serum VEGF and CRP levels are potential predictors of postoperative early recurrence in hepatocellular carcinoma patients.
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Wang C, Lu Y, Chen Y, Feng Y, An L, Wang X, Su S, Bai W, Zhou L, Yang Y, Xu D. Prognostic factors and recurrence of hepatitis B-related hepatocellular carcinoma after argon-helium cryoablation: a prospective study. Clin Exp Metastasis 2009; 26:839-48. [PMID: 19784786 DOI: 10.1007/s10585-009-9283-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2009] [Accepted: 07/21/2009] [Indexed: 02/08/2023]
Abstract
To determine the long-term prognosis of hepatocellular carcinoma (HCC) after argon-helium cryoablation and identify the risk factors that predict metastasis and recurrence. A total of 156 patients with hepatitis B-related HCC less than 5 cm in diameter who underwent curative cryoablation were followed up prospectively for tumor metastasis and recurrence. Immunohistochemistry was used to analyze the expression of vascular endothelial growth factor (VEGF). HBV basal core promoter (BCP) and precore mutations were detected by DNA sequence analysis. Post-treatment prognostic factors influencing survival, tumor metastasis and recurrence were assessed by univariate and multivariate analyses. The variables included the expression of VEGF in HCC tissues, clinical and pathologic characteristics of patients, and HBV features (HBV DNA level, HBV genotype, BCP mutation). The median follow-up period of the 156 patients was 37 months (range 8-48 months). The 1-, 2-, and 3-year overall survival rates were 92, 82 and 64%, respectively. The 1-, 2-, and 3-year recurrence-free survival rates were 72, 56 and 43%, respectively. Eighty-five patients (54.5%) had tumor recurrence or metastasis. The multivariate analysis showed that Child-Pugh class and the expression of VEGF in HCC tissues could be used as independent prognostic factors for overall survival. Meanwhile, the expression of VEGF in HCC tissues and HBV BCP mutations were found to be independent prognostic factors for recurrence-free survival. Strong expression of VEGF in HCC tissues and HBV BCP mutations are important risk predictors for recurrence or metastasis of HCC smaller than 5 cm in diameter.
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Affiliation(s)
- Chunping Wang
- Center of Therapeutic Research for Hepatocellular Carcinoma, 100039 Beijing, China
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Moon JI, Kim JM, Jung GO, Chun JM, Choi GS, Park JB, Kwon CHD, Kim SJ, Jo JW. [Expression of vascular endothelial growth factor (VEGF) family members and prognosis after hepatic resection in HBV-related hepatocellular carcinoma]. THE KOREAN JOURNAL OF HEPATOLOGY 2008; 14:185-96. [PMID: 18617766 DOI: 10.3350/kjhep.2008.14.2.185] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIMS Human hepatocellular carcinoma (HCC) is a hypervascular tumor, and vascular endothelial growth factor (VEGF) plays a key role in the regulation of tumor-associated angiogenesis. In this study, we analyzed the significance of the expression of VEGF family members on the prognosis and clinicopathologic progress of HCC. METHODS Surgically resected specimens of HCC and noncancerous liver tissue were obtained from 323 patients with HCC, and VEGF mRNA was examined by quantitative reverse transcriptase-polymerase chain reactions (RT-PCRs). Patients who were seropositive for hepatitis B surface antigen were selected for the analysis (n=208). The VEGF(tumor)/GAPDH (glyceraldehyde-3-phosphate dehydrogenase)(tumor)/VEGF(nontumor)/GAPDH(nontumor) ratio was calculated using a quantitative RT-PCR assay, and the relationships between the expressions of VEGF family members and clinicopathologic parameters were analyzed to evaluate their significance in the prognosis of HCC. RESULTS The disease-free survival was significantly worse in the high-VEGF-A group than in the low-VEGF-A group (P=0.035), whereas VEGF-A expression was not significantly related to overall survival (P=0.172). The factors significantly related to poor prognosis in univariate analysis were tumor size, portal vein invasion, microvascular thrombi, intrahepatic metastasis, tumor capsule invasion, liver capsule invasion, preoperative serum albumin level, and VEGF-A ratio. Multivariate analysis showed that a poor prognosis in HCC patients was significantly related to portal vein invasion (hazard ratio=3.381, P<0.001), intrahepatic metastasis (hazard ratio=2.379, P<0.001), tumor size (hazard ratio=1.834, P=0.003), and preoperative serum albumin level (hazard ratio=2.050, P=0.006). CONCLUSIONS Our study showed that the expression of VEGF-A is positively correlated with the recurrence rate of HCC after curative resection. Therefore, a high expression of VEGF-A might be predictive of HCC recurrence after curative resection.
