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Li S, Sah DK, Arjunan A, Ameer MY, Lee B, Jung YD. Triptolide suppresses IL-1β-induced expression of interleukin-8 by inhibiting ROS-Mediated ERK, AP-1, and NF-κB molecules in human gastric cancer AGS cells. Front Oncol 2025; 14:1498213. [PMID: 39950099 PMCID: PMC11821500 DOI: 10.3389/fonc.2024.1498213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/26/2024] [Indexed: 02/16/2025] Open
Abstract
Triptolide, the major component of Chinese herbal medicine Tripterygium wilfordii Hook F, possesses potent anticancer and anti-inflammatory effects. IL-8, a proinflammatory cytokine, is associated with cancer cell proliferation and angiogenesis. Here, we found that Triptolide has an inhibitory effect on IL-1β-induced IL-8 expression in human gastric cancer cells, via the suppression of reactive oxygen species (ROS) production, AP-1, and NF-κB activation, which in turn affects human endothelial cell angiogenetic activity in tumor microenvironments. Human gastric AGS cells were treated with IL-1β (10 ng/mL) and Triptolide (0-20 nM), and the ROS generation, ERK, AP-1, and NF-κB signaling were all investigated. These results demonstrate that Triptolide inhibits the IL-1β-induced IL-8 expression in gastric cancer cells by inhibiting ROS production and angiogenesis, via the dose-dependent attenuation of ERK, AP-1, and NF-κB activation. In this study, we showed that Triptolid inhibits ROS/ERK-mediated AP-1 and ROS-mediated NF-κB axes potentially leading to an improved treatment outcome for gastric cancer and its associated tumor microenvironment.
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Affiliation(s)
- Shinan Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Medical University, Taiyuan, China
- Department of Biochemistry, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - Dhiraj Kumar Sah
- Department of Biochemistry, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - Archana Arjunan
- Department of Biochemistry, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - Mohamed Yazeer Ameer
- Department of Biochemistry, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - Bora Lee
- Department of Biochemistry, Chonnam National University Medical School, Hwasun, Republic of Korea
| | - Young-Do Jung
- Department of Biochemistry, Chonnam National University Medical School, Hwasun, Republic of Korea
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Chen P, Wang Y, Zhu X, Huang Y, Chen J, Sun H, Wang Y, Zhao S, You Y, Wu Y, Yang T, Wei T, Duan X, Zhao T, Jia H, Ren J. SiRNA-HIF-1α delivered by attenuated Salmonella enhances the efficacy of Lenvatinib against hepatocellular carcinoma. Int Immunopharmacol 2024; 130:111728. [PMID: 38430801 DOI: 10.1016/j.intimp.2024.111728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 02/03/2024] [Accepted: 02/16/2024] [Indexed: 03/05/2024]
Abstract
The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.
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Affiliation(s)
- Pengfei Chen
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yanling Wang
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Chinese Medicine Hospital of Puyang, Puyang, Henan 457001, PR China
| | - Xingshu Zhu
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yujing Huang
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
| | - Jinwei Chen
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Hao Sun
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
| | - Yang Wang
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
| | - Shenning Zhao
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
| | - Yiqing You
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
| | - Yufei Wu
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
| | - Tongguo Yang
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Tian Wei
- Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
| | - Xuhua Duan
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Tiesuo Zhao
- Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China
| | - Huijie Jia
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Xinxiang Medical University, Xinxiang, Henan 453003, PR China.
| | - Jianzhuang Ren
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
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Ruff SM, Pawlik TM. Emerging therapies targeting growth factors in hepatocellular carcinoma. Expert Opin Pharmacother 2024; 25:255-262. [PMID: 38591252 DOI: 10.1080/14656566.2024.2340714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 03/01/2024] [Indexed: 04/10/2024]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a primary liver cancer that commonly arises in the background of chronic liver inflammation and/or cirrhosis. Chronic liver inflammation results in the production of different growth factors, remodeling of the microenvironment architecture into fibrosis, and eventually carcinogenesis. Overexpression of some growth factors has been associated with worse prognosis in patients with HCC. Targeted therapies against growth factors may disrupt cell signaling and the mechanisms that allow for cell survival (e.g. angiogenesis, proliferation, metastases). AREAS COVERED We herein review potential growth factor targets of HCC and the limited research that exists regarding targeted therapy of these ligands and their receptors. We performed an extensive literature search to investigate preclinical studies, clinical research, and clinical trials. EXPERT OPINION Systemic therapy for patients with HCC is continuing to evolve. Anti-angiogenic therapy holds the most promise among targeted therapy for growth factors among patients with HCC. Improving our understanding of growth factors in HCC will hopefully lead to the development of new targeted therapies and strategies for combination therapies with immune checkpoint inhibitors.
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Affiliation(s)
- Samantha M Ruff
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
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Xu HZ, Lin XY, Xu YX, Xue HB, Lin S, Xu TW. An emerging research: the role of hepatocellular carcinoma-derived exosomal circRNAs in the immune microenvironment. Front Immunol 2023; 14:1227150. [PMID: 37753074 PMCID: PMC10518420 DOI: 10.3389/fimmu.2023.1227150] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/28/2023] [Indexed: 09/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is one of the leading causes of cancer-related death and is associated with a poor prognosis. The tumor microenvironment (TME) of HCC comprises immune, immunosuppressive, and interstitial cells with hypoxic, angiogenic, metabolic reprogramming, inflammatory, and immunosuppressive features. Exosomes are nanoscale extracellular vesicles that secrete biologically active signaling molecules such as deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), microribonucleic acid (miRNA), proteins, and lipids. These signaling molecules act as messengers in the tumor microenvironment, especially the tumor immunosuppressive microenvironment. Exosomal circRNAs reshape the tumor microenvironment by prompting hypoxic stress response, stimulating angiogenesis, contributing to metabolic reprogramming, facilitating inflammatory changes in the HCC cells and inducing tumor immunosuppression. The exosomes secreted by HCC cells carry circRNA into immune cells, which intervene in the activation of immune cells and promote the overexpression of immune checkpoints to regulate immune response, leading tumor cells to acquire immunosuppressive properties. Furthermore, immunosuppression is the final result of a combination of TME-related factors, including hypoxia, angiogenesis, metabolic reprogramming, and inflammation changes. In conclusion, exosomal circRNA accelerates the tumor progression by adjusting the phenotype of the tumor microenvironment and ultimately forming an immunosuppressive microenvironment. HCC-derived exosomal circRNA can affect HCC cell proliferation, invasion, metastasis, and induction of chemoresistance. Therefore, this review aimed to summarize the composition and function of these exosomes, the role that HCC-derived exosomal circRNAs play in microenvironment formation, and the interactions between exosomes and immune cells. This review outlines the role of exosomal circRNAs in the malignant phenotype of HCC and provides a preliminary exploration of the clinical utility of exosomal circRNAs.
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Affiliation(s)
- Huang-Zhen Xu
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Xin-Yi Lin
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yun-Xian Xu
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Hui-Bin Xue
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Tian-Wen Xu
- Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Bashandy SAE, Ebaid H, Al-Tamimi J, Hassan I, Omara EA, Elbaset MA, Alhazza IM, Siddique JA. Protective Effect of Daidzein against Diethylnitrosamine/Carbon Tetrachloride-Induced Hepatocellular Carcinoma in Male Rats. BIOLOGY 2023; 12:1184. [PMID: 37759583 PMCID: PMC10525464 DOI: 10.3390/biology12091184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023]
Abstract
Hepatocellular carcinoma (HCC) is the second-largest cause of death among all cancer types. Many drugs have been used to treat the disease for a long time but have been mostly discontinued because of their side effects or the development of resistance in the patients with HCC. The administration of DZ orally is a great focus to address the clinical crisis. Daidzein (DZ) is a prominent isoflavone polyphenolic chemical found in soybeans and other leguminous plants. It has various pharmacological effects, including anti-inflammatory, antihemolytic, and antioxidant. This present study investigates the protective effect of DZ on chemically induced HCC in rat models. The DZ was administered orally four weeks before HCC induction and continued during treatment. Our study included four treatment groups: control (group 1, without any treatment), HCC-induced rats (group II), an HCC group treated with DZ at 20 mg/kg (group III), and an HCC group treated with DZ at 40 mg/kg (group IV). HCC rats showed elevation in all the HCC markers (AFP, GPC3, and VEGF), liver function markers (ALP, ALT, and AST), inflammatory markers (IL-6, TNF-α, and CRP), and lipid markers concomitant with a decrease in antioxidant enzymes and protein. However, groups III and IV demonstrated dose-dependent alleviation in the previous parameters resulting from HCC. In addition, the high dose of DZ reduces many hepatological changes in HCC rats. All study parameters improved with DZ administration. Due to its antioxidant and anti-inflammatory characteristics, DZ is a promising HCC treatment option for clinical use.
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Affiliation(s)
- Samir A. E. Bashandy
- Pharmacology Department, National Research Centre, 33 El-Bohouth St., Dokki, Cairo 12622, Egypt; (S.A.E.B.); (M.A.E.)
| | - Hossam Ebaid
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (H.E.); (I.M.A.)
| | - Jameel Al-Tamimi
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (H.E.); (I.M.A.)
| | - Iftekhar Hassan
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (H.E.); (I.M.A.)
| | - Enayat A. Omara
- Pathology Department, National Research Centre, 33 El-Bohouth St., Dokki, Cairo 12622, Egypt;
| | - Marawan A. Elbaset
- Pharmacology Department, National Research Centre, 33 El-Bohouth St., Dokki, Cairo 12622, Egypt; (S.A.E.B.); (M.A.E.)
| | - Ibrahim M. Alhazza
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (H.E.); (I.M.A.)
| | - Jamal A. Siddique
- Department of Materials Engineering and Chemistry, Faculty of Civil Engineering, Czech Technical University (CVUT), Praha 6, 16629 Prague, Czech Republic;
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Pinto E, Pelizzaro F, Farinati F, Russo FP. Angiogenesis and Hepatocellular Carcinoma: From Molecular Mechanisms to Systemic Therapies. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1115. [PMID: 37374319 PMCID: PMC10305396 DOI: 10.3390/medicina59061115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/02/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic molecular pathways have been identified as deregulated in HCC. The hypervascular nature and the peculiar vascularization of HCC, as well as deregulated angiogenic pathways, represent major therapeutic targets. To a large extent, intra-arterial locoregional treatments (transarterial-(chemo)embolization) rely on tumor ischemia caused by embolization of tumor feeding arteries, even though this may represent the "primum movens" of tumor recurrence through the activation of neoangiogenesis. Considering systemic therapies, the currently available tyrosine kinase inhibitors (sorafenib, regorafenib, cabozantinib and lenvatinib) and monoclonal antibodies (ramucirumab and bevacizumab, in combination with the anti-PD-L1, atezolizumab) primarily target, among others, angiogenic pathways. Considering the importance of angiogenesis in the pathogenesis and treatment of liver cancer, in this paper, we aim to review the role of angiogenesis in HCC, addressing the molecular mechanisms, available antiangiogenic therapies and prognostic biomarkers in patients receiving these treatments.