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Affiliation(s)
- Ju Ik Moon
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, Ong HS, Chung A, Chow P, Pollock P, Byron S, Tran E. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res 2008; 14:6146-53. [PMID: 18829493 DOI: 10.1158/1078-0432.ccr-08-0509] [Citation(s) in RCA: 175] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. EXPERIMENTAL DESIGN Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. RESULTS Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. CONCLUSION This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.
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Affiliation(s)
- Hung Huynh
- Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore.
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Shim JH, Park JW, Kim JH, An M, Kong SY, Nam BH, Choi JI, Kim HB, Lee WJ, Kim CM. Association between increment of serum VEGF level and prognosis after transcatheter arterial chemoembolization in hepatocellular carcinoma patients. Cancer Sci 2008; 99:2037-44. [PMID: 19016764 PMCID: PMC11158304 DOI: 10.1111/j.1349-7006.2008.00909.x] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2008] [Revised: 06/04/2008] [Accepted: 06/15/2008] [Indexed: 12/12/2022] Open
Abstract
We prospectively investigated the association between a change of serum vascular endothelial growth factor (VEGF) level after transcatheter arterial chemoembolization (TACE) and hepatocellular carcinoma (HCC) patient prognosis. The study involved 147 patients with unresectable HCC treated at the National Cancer Center, Korea, between July and December 2005. Serum samples were collected from each patient before TACE, and 1-2 days and 1 month after TACE. Serum VEGF concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). The log(e)(VEGF/platelets) increased transiently 1-2 days after TACE and declined thereafter. Frequency of previous TACE did not correlate with log(e)(VEGF/platelets). This study found that log(e)(VEGF/platelets) 1-2 days after TACE, but not log(e)(VEGF/platelets) at baseline, was strongly correlated with vascular or nodal invasion and AJCC (American Joint Committee on Cancer)/UICC (International Union Against Cancer) stage, and was significantly greater in men. Relative changes in serum VEGF/platelet levels 1-2 days after TACE (DeltaVEGF) > 0.5 were directly correlated with tumor size, vascular invasion and modified UICC and AJCC/UICC stage (P < 0.05 for each). Additionally, DeltaVEGF > 0.5 was significantly correlated with newly developed extrahepatic metastases one and six months after TACE (P = 0.005 and 0.003, respectively). Progression free survival of patients with DeltaVEGF > 0.5 was significantly worse (P < 0.001) and DeltaVEGF > 0.5 was an independent prognostic factor for PFS (hazard ratio, 3.111; P < 0.001). This study showed that a high increment in serum VEGF level 1-2 days after TACE in HCC patients was associated with distant metastasis and unfavorable outcomes.
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Affiliation(s)
- Ju Hyun Shim
- Center for Liver Cancer, Natinoal Cancer Center, Ilsan-Gu, Goyang, Gyeonggi, Republic of Korea
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Abdel Aziz MT, El-Miligy D, Amin MA, El Ansari A, Ahmed HH, Marzouk S, Sabry D. Molecular evaluation of apoptotic versus antiapoptotic angiogenic markers in hepatocellular carcinoma. Clin Biochem 2008; 41:1008-14. [PMID: 18339319 DOI: 10.1016/j.clinbiochem.2008.02.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2007] [Revised: 01/27/2008] [Accepted: 02/07/2008] [Indexed: 02/05/2023]
Affiliation(s)
- Mohamed T Abdel Aziz
- Unit of Medical Biochemistry and Molecular Biology, Biochemistry Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Hayward RM, Kirk MJ, Sproull M, Scott T, Smith S, Cooley-Zgela T, Crouse NS, Citrin DE, Camphausen K. Post-collection, pre-measurement variables affecting VEGF levels in urine biospecimens. J Cell Mol Med 2008; 12:343-50. [PMID: 18366457 PMCID: PMC2367114 DOI: 10.1111/j.1582-4934.2007.00135.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Angiogenesis, the development and recruitment of new blood vessels, plays an important role in tumour growth and metastasis.Vascular endothelial growth factor (VEGF) is an important stimulator of angiogenesis.Circulating and urinary VEGF levels have been suggested as clinically useful predictors of tumour behaviour, and investigations into these associations are ongoing.Despite recent interest in measuring VEGF levels in patients, little is known about the factors that influence VEGF levels in biospecimens. To begin to address this question, urine samples were collected from patients with solid tumours undergoing radiotherapy and healthy volunteers.Four factors were examined for their effects on VEGF concentrations as measured by chemiluminescent immunoassay: time from sample collection to freezing, number of specimen freeze–thaw cycles, specimen storage tube type and the inclusion or exclusion of urinary sediment. The results of this study indicate that time to freeze up to 4 hrs, number of freeze–thaw cycles between one and five, and different types of polypropylene tubes did not have statistically significant effects on measured urinary VEGF levels. Urinary sediment had higher VEGF levels than supernatant in five of six samples from healthy patients.It is not clear whether there is an active agent in the sediment causing this increase or if the sediment particles themselves are affecting the accuracy of the assay.Therefore, we recommend centrifuging urine, isolating the supernatant, and freezing the sample in polypropylene microcentrifuge tubes or cryogenic vials within 4 hrs of collection.In addition, we recommend the use of samples within five freeze–thaw cycles.
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Affiliation(s)
- Robert M Hayward
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-1002, USA
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Abstract
The process of blood vessel proliferation, known as angiogenesis, is essential during embryonic development and organogenesis. In adult life, it participates in normal tissue repair, wound healing, and cyclical growth of the corpus luteum and the endometrium. Crucial as it is, angiogenesis can become pathological, and abnormal angiogenesis contributes to the pathogenesis of inflammatory and neoplasic diseases. The present review highlights the evidence for the role of angiogenesis in HCC (hepatocellular carcinoma) and discusses the increasing importance of inhibitors of angiogenesis in HCC therapy.
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Shan B, Gao C, Chen JM, Bi XY, Zhang BY, Guo Y, Dong CF, An R, Shi Q, Hu JQ, Zhao P, Han J, Dong XP. Establishment of a sandwich ELISA method for detection of vascular endothelial growth factor in serum samples of hepatocellular carcinoma patients. BIOMEDICAL AND ENVIRONMENTAL SCIENCES : BES 2008; 21:69-74. [PMID: 18478981 DOI: 10.1016/s0895-3988(08)60009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
OBJECTIVE To establish a sandwich ELISA method for detecting vascular endothelial growth factor (VEGF) in sera of population and the patients with hepatocellular carcinoma (HCC). METHODS Full length and two truncated human VEGF cDNA sequences were amplified from a commercial plasmid pBLAST49-hVEGF by PCR and inserted into the prokaryotic-expression plasmid pET-32a or pGEX-2T. Various VEGF proteins were expressed and purified from E. coli in His-Trx or GST fusion forms. The specific VEGF antibodies were elicited in experimental rabbits and mice by immunization of the full length VEGF fusion protein His-Trx-VEGF1-165. After purification of antibodies with chromatograph of Protein G, a sandwich ELISA technique was established. Serum VEGF levels were evaluated in 229 adults and 291 HCC patients. RESULTS SDS-PAGE displayed that the molecular weights of the expressed full length (His-Trx-VEGF1-165), N-terminal (His-Trx-VEGF1-100) and C-terminal (GST-VEGF100-165) human VEGF fusion proteins were about 38KD, 31KD, and 33KD, respectively. Western blots confirmed that the prepared antisera were able to recognize both prokaryoticly and eukaryoticly expressed recombinant VEGF proteins. Assays of serially diluted His-Trx-VEGF1-100 by the established sandwich ELISA method showed that the linear range of the standard curve was 0.625-320 ng/mL, with the squared correlation coefficient R2 = 0.991. Screening of a serum panel containing 291 serum samples of HCC patients and 229 health adults revealed that the average VEGF level in HCC patients was higher than that in healthy controls, with a statically significant difference. CONCLUSION The established sandwich ELISA reflects the level of serum VEGF and provide scientific basis for screening metastasis and recurrence of HCC using serum VEGF as an index.