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Affiliation(s)
- Elisa Pinto
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (F.F.)
- Azienda Ospedaliera di Padova, 35128 Padova, Italy
| | - Filippo Pelizzaro
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (F.F.)
- Azienda Ospedaliera di Padova, 35128 Padova, Italy
| | - Fabio Farinati
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (F.F.)
- Azienda Ospedaliera di Padova, 35128 Padova, Italy
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; (F.P.); (F.F.)
- Azienda Ospedaliera di Padova, 35128 Padova, Italy
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Oura K, Morishita A, Hamaya S, Fujita K, Masaki T. The Roles of Epigenetic Regulation and the Tumor Microenvironment in the Mechanism of Resistance to Systemic Therapy in Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:2805. [PMID: 36769116 PMCID: PMC9917861 DOI: 10.3390/ijms24032805] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/29/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita 761-0793, Kagawa, Japan
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Sultana MF, Abo H, Kawashima H. Human and mouse angiogenins: Emerging insights and potential opportunities. Front Microbiol 2022; 13:1022945. [PMID: 36466652 PMCID: PMC9714274 DOI: 10.3389/fmicb.2022.1022945] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/01/2022] [Indexed: 12/27/2023] Open
Abstract
Angiogenin, a well-known angiogenic factor, is crucial to the angiogenesis in gastrointestinal tumors. Human angiogenin has only one gene, whereas the murine angiogenin family has extended to incorporate six genes. Evolutionary studies have suggested functional variations among murine angiogenin paralogs, even though the three-dimensional structures of angiogenin proteins are remarkably similar. In addition to angiogenesis, the ubiquitous pattern of angiogenin expression suggests a variety of functions, such as tumorigenesis, neuroprotective, antimicrobial activity, and innate immunity. Here, we comprehensively reviewed studies on the structures and functions of human and mouse angiogenins. Understanding the structure and function of angiogenins from a broader perspective could facilitate future research related to development of novel therapeutics on its biological processes, especially in gastrointestinal cancers.
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Affiliation(s)
- Mst. Farzana Sultana
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
- Department of Pharmacy, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Hirohito Abo
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Hiroto Kawashima
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
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Li SQ, Yang Y, Ye LS. Angiogenesis and immune checkpoint dual blockade: Opportunities and challenges for hepatocellular carcinoma therapy. World J Gastroenterol 2022; 28:6034-6044. [PMID: 36405383 PMCID: PMC9669824 DOI: 10.3748/wjg.v28.i42.6034] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/06/2022] [Accepted: 11/03/2022] [Indexed: 11/10/2022] Open
Abstract
The disease burden related to hepatocellular carcinoma (HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors (ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase III clinical trial IMBrave150 [atezolizumab (anti-programmed cell death ligand 1 antibody) combined with bevacizumab (anti-vascular endothelial growth factor monoclonal antibody)], showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of anti-angiogenics and ICIs, and point out the existing challenges of the combination therapy.
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Affiliation(s)
- Si-Qi Li
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Lin-Sen Ye
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
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siRNA targeting PD-L1 delivered with attenuated Salmonella enhanced the anti-tumor effect of lenvatinib on mice bearing Hepatocellular carcinoma. Int Immunopharmacol 2022; 111:109127. [PMID: 35964407 DOI: 10.1016/j.intimp.2022.109127] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/22/2022] [Accepted: 08/01/2022] [Indexed: 11/21/2022]
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer representing serious harm to human health. The effective treatment of HCC is challenging. Lenvatinib is an inhibitor of polytyrosine kinase that exerts an effect against HCC by blocking the VEGF signaling pathway. However, its efficacy in most patients remains unsatisfactory. The factors influencing tumorigenesis are diverse; thus, combined treatment is an important strategy against tumors. Programmed death ligand-1 (PD-L1), which binds to programmed death-1 (PD-1), significantly compromises the anti-tumor effect of T cells. Therefore, we designed a siRNA-PD-L1 and delivered it using attenuated Salmonella, and its synergistic effects with Lenvatinib against HCC were evaluated. The results showed that the combination of Lenvatinib and siRNA-PD-L1 inhibited tumor growth in H22 tumor-bearing mice, arrested cell proliferation, and increased cell apoptosis in the tumor. The combination treatment synergistically inhibited the expression of VEGF and PD-L1 and contributed to the increase in T-cell infiltration in the tumor tissues and the ratio of T cells in the spleen. Furthermore, the combination treatment increased the number of granzyme B+ T cells, indicating a significantly improved anti-tumor immunity in mice. Therefore, this combination might be a potential novel strategy for HCC treatment.
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Ionescu CA, Aschie M, Matei E, Cozaru GC, Deacu M, Mitroi AF, Baltatescu GI, Nicolau AA, Mazilu L, Tuta LA, Iorga IC, Stanigut A, Enciu M. Characterization of the Tumor Microenvironment and the Biological Processes with a Role in Prostatic Tumorigenesis. Biomedicines 2022; 10:1672. [PMID: 35884977 PMCID: PMC9313300 DOI: 10.3390/biomedicines10071672] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/25/2022] [Accepted: 07/06/2022] [Indexed: 12/25/2022] Open
Abstract
Prostate intratumoral heterogeneity, driven by epithelial−mesenchymal plasticity, contributes to the limited treatment response, and it is therefore necessary to use the biomarkers to improve patient prognostic survival. We aimed to characterize the tumor microenvironment (T lymphocyte infiltration, intratumoral CD34, and KI-67 expressions) by immunohistochemistry methods and to study the biological mechanisms (cell cycle, cell proliferation by adhesion glycoproteins, cell apoptosis) involved in the evolution of the prostate tumor process by flow-cytometry techniques. Our results showed that proliferative activity (S-phase) revealed statistically significant lower values of prostate adenocarcinoma (PCa) and benign prostatic hyperplasia (BPH) reported at non-malignant adjacent cell samples (PCa 4.32 ± 4.91; BPH 2.35 ± 1.37 vs. C 10.23 ± 0.43, p < 0.01). Furthermore, 68% of BPH cases and 88% of patients with PCa had aneuploidy. Statistically increased values of cell proliferation (CD34+ CD61+) were observed in prostate adenocarcinoma and hyperplasia cases reported to non-malignant adjacent cell samples (PCa 28.79 ± 10.14; BPH 40.65 ± 11.88 vs. C 16.15 ± 2.58, p < 0.05). The CD42b+ cell population with a role in cell adhesion, and metastasis had a significantly increased value in PCa cases (38.39 ± 11.23) reported to controls (C 26.24 ± 0.62, p < 0.01). The intratumoral expression of CD34 showed a significantly increased pattern of PCa tissue samples reported to controls (PCa 26.12 ± 6.84 vs. C 1.50 ± 0.70, p < 0.01). Flow cytometric analysis of the cell cycle, apoptosis, and adhesion glycoproteins with a critical role in tumoral cell proliferation, T cell infiltrations, Ki-67, and CD 34 expressions by IHC methods are recommended as techniques for the efficient means of measurement for adenocarcinoma and hyperplasia prostate tissue samples and should be explored in the future.
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Affiliation(s)
- Cristina-Anita Ionescu
- Chemical Carcinogenesis and Molecular Biology Laboratory, Institute of Oncology “Prof. Dr. Alexandru Trestioreanu”, 022328 Bucharest, Romania;
- Medicine Faculty, “Ovidius” University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania; (M.A.); (M.D.); (L.M.); (L.A.T.); (I.C.I.); (A.S.); (M.E.)
| | - Mariana Aschie
- Medicine Faculty, “Ovidius” University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania; (M.A.); (M.D.); (L.M.); (L.A.T.); (I.C.I.); (A.S.); (M.E.)
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania; (G.C.C.); (A.F.M.); (G.I.B.); (A.-A.N.)
- Clinical Service of Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Elena Matei
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania; (G.C.C.); (A.F.M.); (G.I.B.); (A.-A.N.)
| | - Georgeta Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania; (G.C.C.); (A.F.M.); (G.I.B.); (A.-A.N.)
- Clinical Service of Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Mariana Deacu
- Medicine Faculty, “Ovidius” University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania; (M.A.); (M.D.); (L.M.); (L.A.T.); (I.C.I.); (A.S.); (M.E.)
- Clinical Service of Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Anca Florentina Mitroi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania; (G.C.C.); (A.F.M.); (G.I.B.); (A.-A.N.)
- Clinical Service of Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Gabriela Isabela Baltatescu
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania; (G.C.C.); (A.F.M.); (G.I.B.); (A.-A.N.)
- Clinical Service of Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Antonela-Anca Nicolau
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania; (G.C.C.); (A.F.M.); (G.I.B.); (A.-A.N.)
- Clinical Service of Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Laura Mazilu
- Medicine Faculty, “Ovidius” University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania; (M.A.); (M.D.); (L.M.); (L.A.T.); (I.C.I.); (A.S.); (M.E.)
- Oncology Department, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Liliana Ana Tuta
- Medicine Faculty, “Ovidius” University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania; (M.A.); (M.D.); (L.M.); (L.A.T.); (I.C.I.); (A.S.); (M.E.)
- Nephrology Department, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Ionut Ciprian Iorga
- Medicine Faculty, “Ovidius” University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania; (M.A.); (M.D.); (L.M.); (L.A.T.); (I.C.I.); (A.S.); (M.E.)
- Urology Department, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Alina Stanigut
- Medicine Faculty, “Ovidius” University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania; (M.A.); (M.D.); (L.M.); (L.A.T.); (I.C.I.); (A.S.); (M.E.)
- Nephrology Department, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Manuela Enciu
- Medicine Faculty, “Ovidius” University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania; (M.A.); (M.D.); (L.M.); (L.A.T.); (I.C.I.); (A.S.); (M.E.)
- Clinical Service of Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
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12
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Li X, Su X, Yan C, Ma Y, Li H, Xia J, Li H, Jiang Q, Zhou L, Zou Z. Role of vascular endothelial growth factor in radiotherapy resistance to esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 2022; 149:2543-2550. [PMID: 35767192 DOI: 10.1007/s00432-022-04122-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 06/07/2022] [Indexed: 10/17/2022]
Abstract
Vascular endothelial growth factor (VEGF) is related to the radiation resistance of tumors, resulting in the failure of tumor radiotherapy. The purpose of this study was to discuss the role of VEGF in radiotherapy resistance of esophageal squamous cell carcinoma (ESCC). We used the VEGF kit by ELISA to detect the serum VEGF level of ESCC patients who only received radiotherapy. The expression of VEGF in ESCC cells after siRNA treatment was verified by Western blot. The sensitivity of ESCC cells to radiation after knocking down VEGF was analyzed by Clonogenic assay and Cell counting kit (CCK-8). The results showed that the level of serum VEGF in patients with ESCC before and after radiotherapy was related to the clinical response, and it was confirmed that knocking down the expression of VEGF in ESCC cells improved the sensitivity to radiation.
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Affiliation(s)
- Xin Li
- Department of Radiation Oncology, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an City, Jiangsu Province, China
| | - Xinyu Su
- Department of Radiation Oncology, The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Chen Yan
- Department of Radiation Oncology, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an City, Jiangsu Province, China
| | - Yuanyuan Ma
- Department of Radiation Oncology, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an City, Jiangsu Province, China
| | - Heng Li
- Department of Radiation Oncology, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an City, Jiangsu Province, China
| | - Jianhong Xia
- Department of Radiation Oncology, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an City, Jiangsu Province, China
| | - Hongliang Li
- Department of Radiation Oncology, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an City, Jiangsu Province, China
| | - Qian Jiang
- Department of Radiation Oncology, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an City, Jiangsu Province, China
| | - Liqing Zhou
- Department of Radiation Oncology, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an City, Jiangsu Province, China.
| | - Zhengyun Zou
- Department of Radiation Oncology, The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China. .,Department of Radiation Oncology, The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China. .,Department of Radiation Oncology, The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
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13
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Wang Z, Hou Y, Yao Z, Zhan Y, Chen W, Liu Y. Expressivity of Interleukin-8 and Gastric Cancer Prognosis Susceptibility: A Systematic Review and Meta-Analysis. Dose Response 2021; 19:15593258211037127. [PMID: 34531708 PMCID: PMC8438942 DOI: 10.1177/15593258211037127] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 12/23/2022] Open
Abstract
Background The relationship between interleukin-8 (IL-8) expression and the prognosis of gastric cancer (GC) patients has been reported, but the results are contradictory. Aim To investigate the effect of IL-8 expression on the prognosis of patients with GC. Method A comprehensive search strategy was used to search the PubMed, Web of Science and Cochrane Library databases. The total survival time was analysed using the RevMan 5.4 software. Through extensive search and meta-analysis of relevant studies, studies examining the relationship between IL-8 expression and prognosis in patients with GC were conducted to obtain more accurate estimates. Findings Eight studies (1843 patients) were included. The combined results of all the studies showed that high expression of IL-8 was a risk factor for poor prognosis in patients with GC (hazard ratio (HR): 2.08; 95% CI: 1.81–2.39). Sensitivity analysis suggested that the pooled HR was stable, and omitting a single study did not change the significance of the pooled HR. Funnel plots revealed no significant publication bias in the meta-analysis. Conclusion High IL-8 expression could be a negative prognostic biomarker for patients with GC.
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Affiliation(s)
- Zhenzhen Wang
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuhan Hou
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhen Yao
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanyan Zhan
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Wenyue Chen
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yulong Liu
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China.,State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China.,Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, China
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14
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Wong JSL, Dong Y, Tang V, Leung T, Yeung CSY, Tai A, Law A, Shum T, Kwok GGW, Li BCW, Leung R, Chiu J, Ma KW, She WH, Tsang J, Cheung TT, Yau T. The Use of Cabozantinib in Advanced Hepatocellular Carcinoma in Hong Kong-A Territory-Wide Cohort Study. Cancers (Basel) 2021; 13:2002. [PMID: 33919277 PMCID: PMC8122581 DOI: 10.3390/cancers13092002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/16/2021] [Accepted: 04/17/2021] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Cabozantinib is approved in sorafenib-exposed advanced hepatocellular carcinoma (aHCC). We evaluated the real-life pattern of use, efficacy, and tolerability of cabozantinib in aHCC. (2) Methods: This territory-wide study included consecutive aHCC patients who received cabozantinib between February 2018 and September 2020 in Hong Kong. The objective response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events (AE) were assessed. (3) Results: Overall, 42 patients were included. Approximately 83.3% had Child-Pugh A cirrhosis. About 64.3% received cabozantinib as a single agent, and the remaining 35.7% received cabozantinib as an add-on to immune checkpoint inhibitors (ICIs). For single-agent patients, the median follow-up was 6.7 months. The ORR was 3.7%, DCR was 44.4%, and the median OS was 8.28 months. About 74.1% of patients experienced any AEs with 7.4% having grade ≥3 AEs. Among patients who received prior ICIs (n = 16), the ORR was 6.3%, and the median OS was 8.28 months. An exploratory analysis of patients who received cabozantinib as an add-on to ICIs showed an ORR of 6.7% and a median OS of 15.1 months, with 73.3% having any AE and 13.3% having grade ≥3 AEs. (4) Conclusions: Cabozantinib had good anti-tumor activity, survival benefits, and acceptable tolerability in real-life aHCC patients.
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Affiliation(s)
- Jeffrey Sum-Lung Wong
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (J.S.-L.W.); (Y.D.); (V.T.); (G.G.-W.K.); (B.C.-W.L.); (R.L.); (J.C.); (J.T.)
| | - Yawen Dong
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (J.S.-L.W.); (Y.D.); (V.T.); (G.G.-W.K.); (B.C.-W.L.); (R.L.); (J.C.); (J.T.)
| | - Vikki Tang
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (J.S.-L.W.); (Y.D.); (V.T.); (G.G.-W.K.); (B.C.-W.L.); (R.L.); (J.C.); (J.T.)
| | - Thomas Leung
- Department of Medicine, Hong Kong Sanatorium and Hospital, Hong Kong, China;
| | | | - Anna Tai
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China;
| | - Ada Law
- Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China;
| | - Tracy Shum
- Department of Clinical Oncology, Princess Margaret Hospital, Hong Kong, China;
| | - Gerry Gin-Wai Kwok
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (J.S.-L.W.); (Y.D.); (V.T.); (G.G.-W.K.); (B.C.-W.L.); (R.L.); (J.C.); (J.T.)
| | - Bryan Cho-Wing Li
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (J.S.-L.W.); (Y.D.); (V.T.); (G.G.-W.K.); (B.C.-W.L.); (R.L.); (J.C.); (J.T.)
| | - Roland Leung
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (J.S.-L.W.); (Y.D.); (V.T.); (G.G.-W.K.); (B.C.-W.L.); (R.L.); (J.C.); (J.T.)
| | - Joanne Chiu
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (J.S.-L.W.); (Y.D.); (V.T.); (G.G.-W.K.); (B.C.-W.L.); (R.L.); (J.C.); (J.T.)
| | - Ka-Wing Ma
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (K.W.-M.); (W.H.-S.); (T.T.-C.)
| | - Wong-Hoi She
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (K.W.-M.); (W.H.-S.); (T.T.-C.)
| | - Josephine Tsang
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (J.S.-L.W.); (Y.D.); (V.T.); (G.G.-W.K.); (B.C.-W.L.); (R.L.); (J.C.); (J.T.)
| | - Tan-To Cheung
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (K.W.-M.); (W.H.-S.); (T.T.-C.)
| | - Thomas Yau
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; (J.S.-L.W.); (Y.D.); (V.T.); (G.G.-W.K.); (B.C.-W.L.); (R.L.); (J.C.); (J.T.)
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15
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Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:217-233. [PMID: 33131349 DOI: 10.1080/17474124.2021.1842732] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Persistent inflammation and hypoxia are strong stimulus for pathological angiogenesis and vascular remodeling, and are also the most important elements resulting in liver fibrosis. Sustained inflammatory process stimulates fibrosis to the end-point of cirrhosis and sinusoidal portal hypertension is an important feature of cirrhosis. Neovascularization plays a pivotal role in collateral circulation formation of portal vein, mesenteric congestion, and high perfusion. Imbalance of hepatic artery and portal vein blood flow leads to the increase of hepatic artery inflow, which is beneficial to the formation of nodules. Angiogenesis contributes to progression from liver fibrosis to cirrhosis and hepatocellular carcinoma (HCC) and anti-angiogenesis therapy can improve liver fibrosis, reduce portal pressure, and prolong overall survival of patients with HCC. Areas covers: This paper will try to address the difference of the morphological characteristics and mechanisms of neovascularization in the process from liver fibrosis to cirrhosis and HCC and further compare the different efficacy of anti-angiogenesis therapy in these three stages. Expert opinion: More in-depth understanding of the role of angiogenesis factors and the relationship between angiogenesis and other aspects of the pathogenesis and transformation may be the key to enabling future progress in the treatment of patients with liver fibrosis, cirrhosis, and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine , Chengdu, Sichuan Province, P. R. China
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16
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Wang J, Zhang M, Zhou T, Zhao S, Su Z, Liu X. Role of platelet infiltration as independent prognostic marker for gastric adenocarcinomas. J Clin Lab Anal 2020; 34:e23320. [PMID: 32233046 PMCID: PMC7439343 DOI: 10.1002/jcla.23320] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 03/05/2020] [Accepted: 03/10/2020] [Indexed: 01/27/2023] Open
Abstract
Background In recent years, the relationship between malignant tumors and platelets has been paid more attention. The increase of platelets is an independent risk factor for the poor prognosis of some malignant tumors. Methods This study retrospectively analyzed the clinical and pathological data of 114 patients with initial gastric cancer from August 2005 to August 2018 in Shandong Provincial Hospital. Single‐factor and multifactor survival analysis were used to evaluate the effect of platelet elevation on postoperative survival. The gastric cancer tissues of the Jinan Central Hospital and its matched paracancerous tissues were collected. The expression of platelets in tissues was detected by immunofluorescence technique. Different numbers of platelets were co‐cultured with MKN‐45 cells, CCK‐8 assay and transwell assay were performed, and the expression of epithelial‐mesenchymal transition‐related proteins was detected. Results Platelet count was independent factors affecting prognosis. The stratified analysis showed that there was a statistically significant difference in the 5‐year survival rate between the platelet‐increase group and the normal platelet group in the TNM stages I‐II. The expression of platelets in gastric cancer tissues was higher than that in adjacent tissues. The results of CCK‐8 and transwell showed that platelets significantly enhanced the proliferation and metastasis capability of MKN‐45 cells in a concentration‐dependent manner. After co‐culture, the expression level of E‐cadherin protein in MKN‐45 cells decreased, and the protein expression levels of N‐cadherin, vimentin, and VEGFA increased. Conclusion Platelet elevation is closely related to the occurrence, development, and metastasis of gastric cancer, and platelet count can be used as a prognostic indicator for malignant tumors.