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Affiliation(s)
- Bing Shan
- State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 100052, China
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Höpfner M, Schuppan D, Scherübl H. Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer. World J Gastroenterol 2008; 14:1-14. [PMID: 18176955 PMCID: PMC2673371 DOI: 10.3748/wjg.14.1] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer (HCC). Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors (“small molecule inhibitors”) and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin (mTOR) upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation. mTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.
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Kong SY, Park JW, Lee JA, Park JE, Park KW, Hong EK, Kim CM. Association between vascular endothelial growth factor gene polymorphisms and survival in hepatocellular carcinoma patients. Hepatology 2007; 46:446-55. [PMID: 17659575 DOI: 10.1002/hep.21720] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and progression of tumor, including hepatocellular carcinoma (HCC), and elevated VEGF levels in serum and tissues have been known to be related with poor prognosis in patients with HCC. However, the effect of such polymorphisms of the VEGF gene on HCC prognosis has not been elucidated. In the present study, we investigated the association between VEGF gene polymorphisms and HCC patient prognosis. The study involved 416 HCC patients treated at the National Cancer Center Korea from November 2000 to December 2005. The median patient age was 57 years, and 328 patients (78.8%) were men. A total of 19 polymorphisms were analyzed, and the hazard ratios (HRs) for genotypes and haplotypes were determined in terms of risk for overall survival using Cox proportional hazard regression analysis. Of the 19 alleles, 7 showed no heterozygous allele. PHASE analysis identified a total of 36 haplotypes. The -2578 to -1498 region of the VEGF gene showed a strong linkage disequilibrium (correlation coefficient, r(2) = 0.91; Lewontin's D', D' = 0.982). The adjusted HRs were 0.67 [95% confidence interval (CI), 0.46 to 0.99] for -634CC genotype carriers and 0.57 (95% CI, 0.36 to 0.92) for homozygous haplotype 1 (Ht1: CCGAGCCC at -2578/-1203/-1190/-1179/-1154/-634/-7/+936) carriers compared with noncarriers. CONCLUSION These findings suggest that VEGF polymorphisms may be significant prognostic indicators for HCC patients.
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Affiliation(s)
- Sun-Young Kong
- Center for Clinical Services, Department of Laboratory Medicine, Research Institute and Hospital, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
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Poon RTP, Lau C, Pang R, Ng KK, Yuen J, Fan ST. High serum vascular endothelial growth factor levels predict poor prognosis after radiofrequency ablation of hepatocellular carcinoma: importance of tumor biomarker in ablative therapies. Ann Surg Oncol 2007; 14:1835-45. [PMID: 17406950 DOI: 10.1245/s10434-007-9366-z] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2006] [Accepted: 01/09/2007] [Indexed: 12/23/2022]
Abstract
BACKGROUND Radiofrequency ablation (RFA) is a recently developed treatment for hepatocellular carcinoma (HCC). Thus far, the prognostic impact of tumor biomarkers has not been evaluated in this treatment. High serum level of vascular endothelial growth factor (VEGF) has been shown to predict microscopic vascular invasion and metastasis in HCC. This study investigated the prognostic significance of pre-treatment serum VEGF level in patients with HCC undergoing RFA treatment. METHODS Serum VEGF levels were measured using enzyme-linked immunosorbent assay in 120 patients with HCC undergoing RFA, and in 15 healthy controls. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The prognostic significance of serum VEGF levels was assessed by univariate and multivariate analyses. RESULTS The median serum VEGF level in the HCC patients was 240 pg/mL (range 17-1162), significantly higher than that of healthy controls (p = .024). The serum VEGF levels were significantly correlated with platelet counts (r = .487, p < .001) but not other clinicopathological features. Patients with serum VEGF level > 240 pg/mL had worse overall and recurrence-free survival compared with those with serum VEGF level > 240 pg/mL (p = .005 and .002, respectively). By multivariate analysis, serum VEGF level was a significant prognostic factor of both overall and recurrence-free survival. CONCLUSIONS High pre-treatment serum VEGF levels predict poor prognosis after RFA of HCC. This study highlights the importance of tumor biomarker as a prognostic predictor in ablative therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.
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Affiliation(s)
- Ronnie T P Poon
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China.
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