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Affiliation(s)
- Jing Wang
- Department of LaboratoryBinzhou Medical UniversityYantaiChina
| | - Miao Zhang
- Department of Clinical LaboratoryShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
| | - Ting Zhou
- Department of LaboratoryChongqing Medical UniversityChongqingChina
| | - Shengmei Zhao
- Department of Clinical LaboratoryShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
| | - Zhenguo Su
- Department of LaboratoryBinzhou Medical UniversityYantaiChina
| | - Xiangdong Liu
- Department of Clinical LaboratoryShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
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17
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Okamura S, Osaki T, Nishimura K, Ohsaki H, Shintani M, Matsuoka H, Maeda K, Shiogama K, Itoh T, Kamoshida S. Thymidine kinase-1/CD31 double immunostaining for identifying activated tumor vessels. Biotech Histochem 2018; 94:60-64. [DOI: 10.1080/10520295.2018.1499962] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- S. Okamura
- Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - T. Osaki
- Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - K. Nishimura
- Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - H. Ohsaki
- Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - M. Shintani
- Department of Medical Technology, Kobe Tokiwa University, Japan
| | - H. Matsuoka
- Department of Surgery, Fujita Health University School of Medicine
| | - K. Maeda
- Department of Surgery, Fujita Health University School of Medicine
| | - K. Shiogama
- Department of Morphology and Cell Function, Fujita Health University School of Health Sciences, Toyoake, Japan
| | - T. Itoh
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - S. Kamoshida
- Laboratory of Pathology, Department of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
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18
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Morse MA, Sun W, Kim R, He AR, Abada PB, Mynderse M, Finn RS. The Role of Angiogenesis in Hepatocellular Carcinoma. Clin Cancer Res 2018; 25:912-920. [PMID: 30274981 DOI: 10.1158/1078-0432.ccr-18-1254] [Citation(s) in RCA: 385] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 08/17/2018] [Accepted: 09/26/2018] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) accounts for about 90% of all primary liver cancers and is the second leading cause of cancer-related deaths worldwide. The hypervascular nature of most HCC tumors underlines the importance of angiogenesis in the pathobiology of these tumors. Several angiogenic pathways have been identified as being dysregulated in HCC, suggesting they may be involved in the development and pathogenesis of HCC. These data provide practical targets for systemic treatments such as those targeting the vascular endothelial growth factor receptor and its ligand. However, the clinical relevance of other more recently identified angiogenic pathways in HCC pathogenesis or treatment remains unclear. Research into molecular profiles and validation of prognostic or predictive biomarkers will be required to identify the patient subsets most likely to experience meaningful benefit from this important class of agents.
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Affiliation(s)
- Michael A Morse
- Department of Medicine, Division of Medical Oncology, Duke University Health System, Durham, North Carolina.
| | - Weijing Sun
- Division of Medical Oncology, University of Kansas School of Medicine, Kansas City, Kansas
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Aiwu Ruth He
- Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | | | | | - Richard S Finn
- Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, California
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Plasminogen kringle 5 suppresses gastric cancer via regulating HIF-1α and GRP78. Cell Death Dis 2017; 8:e3144. [PMID: 29072683 PMCID: PMC5682690 DOI: 10.1038/cddis.2017.528] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 07/13/2017] [Accepted: 07/14/2017] [Indexed: 01/26/2023]
Abstract
Inhibition of tumour angiogenesis has an important role in antitumour therapy. However, a recent study indicates that antiangiogenesis therapy may lead to glucose-related protein 78 (GRP78) associated antiapoptotic resistance. The present study aims to elucidate the dual effects of plasminogen kringle 5 (K5) on tumour angiogenesis and apoptosis induction by targeting hypoxia-inducible factor 1α (HIF-1α) and GRP78. Co-immunoprecipitation and western blotting were used for examining the ubiquitination of HIF-1α and analysing angiogenesis and apoptosis-associated proteins. K5 promoted the sumo/ubiquitin-mediated proteasomal degradation of HIF-1α by upregulating von Hippel-Lindau protein under hypoxia, resulting in the reduction of vascular endothelial growth factor and thus suppressing tumour angiogenesis. Furthermore, K5 decreased GRP78 expression via downregulation of phosphorylated extracellular-regulated protein kinase, leading to caspase-7 cleavage and tumour cell apoptosis. Blocking voltage-dependent anion channel abrogated the effects of K5 on both HIF-1α and GRP78. K5 significantly inhibited the growth of gastric carcinoma xenografts by inhibiting both angiogenesis and apoptosis. The dual effects suggest that K5 might be a promising bio-therapeutic agent in the treatment of gastric cancer, particularly in patients who exhibit the induction of GRP78.
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20
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Lin J, Lin Y, Su L, Su Q, Guo W, Huang X, Wang C, Lin L. The role of Jagged1/Notch pathway-mediated angiogenesis of hepatocarcinoma cells in vitro, and the effects of the spleen-invigorating and blood stasis-removing recipe. Oncol Lett 2017; 14:3616-3622. [PMID: 28927121 PMCID: PMC5588019 DOI: 10.3892/ol.2017.6611] [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: 05/31/2017] [Accepted: 07/05/2017] [Indexed: 12/30/2022] Open
Abstract
The objective of this study was to observe the effect of Jagged1/Notch pathway-mediated angiogenesis on the in vitro proliferation of hepatocellular carcinoma cells, and the effect and possible mechanism of the spleen-invigorating and blood stasis-removing recipe. Spleen-invigorating and blood stasis-removing recipe serum from SPF grade nude mice was prepared, and the fingerprint of the drugs of the spleen-invigorating and blood stasis-removing recipe and drug serum were identified by HPLC. SMMC-7721 human hepatocellular carcinoma cells were divided into the normal control group, DAPT inhibitor control group, and drug serum group according to the different treatments. The Cell Counting Kit-8 (CCK-8) method was used to determine cell proliferation ability, and angiogenesis was observed under an inverted microscope. The expression of Jagged1, Notch1, and VEGF was measured by qPCR and western blot analysis. The interaction of Jagged1 and Notch1 was detected by Co-IP. The CCK-8 assay indicated that cell proliferation was inhibited in response to drug treatment (P<0.01). The expression of Jagged1, Notch1, and VEGF in the drug serum group was significantly lower than in the normal control group (P<0.01). Compared with the control group, the new vascular area of the DAPT inhibitor control group and drug serum group was smaller, and the blood vessels of the DAPT inhibitor control group and drug serum group were more sparse. The levels of Jagged1, Notch1, VEGF protein and the interaction between Jagged1 and Notch1 in the DAPT inhibitor control group and drug serum group were significantly lower than in the control serum group (P<0.01). In conclusion, the spleen-invigorating and blood stasis-removing recipe can inhibit the proliferation of hepatocellular carcinoma cells, and tumor angiogenesis in vitro. The function is related to the reduced expression of Jagged1, reduced interaction between Jagged1 and Notch1, and the reduced expression and activity of VEGF.
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Affiliation(s)
- Juze Lin
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China.,Department of Traditional Chinese Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatric Institute, Guangzhou, Guangdong, P.R. China
| | - Yongxin Lin
- Guangzhou Traditional Chinese Medicine Hospital Affiliated to Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
| | - Le Su
- Guangzhou Traditional Chinese Medicine Hospital Affiliated to Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
| | - Qiao Su
- Animal Experiment Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China
| | - Wei Guo
- Tropical Medicine Institute, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
| | - Xuhui Huang
- Department of Traditional Chinese Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatric Institute, Guangzhou, Guangdong, P.R. China
| | - Changjun Wang
- Department of Traditional Chinese Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatric Institute, Guangzhou, Guangdong, P.R. China
| | - Lizhu Lin
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
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Chen G, Li X, Yang J, Li J, Wang X, He J, Huang Z. Prognostic significance of cyclooxygenase-2 expression in patients with hepatocellular carcinoma: a meta-analysis. Arch Med Sci 2016; 12:1110-1117. [PMID: 27695503 PMCID: PMC5016591 DOI: 10.5114/aoms.2016.61916] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 01/05/2015] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION Cyclooxygenase-2 (COX-2) is believed to be an important enzyme in the carcinogenesis of hepatocellular carcinoma (HCC). However, it is still controversial whether COX-2 expression can be regarded as a prognostic factor for HCC patients. We performed a systematic review and meta-analysis of studies assessing the clinical and prognostic significance of COX-2 expression in HCC. MATERIAL AND METHODS Identification and review of publications assessing clinical or prognostic significance of COX-2 expression in HCC until November 1, 2014. A meta-analysis was performed to clarify the association between COX-2 expression and clinical outcomes. RESULTS A total of 11 publications met the criteria and included 943 cases. Analysis of these data showed that COX-2 expression was not significantly correlated with capsular formation (OR = 0.84, 95% confidence interval (CI): 0.46-1.55, p = 0.58), tumor TNM stage (OR = 0.73, 95% CI: 0.23-2.33, p = 0.59), vascular invasion (OR = 1.04, 95% CI: 0.25-4.35, p = 0.96), tumor size (OR = 0.78, 95% CI: 0.21-2.86, p = 0.71), or tumor differentiation degree (OR = 1.08, 95% CI: 0.42-2.79, p = 0.87). However, in the identified studies, COX-2 expression was strongly associated with high alpha-fetoprotein level (OR = 1.83, 95% CI: 1.01-3.33, p = 0.05), HBsAg status (OR = 1.85, 95% CI: 1.13-3.03, p = 0.01), decreased overall survival (relative risk (RR): 1.54, 95% CI: 1.18-2.02, p = 0.001) and decreased disease-free survival (RR = 1.49, 95% CI: 1.22-1.81, p < 0.001). CONCLUSIONS This meta-analysis shows that COX-2 expression in HCC is associated with decreased overall and disease-free survival and thus marks a worse prognosis. Nevertheless, more large sample and well-designed studies are warranted to confirm this finding.
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Affiliation(s)
- Guodong Chen
- Department of General Surgery, First Affiliated Hospital, University of South China, Hengyang, China
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyan Li
- Department of Endocrinology, Hengyang Central Hospital, Hengyang, China
| | - Jing Yang
- Department of General Surgery, First Affiliated Hospital, University of South China, Hengyang, China
| | - Jie Li
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xia Wang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jun He
- Department of General Surgery, First Affiliated Hospital, University of South China, Hengyang, China
| | - Zonghai Huang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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22
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Xia W, Chen W, Zhang Z, Wu D, Wu P, Chen Z, Li C, Huang J. Prognostic value, clinicopathologic features and diagnostic accuracy of interleukin-8 in colorectal cancer: a meta-analysis. PLoS One 2015; 10:e0123484. [PMID: 25856316 PMCID: PMC4391830 DOI: 10.1371/journal.pone.0123484] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2014] [Accepted: 02/19/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The prognostic value and diagnostic accuracy of Interleukin-8 (IL-8) in colorectal cancer have been assessed with several studies, but the conclusions were inconclusive. Thus we performed a meta-analysis to evaluate the impact of IL-8 expression on colorectal cancer prognosis, clinicopathologic features and diagnostic accuracy. METHODS Comprehensive search strategies were used to search relevant literature in the PubMed, EBSCO and the ISI Web of Science databases. The correlation between IL-8 expression and prognosis, clinicopathologic features and diagnostic accuracy was analyzed. RESULTS A total of 18 articles met the inclusion criteria, including 1509 patients for clinicopathologic features or prognosis evaluation and 725 participants for diagnostic evaluation. The results suggested that overexpression of IL-8 was significantly associated with poor prognosis in colorectal cancer (HR = 1.54, 95%CI 1.03-2.32), especially in Union for International Cancer Control (UICC) stage IV patients (HR = 2.28, 95%CI 1.60-3.25). With further subgroup analysis, we found that high IL-8 level in serum was significantly correlated with poor prognosis (HR = 2.13, 95%CI 1.49-3.05). In addition, significant correlations were observed between high IL-8 expression and advanced stage (OR = 3.01, 95%CI 1.98-4.56), lymphatic metastasis (OR = 2.24, 95%CI 1.39-3.63), and liver metastasis (OR = 3.47, 95%CI 1.74-6.89). Moreover, IL-8 had high diagnostic accuracy, with pooled sensitivity 0.70(95%CI 0.66-0.74), specificity 0.91(95%CI 0.86-0.94), positive likelihood ratio (LR) 7.00(95%CI 2.48-19.73), negative LR 0.24(95%CI 0.09-0.64), diagnostic OR 24.00(95%CI 5.52-104.38). CONCLUSIONS This study showed that IL-8 could be a potential indicator for detecting colorectal cancer and predicting prognosis. In addition, high IL-8 level was significantly correlated with advanced stage, lymphatic metastasis, liver metastasis.
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Affiliation(s)
- Wenjie Xia
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute, Key Laboratory of Cancer Prevention&Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China
| | - Wuzhen Chen
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute, Key Laboratory of Cancer Prevention&Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhigang Zhang
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute, Key Laboratory of Cancer Prevention&Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China
| | - Dang Wu
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute, Key Laboratory of Cancer Prevention&Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China
| | - Pin Wu
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute, Key Laboratory of Cancer Prevention&Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhigang Chen
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute, Key Laboratory of Cancer Prevention&Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Li
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Huang
- Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute, Key Laboratory of Cancer Prevention&Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China
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Suga H, Okabe Y, Tsuruta O, Naito Y, Kinoshita H, Toyonaga A, Ono N, Oho K, Kojiro M, Sata M. Contrast-enhanced ultrasonograpic studies on pancreatic carcinoma with special reference to staining and muscular arterial vessels. Kurume Med J 2014; 60:71-8. [PMID: 24531182 DOI: 10.2739/kurumemedj.ms63006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Comparative study of contrast-enhanced ultrasonography (CE-US) and histopathology of surgically resected specimens in 13 patients with pancreatic carcinoma. A time intensity curve was used to determine the percentage brightness increase in cancerous and normal regions and the patients were divided into two groups, hyperperfusion, with a percentage brightness increase over 80% (n=6) and hypoperfusion, with an increase of less than 80% (n=7) on CE-US. The hyperperfusion group included well-differentiated tubular adenocarcinoma, adenosquamous cell carcinoma and acinar cell carcinoma, while all 7 patients in the hypoperfusion group had moderately differentiated tubular adenocarcinoma. Immunological staining (α-SMA and anti-CD34) of the resected specimens showed significantly higher microartery count (MAC) in the hyperperfusion group (p<0.005) than in the hypoperfusion group or normal pancreas. In the normal pancreas, the mean vessel diameter was significantly higher (over 100 μm) than in the hyperperfusion group (30 μm; p<0.005). It was concluded that a muscular arterial vessel density of less than 30 μm is an important factor in determining staining degree and carcinoma progression by CE-US in pancreatic carcinoma.
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Affiliation(s)
- Hideya Suga
- Division of Gastroenterology Department of Medicine, Kurume University School of Medicine
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Prognostic significance of cyclooxygenase-2, epidermal growth factor receptor 1, and microvascular density in gastric cancer. Med Oncol 2011; 29:1739-47. [PMID: 22048943 DOI: 10.1007/s12032-011-0098-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2011] [Accepted: 10/19/2011] [Indexed: 12/20/2022]
Abstract
Gastric cancer remains a significant global health burden with poor treatment outcome. New treatment modalities that target inflammation, proliferation, and angiogenesis have been used in various cancers, including gastric cancer. We sought to study the pattern of expression of two important proteins, cyclooxygenase-2 and epidermal growth factor receptor, and their association with microvascular density, clinicopathological features, and survival in Arab Omani patients with gastric cancer. Formalin-fixed, paraffin-embedded tumors were studied by immunohistochemistry using monoclonal antibodies to cyclooxygenase-2, epidermal growth factor receptor, and CD34. The immunohistochemical results were correlated with clinicopathological features and survival. In our study population, we found a male/female ratio of 72:43, a median age of 59 years, stage III and IV incidence of 66.9%, and a median follow-up of 96 months. Positive expression rates of cyclooxygenase-2 and epidermal growth factor receptor were 89.6 and 23.5%, respectively. The median microvascular density value was 52.5. When this value was determined as the cut-off point, 50% of patients were found to have high microvascular density. Epidermal growth factor receptor over-expression correlated with high microvascular density values, advanced lymph node involvement (N3), and TNM stage presentation (III and IV). Similarly, lymph node involvement was associated with cyclooxygenase-2 over-expression and high microvascular density. Univariate analysis showed that epidermal growth factor receptor over-expression, pathological T3 and T4 disease, and overall stage III and IV disease were adverse prognostic factors. On multivariate analysis using a Cox regression model, expression of epidermal growth factor receptor, and advanced TNM stage were significant adverse prognostic factors for overall survival. Expression of epidermal growth factor receptor in Arab Omani patients with gastric cancer correlates with aggressive tumor characteristics and is an independent prognostic factor. Further clinical studies are needed to evaluate the utility of epidermal growth factor receptor immunohistochemistry as a tool for gastric cancer treatment.
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Abstract
Hepatocellular carcinoma represents the main cause of death in patients with Child-A cirrhosis. Surveillance programs aimed at the early diagnosis of hepatocellular carcinoma, at potentially treatable stages, are mandatory in Child-A cirrhotic patients and in Child-B cirrhotic patients, provided liver transplantation can be pursued. Surveillance allows stage migration and in definite subgroups of patients, it improves survival as well. Even though several circulating markers have been tested, none of them, including serum AFP determination, is actually recommended in the setting of surveillance. Thus ultrasound scan is the only recommended test, and it should be performed at 6-month intervals. Upon detection of a new nodule, a diagnostic algorithm based on the size of the nodule should be applied. In the western countries, the BCLC proposal is the most widely used and validated staging system and it helps to choice of the best treatment option even though each patient deserves a multidisciplinary evaluation due to the complexity of the coexistence of two diseases: hepatocellular carcinoma and liver cirrhosis.
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Affiliation(s)
- Luigi Bolondi
- Department of Digestive Diseases and Internal Medicine, University of Bologna-Policlinico S. Orsola Malpighi Bologna, Via Albertoni 15, Bologna, Italy.
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Tonino P, Abreu C. Microvessel Density Is Associated with VEGF and α-SMA Expression in Different Regions of Human Gastrointestinal Carcinomas. Cancers (Basel) 2011; 3:3405-18. [PMID: 24212960 PMCID: PMC3759202 DOI: 10.3390/cancers3033405] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Revised: 08/23/2011] [Accepted: 08/25/2011] [Indexed: 01/26/2023] Open
Abstract
Tumor angiogenesis is known to be regulated by growth factors secreted by host and tumor cells. Despite the importance of tumor vasculature and angiogenic heterogeneity in solid tumors, few studies have compared the vasculature in different regions of human cancer. Blood vessels from different regions of carcinomas might have morphofunctional implications in tumor angiogenesis. In the present study, therefore, we have examined the relationship between microvascular density (MVD) and vascular endothelial growth factor (VEGF) expression and alpha smooth muscle actin (α-SMA) expression in the center of the tumor (CT), periphery (P) and metastasis (M) regions from gastrointestinal carcinomas (GITC), as well as the association of MVD with clinicopathological factors. Surgically resected specimens corresponding to the CT, P and M from 27 patients were examined for FVIII, VEGF and α-SMA by immunohistochemistry. The MVD was not significantly different in the CT, P and M regions from GITC. The MVD in the VEGF positive group was significantly higher than in the VEGF negative group (CT, p = 0.034; P, p = 0.030; M, p = 0.032). The MVD as a function of α-SMA expression was also significantly higher in the CT and P region compared to the M region (p = 0.0008). In conclusion, the MVD association with VEGF and α-SMA expression, might indicate an increase of the number of neoformed and preexisting blood vessels uniformly or partially covered by pericytes in different regions of GITC, suggesting that not only MVD and VEGF are important parameters to the tumor vasculature, but also blood vessels maturation is a crucial factor for gastrointestinal tumor angiogenesis regulation and possible target of vascular therapy.
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Affiliation(s)
- Paola Tonino
- Centro de Microscopía Electrónica “Dr. Mitsuo Ogura”, Facultad de Ciencias, Universidad Central de Venezuela, Apartado 76963, El Marqués 1070, Caracas, Venezuela
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +58-212-605-1607
| | - Carmen Abreu
- Instituto Anatomopatológico, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela; E-Mail:
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Martins SF, Reis RM, Rodrigues AM, Baltazar F, Filho AL. Role of endoglin and VEGF family expression in colorectal cancer prognosis and anti-angiogenic therapies. World J Clin Oncol 2011; 2:272-80. [PMID: 21773077 PMCID: PMC3139037 DOI: 10.5306/wjco.v2.i6.272] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 03/02/2011] [Accepted: 04/05/2011] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the cancer models and most of the carcinogenic steps are presently well understood. Therefore, successful preventive measures are currently used in medical practice. However, CRC is still an important public health problem as it is the third most common cancer and the fourth most frequent cause of cancer death worldwide. Nowadays, pathologic stage is a unique and well-recognized prognostic indicator, however, more accurate indicators of the biologic behavior of CRC are expected to improve the specificity of medical treatment. Angiogenesis plays an important role in the growth and progression of cancer but its role as a prognostic factor is still controversial. Probably the most important clinical implication of tumor angiogenesis is the development of anti-angiogenic therapy. The goal of this review is to critically evaluate the role of angiogenic markers, assessed by either endoglin-related microvessel density or expression of vascular endothelial growth factor family members in the CRC setting and discuss the role of these angiogenic markers in anti-angiogenic therapies.
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Affiliation(s)
- Sandra F Martins
- Sandra F Martins, Rui M Reis, Fátima Baltazar, Adhemar Longatto Filho, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Portugal - Campos of Gualtar - 4710-057 Braga, Portugal
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Kaseb AO, Hassan MM, Lin E, Xiao L, Kumar V, Pathak P, Lozano R, Rashid A, Abbruzzese JL, Morris JS. V-CLIP: Integrating plasma vascular endothelial growth factor into a new scoring system to stratify patients with advanced hepatocellular carcinoma for clinical trials. Cancer 2010; 117:2478-88. [PMID: 24048796 DOI: 10.1002/cncr.25791] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Revised: 09/29/2010] [Accepted: 10/15/2010] [Indexed: 12/21/2022]
Abstract
BACKGROUND Several staging systems have been proposed for hepatocellular carcinoma (HCC); however, none has incorporated circulating angiogenic biomarkers. The purpose of this study was to determine whether vascular endothelial growth factor (VEGF) could independently predict overall survival in patients with HCC, and whether adding VEGF level into the Cancer of the Liver Italian Program (CLIP) score could improve patient stratification and prediction of overall survival. METHODS Between 2001 and 2008, baseline plasma VEGF levels were available from 288 patients, and multivariate Cox regression models and median survival (95% confidence intervals) were calculated. Recursive partitioning was used to determine the optimal cutpoint for VEGF, using 10 repeated training/validation samples, each using two-thirds of the data to determine the best cutpoint and the remaining one-third to validate it. Prognostic ability of CLIP and V-CLIP was compared using the concordence index. RESULTS Plasma VEGF was a significant independent predictor of overall survival, with an optimal VEGF cutpoint of 450 pg/mL. After CLIP validation in our patients, we added VEGF to the CLIP score and found that the new V-CLIP score better separates patients into homogenous prognostic groups (P = .005). CONCLUSIONS The assessment of baseline plasma VEGF levels increases the precision of the CLIP scoring system for predicting HCC prognosis, which may assist in equally randomizing patients with HCC in clinical trials. Prospective validation of the V-CLIP scoring system is warranted.
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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.
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Cheng P, Jiang FH, Zhao LM, Dai Q, Yang WY, Zhu LM, Wang BJ, Xu C, Bao YJ, Zhang YJ. Human macrophage metalloelastase correlates with angiogenesis and prognosis of gastric carcinoma. Dig Dis Sci 2010. [PMID: 20127415 DOI: 10.1007/s10620-010-] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS The function of human macrophage metalloelastase (HME) also known as matrix metalloproteinase 12, in tumorigenesis is contradictory. The current study was designed to investigate the association of HME expression with angiogenesis and prognosis of gastric carcinomas. METHODS In situ hybridization and immunohistochemistry were used to detect HME in human gastric carcinomas, chronic gastritis with atypical hyperplasia, and normal gastric epithelium mucosa. The results were further confirmed by RT-PCR or semi-quantitative reverse transcription polymerase chain reaction and Western blotting in gastric carcinomas and paired noncancerous tissues. VEGF and microvessel density count were also detected by immunohistochemical staining in all carcinoma tissues. The prognostic significance of HME was assessed with multiple linear regression analysis and Cox proportional hazards model. RESULTS High expression of HME protein/mRNA was observed in gastric carcinomas and atypical hyperplasia tissues compared with normal gastric epithelium mucosa, or paired noncancerous tissues. HME protein/mRNA were negatively correlated with MVD (p < 0.01), VEGF (p < 0.01), tumor differentiation grade (p < 0.05), vascular invasion (p < 0.01), and recurrence (p < 0.05-0.01). HME protein was an independent influential factor of MVD (p < 0.01). HME protein/mRNA was an independent prognostic factor of gastric carcinoma (p < 0.05-0.01). Patients with overexpression of HME protein/mRNA demonstrated a significantly better survival rate compared with those who did not (p < 0.05-0.01). CONCLUSIONS Overexpression of HME is strongly correlated with the reduced angiogenesis and vascular invasion of gastric carcinoma, and may serve as a useful predictive indicator in patients with this disease.
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Affiliation(s)
- Peng Cheng
- Digestive Department, No. 3 People's Hospital/Shanghai Jiaotong University School of Medicine, 280 Mohe Road, Shanghai, China
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Cheng P, Jiang FH, Zhao LM, Dai Q, Yang WY, Zhu LM, Wang BJ, Xu C, Bao YJ, Zhang YJ. Human macrophage metalloelastase correlates with angiogenesis and prognosis of gastric carcinoma. Dig Dis Sci 2010; 55:3138-46. [PMID: 20127415 DOI: 10.1007/s10620-010-1127-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2009] [Accepted: 01/11/2010] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS The function of human macrophage metalloelastase (HME) also known as matrix metalloproteinase 12, in tumorigenesis is contradictory. The current study was designed to investigate the association of HME expression with angiogenesis and prognosis of gastric carcinomas. METHODS In situ hybridization and immunohistochemistry were used to detect HME in human gastric carcinomas, chronic gastritis with atypical hyperplasia, and normal gastric epithelium mucosa. The results were further confirmed by RT-PCR or semi-quantitative reverse transcription polymerase chain reaction and Western blotting in gastric carcinomas and paired noncancerous tissues. VEGF and microvessel density count were also detected by immunohistochemical staining in all carcinoma tissues. The prognostic significance of HME was assessed with multiple linear regression analysis and Cox proportional hazards model. RESULTS High expression of HME protein/mRNA was observed in gastric carcinomas and atypical hyperplasia tissues compared with normal gastric epithelium mucosa, or paired noncancerous tissues. HME protein/mRNA were negatively correlated with MVD (p < 0.01), VEGF (p < 0.01), tumor differentiation grade (p < 0.05), vascular invasion (p < 0.01), and recurrence (p < 0.05-0.01). HME protein was an independent influential factor of MVD (p < 0.01). HME protein/mRNA was an independent prognostic factor of gastric carcinoma (p < 0.05-0.01). Patients with overexpression of HME protein/mRNA demonstrated a significantly better survival rate compared with those who did not (p < 0.05-0.01). CONCLUSIONS Overexpression of HME is strongly correlated with the reduced angiogenesis and vascular invasion of gastric carcinoma, and may serve as a useful predictive indicator in patients with this disease.
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Affiliation(s)
- Peng Cheng
- Digestive Department, No. 3 People's Hospital/Shanghai Jiaotong University School of Medicine, 280 Mohe Road, Shanghai, China
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Cavazzola LT, Rosa ARPD, Schirmer CC, Gurski RR, Telles JPB, Mielke F, Meurer L, Edelweiss MIA, Kruel CDP. Immunohistochemical evaluation for P53 and VEGF (Vascular Endothelial Growth Factor) is not prognostic for long term survival in end stage esophageal adenocarcinoma. Rev Col Bras Cir 2010; 36:24-34. [PMID: 20076865 DOI: 10.1590/s0100-69912009000100007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2008] [Accepted: 10/28/2008] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVES To correlate the expression of p53 protein and VEGF with the prognosis of patients submitted to curative resection to treat esophageal adenocarcinoma. METHODS Forty-six patients with esophageal adenocarcinoma, submitted to curative resection, were studied. The expressions of p53 protein and VEGF were assessed by immunohistochemistry in 52.2% and 47.8% of tumors, respectively. RESULTS P53 protein and VEGF expressions coincided in 26% of the cases, and no correlation between these expressions was observed. None of the clinicopathological factors showed a significant correlation with p53 protein or VEGF expressions. There was no significant association between p53 protein and VEGF expressions and long-term survival. CONCLUSION The expression of p53 protein and VEGF did not correlate with prognosis in esophageal adenocarcinoma patients submitted to curative resection.
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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: 102] [Impact Index Per Article: 6.8] [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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Takala H, Saarnio J, Wiik H, Ohtonen P, Soini Y. HIF-1α and VEGF are associated with disease progression in esophageal carcinoma. J Surg Res 2010; 167:41-8. [PMID: 20451923 DOI: 10.1016/j.jss.2009.11.725] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2009] [Revised: 08/12/2009] [Accepted: 11/19/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hypoxia inducible factor-1alpha (HIF-1α) is a transcription factor that regulates the transcription of genes associated with cell proliferation and angiogenesis. The purpose of this study is to clarify the correlation of HIF-1α protein expression with vascular endothelial growth factor (VEGF) and inducible (iNOS), endothelial (eNOS), and neuronal nitric oxide synthase (nNOS) expression in esophageal tumors. Additionally, vascular density in tumor tissue was assessed. MATERIALS AND METHODS Eighty-eight esophageal carcinomas were analyzed by immunohistochemistry in paraffin embedded sections. RESULTS HIF-1α immunoreactivity was seen in 71.2 % of the tumors. Squamous cell carcinomas expressed more often HIF-1α than adenocarcinomas (P = 0.009). HIF-1α immunoreactivity was associated with iNOS (P = 0.049), and iNOS positivity was also more commonly seen in squamous cell carcinomas than adenocarcinomas (P = 0.016). VEGF immunoreaction tended to associate with HIF-1α (P = 0.073) and iNOS (P = 0.08). ENOS did not associate with HIF-1α, but tended to associate with VEGF (P = 0.072). T1-T2 tumors were more often VEGF negative than T3-T4 tumors (P = 0.063). In the subgroup of 78 operatively treated ECs patients with HIF-1α positivity (> +) had more often distant metastases (P = 0.036). There was no association between iNOS, eNOS, nNOS, or VEGF, and microvessel density in tumor tissue, tumor marginal zone, or in peripheral tissue. CONCLUSIONS These results show that there is a link in expression between HIF-1α, iNOS, (eNOS), and VEGF in esophageal cancer. This is in line with the fact of HIF-1α's function as a transcriptional factor for these angiogenic factors. Results also show that squamous cell and adenocarcinomas differ in their expression of HIF-1α and iNOS. VEGF appear to have association with depth of invasion in esophageal carcinomas. In our material HIF-1α positivity was associated with distant metastases, but not with patient survival.
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Affiliation(s)
- Heikki Takala
- Department of Surgery, University Hospital of Oulu, Oulu, Finland.
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Vidal O, Metges JP, Elizalde I, Valentíni M, Volant A, Molina R, Castells A, Pera M. High preoperative serum vascular endothelial growth factor levels predict poor clinical outcome after curative resection of gastric cancer. Br J Surg 2009; 96:1443-51. [PMID: 19918848 DOI: 10.1002/bjs.6780] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Tumour vascular endothelial growth factor (VEGF) and tumour urokinase-type plasminogen activator (uPA) are prognostic factors in gastric cancer but surgical specimens are required for testing. The prognostic value of preoperative serum VEGF (s-VEGF) and serum uPA (s-uPA) levels was evaluated in patients undergoing potentially curative (R0) gastric cancer resection. METHODS Concentrations of s-VEGF and s-uPA were measured 97 patients with gastric cancer and 20 controls. Angiogenesis was measured in vitro based on human endothelial cell tube formation. RESULTS Levels of s-VEGF were higher in patients with gastric cancer than controls (median 288 versus 189 pg/ml respectively; P = 0.002). They were associated with pathological tumour node metastasis (pTNM) stage, pT, pN, lymph node ratio and perineural invasion, and correlated with platelet counts. In multivariable analysis, s-VEGF over 320 pg/ml was the only preoperative predictor of both recurrence and disease-specific survival. Serum from patients with raised s-VEGF levels enhanced angiogenesis in vitro significantly more than serum from those with a s-VEGF level of 320 pg/ml or less. CONCLUSION High preoperative s-VEGF level is an independent prognostic factor for recurrence and survival after R0 resection of gastric cancer. This may provide a useful guide to decision making regarding neoadjuvant and adjuvant therapies.
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Affiliation(s)
- O Vidal
- Service of General and Digestive Surgery, Institut de Malalties Digestives i Metabolisme, Barcelona, Spain
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Wada H, Nagano H, Yamamoto H, Noda T, Murakami M, Kobayashi S, Marubashi S, Eguchi H, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M. Combination of interferon-alpha and 5-fluorouracil inhibits endothelial cell growth directly and by regulation of angiogenic factors released by tumor cells. BMC Cancer 2009; 9:361. [PMID: 19821965 PMCID: PMC2767355 DOI: 10.1186/1471-2407-9-361] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2009] [Accepted: 10/12/2009] [Indexed: 12/22/2022] Open
Abstract
Background The combination therapy of interferon (IFN)-alpha and 5-fluorouracil (5-FU) improved the prognosis of the patients with hepatocellular carcinoma (HCC). To determine the molecular mechanisms of the anti-tumor and anti-angiogenic effects, we examined the direct anti-proliferative effects on human umbilical vein endothelial cells (HUVEC) and indirect effects by regulating secretion of angiogenic factors from HCC cells. Methods The direct effects on HUVEC were examined by TUNEL, Annexin-V assays and cell cycles analysis. For analysis of the indirect effects, the apoptosis induced by the conditioned medium from HCC cell treated by IFN-alpha/5-FU and expression of angiogenic factors was examined. Results IFN-alpha and 5-FU alone had anti-proliferative properties on HUVEC and their combination significantly inhibited the growth (compared with control, 5-FU or IFN alone). TUNEL and Annexin-V assays showed no apoptosis. Cell cycle analysis revealed that IFN-alpha and 5-FU delayed cell cycle progression in HUVEC with S-phase accumulation. The conditioned medium from HuH-7 cells after treatment with IFN/5-FU significantly inhibited HUVEC growth and induced apoptosis, and contained high levels of angiopoietin (Ang)-1 and low levels of vascular endothelial growth factor (VEGF) and Ang-2. Knockdown of Ang-1 in HuH-7 cells abrogated the anti-proliferative effects on HUVEC while knockdown of Ang-2 partially rescue the cells. Conclusion These results suggested that IFN-alpha and 5-FU had direct growth inhibitory effects on endothelial cells, as well as anti-angiogenic effects through regulation of angiogenic factors released from HCC cells. Modulation of VEGF and Angs secretion by IFN-alpha and 5-FU may contribute to their anti-angiogenic and anti-tumor effects on HCC.
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Affiliation(s)
- Hiroshi Wada
- Department of Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita 565-0871 Osaka, Japan.
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Kirk MJ, Hayward RM, Sproull M, Scott T, Smith S, Cooley-Zgela T, Crouse NS, Citrin DE, Camphausen K. Non-patient related variables affecting levels of vascular endothelial growth factor in urine biospecimens. J Cell Mol Med 2008; 12:1250-5. [PMID: 18782189 PMCID: PMC3865669 DOI: 10.1111/j.1582-4934.2008.00182.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Vascular endothelial growth factor (VEGF) is an angiogenic protein proposed to be an important biomarker for the prediction of tumour growth and disease progression. Recent studies suggest that VEGF measurements in biospecimens, including urine, may have predictive value across a range of cancers. However, the reproducibility and reliability of urinary VEGF measurements have not been determined. We collected urine samples from patients receiving radiation treatment for glioblastoma multiforme (GBM) and examined the effects of five variables on measured VEGF levels using an ELISA assay. To quantify the factors affecting the precision of the assay, two variables were examined: the variation between ELISA kits with different lot numbers and the variation between different technicians. Three variables were tested for their effects on measured VEGF concentration: the time the specimen spent at room temperature prior to assay, the addition of protease inhibitors prior to specimen storage and the alteration of urinary pH. This study found that VEGF levels were consistent across three different ELISA kit lot numbers. However, significant variation was observed between results obtained by different technicians. VEGF concentrations were dependent on time at room temperature before measurement, with higher values observed 3-7 hrs after removal from the freezer. No significant difference was observed in VEGF levels with the addition of protease inhibitors, and alteration of urinary pH did not significantly affect VEGF measurements. In conclusion, this determination of the conditions necessary to reliably measure urinary VEGF levels will be useful for future studies related to protein biomarkers and disease progression.
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Affiliation(s)
- M J Kirk
- 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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Meteoglu I, Meydan N, Erkus M. Id-1: regulator of EGFR and VEGF and potential target for colorectal cancer therapy. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2008; 27:69. [PMID: 19014499 PMCID: PMC2588562 DOI: 10.1186/1756-9966-27-69] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Accepted: 11/12/2008] [Indexed: 05/03/2023]
Abstract
Background The helix-loop-helix transcription factor Id-1 (an inhibitor of differentiation and DNA binding) plays a role in development and progression of many tumours. Id-1 is known to exert its effects on the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). The aim of this study was to reveal whether there was a relationship between Id-1 and EGFR and VEGF in colorectal carcinoma. Methods Tumour and non-tumour tissue specimens from 46 cases of colorectal carcinoma were exposed to immunohistochemical staining for Id-1, EGFR and VEGF. The relationship between the degree of staining and tumour grade, tumour stage and all tumour markers was investigated. Results Tumour cells showed positive staining for Id-1 in 43 cases (93.5%), for EGFR in 41 cases (89%) and for VEGF in 42 cases (91%). There was a significant relation between the tumour grade and the degree of staining for Id-1, EGFR and VEGF. The relation between the tumour stage and the degree of staining for Id-1, EGFR and VEGF was also significant. There was a significant relation between Id-1 expression and EGFR and VEGF expressions. Non-tumoural tissue specimens were not stained with Id-1 and EGFR antibodies in any of the cases, but stained with VEGF antibody in 3 cases. Conclusion This study revealed that Id-1, EGFR and VEGF took part in development and progression of colorectal carcinomas and that Id-1 was associated with regulations of EGFR and VEGF. The results of this study support the idea that not only EGFR and VEGF but also Id-1 could be new targets in cancer treatment.
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Affiliation(s)
- Ibrahim Meteoglu
- Adnan Menderes University, Medical Faculty, Department of Pathology, 09100-Aydin/Turkey.
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Zhu B, Lu L, Cai W, Yang X, Li C, Yang Z, Zhan W, Ma JX, Gao G. Kallikrein-binding protein inhibits growth of gastric carcinoma by reducing vascular endothelial growth factor production and angiogenesis. Mol Cancer Ther 2008; 6:3297-306. [PMID: 18089723 DOI: 10.1158/1535-7163.mct-06-0798] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Kallikrein-binding protein (KBP) has been identified as an endogenous angiogenic inhibitor. We previously showed that KBP inhibited rat retinal neovascularization by down-regulation of vascular endothelial growth factor (VEGF) in endothelial cells. However, its antiangiogenic potential for inhibition of gastric carcinoma and the effect on VEGF in tumor cells have not been elucidated. The present study was designed to investigate the effect of KBP on growth of gastric carcinoma and the possible molecular mechanism. Recombinant KBP dose dependently inhibited proliferation and induced apoptosis of endothelial cells, but no effect on proliferation and apoptosis of SGC-7,901 gastric carcinoma cells. I.p. injection of KBP resulted in growth inhibition of both heterotopic and orthotopic gastric carcinoma xenografts at 61.4% and 52.3%, respectively. Microvessel density in tumor tissues treated with KBP was significantly decreased, suggesting that KBP suppressed tumor growth by antiangiogenesis. The expression and release of VEGF, a major angiogenic stimulator, were down-regulated by KBP in SGC-7,901 cells and gastric carcinoma xenografts. RNA levels of VEGF in SGC-7,901 cells were also decreased by KBP, thus suggesting the regulation at the transcriptional level. Therefore, hypoxia-inducible factor 1alpha (HIF-1alpha), a crucial transcriptional factor for VEGF expression, was examined in SGC-7,901 cells treated by KBP. KBP reduced HIF-1alpha protein level and nuclear translocation, which may be responsible for the down-regulation of VEGF transcription. Down-regulation of VEGF expression and release in tumor cells through inhibiting HIF-1alpha, thus attenuating the paracrine effect of VEGF on endothelial cell proliferation and vascular permeability in tumor tissues, may represent a novel mechanism for the antiangiogenic and antitumor activity of KBP.
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Affiliation(s)
- Baohe Zhu
- Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, No. 74 Zhongshan Road II, Guangzhou 510089, 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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Lee TK, Poon RTP, Yuen AP, Ling MT, Wang XH, Wong YC, Guan XY, Man K, Tang ZY, Fan ST. Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma. Clin Cancer Res 2007; 12:6910-9. [PMID: 17145808 DOI: 10.1158/1078-0432.ccr-06-0489] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE Metastasis is commonly associated with poor prognosis of hepatocellular carcinoma (HCC). Being an important angiogenic factor, vascular endothelial growth factor (VEGF) plays a central role in HCC growth and metastasis. Recently, Id-1 (inhibitor of differentiation/DNA synthesis) has been suggested to be a key factor in cancer progression but the molecular mechanism remains unknown. EXPERIMENTAL DESIGN We first showed that overexpression of Id-1 was correlated with HCC metastasis (P < 0.001) and its expression was significantly correlated with VEGF expression by tissue microarray. By ectopic transfection of Id-1 into HCC cells, Id-1 was able to induce VEGF secretion through activation of VEGF transcription. RESULTS Increased VEGF secretion in Id-1 transfectants induced morphologic change and proliferation of human umbilical vascular endothelial cell resulting in promotion of angiogenesis. Id-1 induced transcriptional activation of VEGF by stabilizing hypoxia-inducible factor-1alpha protein. Down-regulation of Id-1 by antisense approach led to suppression of hypoxia-inducible factor-1alpha-mediated VEGF production. In addition, Id-1 suppression resulted in retardation of cell invasion through down-regulation of VEGF. CONCLUSIONS Id-1 is a novel angiogenic factor for HCC metastasis and down-regulation of Id-1 may be a novel target to inhibit HCC metastasis through suppression of angiogenesis.
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MESH Headings
- Animals
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/physiopathology
- Carcinoma, Hepatocellular/secondary
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Down-Regulation/drug effects
- Endothelial Cells/drug effects
- Gene Expression Profiling
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Inhibitor of Differentiation Protein 1/antagonists & inhibitors
- Inhibitor of Differentiation Protein 1/genetics
- Inhibitor of Differentiation Protein 1/metabolism
- Liver Neoplasms/drug therapy
- Liver Neoplasms/physiopathology
- Liver Neoplasms/secondary
- Mice
- Mice, Nude
- Neovascularization, Pathologic/metabolism
- Oligodeoxyribonucleotides, Antisense/pharmacology
- Oligodeoxyribonucleotides, Antisense/therapeutic use
- Reverse Transcriptase Polymerase Chain Reaction
- Structure-Activity Relationship
- Tissue Array Analysis
- Transplantation, Heterologous
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Terence K Lee
- Department of Surgery, The University of Hong Kong, Hong Kong, China
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Bangoura G, Liu ZS, Qian Q, Jiang CQ, Yang GF, Jing S. Prognostic significance of HIF-2α/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol 2007; 13:3176-82. [PMID: 17589895 PMCID: PMC4436602 DOI: 10.3748/wjg.v13.i23.3176] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the prognostic significance of HIF-2α/EPAS1 expression in hepatocellular carcinoma (HCC).
METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 cases of normal liver tissue were investigated by immunohistochemistry (IHC) for HIF-2α/EPAS1 using a standard detection system. Correlations with clinicopathological factors, VEGF, microvessel density (MVD), and prognosis were analyzed.
RESULTS: Immunoreactivity of HIF-2α/EPAS1 was positive in 69.5% of HCC, 55.6% of adjacent noncancerous tissue, and 0% of normal liver tissue. And it was significantly correlated with tumor grade, venous invasion, intrahepatic metastasis, necrosis, and capsule infiltration. Correlation analysis of HIF-2α/EPAS1 with angiogenic factor VEGF (P < 0.001), and MVD (P = 0.016) was also noted. HIF-2α/EPAS1 protein was less frequently expressed in low MVD cases, whereas a high rate of expression was noted in cases with both medium and high MVD (P = 0.042). By Kaplan-Meier analysis, strong HIF-2α/EPAS1 staining (> 50% of tumor cells) in HCC correlated with a shortened survival in patients (Cox's regression, P < 0.001, r = 3.699).
CONCLUSION: We conclude that HIF-2α/EPAS1 expression may play an important role in tumor progression and prognosis of HCC. Assessment of HIF-2α/EPAS1 expression in HCC may be used as a diagnostic tool and possibly a target in the treatment of HCC.
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Affiliation(s)
- Gassimou Bangoura
- Department of General Surgery and Liver Cancer Laboratory, Zhong Nan Hospital, Wuhan University School of Medicine, Wuhan 430071, Hubei Province, China
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Abstract
INTRODUCTION Angiogenesis is the process of new blood vessel formation from pre-existing vessels, and is a key feature of malignant tumours. Surgeons involved in the management of patients with malignant disease need to be aware of angiogenic mechanisms and their surgical implications. PATIENTS AND METHODS A literature search was used to review recent developments in our understanding of the factors and processes involved in tumour angiogenesis, and how these will impact on the care of patients with malignant disease encountered by surgeons. RESULTS Angiogenesis is fundamental to all stages of the malignant process, and involves a complex interaction between mediators secreted by tumour cells and host cells. Intense investigation continues into therapies targeting components of the angiogenic cascade. Imaging modalities capable of measuring the angiogenic activity of a tumour are also being studied in order to predict prognosis and select suitable patients for anti-angiogenic therapy. CONCLUSIONS As the use of these anti-angiogenic therapies becomes more wide-spread, they may have implications on the healing rates of cutaneous wounds and intracorporeal anastomoses.
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Affiliation(s)
- G K Atkin
- Department of Surgery, Ealing Hospital NHS Trust, Middlesex, UK
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Nie F, Xu HX, Tang Q, Lu MD. Microbubble-enhanced ultrasound exposure improves gene transfer in vascular endothelial cells. World J Gastroenterol 2006; 12:7508-13. [PMID: 17167842 PMCID: PMC4087599 DOI: 10.3748/wjg.v12.i46.7508] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effects of ultrasound exposure combined with microbubble contrast agent (SonoVue) on the permeability of the cellular membrane and on the expression of plasmid DNA encoding enhanced green fluorescent protein (pEGFP) transfer into human umbilical vein endothelial cells (HUVECs).
METHODS: HUVECs with fluorescein isothiocyanate-dextran (FD500) and HUVECs with pEGFP were exposed to continuous wave (1.9 MHz, 80.0 mW/cm2) for 5 min, with or without a SonoVue. The percentage of FD500 taken by the HUVECs and the transient expression rate of pEGFP in the HUVECs were examined by fluorescence microscopy and flow cytometry, respectively.
RESULTS: The percentage of FD500-positive HUVECs in the group of ultrasound exposure combined with SonoVue was significantly higher than that of the group of ultrasound exposure alone (24.0% ± 5.5% vs 66.6% ± 4.1%, P < 0.001). Compared with the group of ultrasound exposure alone, the transfection expression rate of pEGFP in HUVECs was markedly increased with the addition of SonoVue (16.1% ± 1.9% vs 1.5% ± 0.2%, P < 0.001). No statistical significant difference was observed in the HUVECs survival rates between the ultrasound group with and without the addition of SonoVue (94.1% ± 2.3% vs 91.1% ± 4.1%).
CONCLUSION: The cell membrane permeability of HUVECs and the transfection efficiency of pEGFP into HUVECs exposed to ultrasound are significantly increased after addition of an ultrasound contrast agent without obvious damage to the survival of HUVECs. This non-invasive gene transfer method may be a useful tool for clinical gene therapy of hepatic tumors.
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Affiliation(s)
- Fang Nie
- Department of Medical Ultrasonics, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China
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Des Guetz G, Uzzan B, Nicolas P, Cucherat M, Morere JF, Benamouzig R, Breau JL, Perret GY. Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br J Cancer 2006; 94:1823-32. [PMID: 16773076 PMCID: PMC2361355 DOI: 10.1038/sj.bjc.6603176] [Citation(s) in RCA: 284] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n = 957) for RFS and 18 for OS (n = 2383) and for VEGF in 17 studies, including nine studies for RFS (n = 1064) and 10 for OS (n = 1301). High MVD significantly predicted poor RFS (RR = 2.32 95% CI: 1.39-3.90; P < 0.001) and OS (RR = 1.44; 95% CI: 1.08-1.92; P = 0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR = 2.84; 95% CI: 1.95-4.16) and OS (RR=1.65; 95% CI: 1.27-2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies.
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Affiliation(s)
- G Des Guetz
- APHP. Department of Oncology, Hôpital Avicenne, Bobigny, France.
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Pang R, Poon RTP. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett 2006; 242:151-67. [PMID: 16564617 DOI: 10.1016/j.canlet.2006.01.008] [Citation(s) in RCA: 151] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2005] [Revised: 01/06/2006] [Accepted: 01/09/2006] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization, which plays an important role in the growth and progression of HCC. Angiogenesis provides a target for novel prognostic and therapeutic approaches to HCC. Assessment of microvessel density using immunohistochemical staining for specific endothelial cell markers such as CD34 has been shown to provide prognostic information independent of conventional pathological parameters in HCC patients. Recent studies have unveiled the important angiogenic factors involved in the regulation of angiogenesis in HCC, although the exact molecular pathways are far from clear. Current data suggest that vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis of HCC. Tumor expression of VEGF has been shown to correlate with tumor invasiveness and prognosis in patients with HCC. VEGF is an important molecular target for antiangiogenic therapy. Studies in animal models have demonstrated the efficacy of antiangiogenic agents such as anti-VEGF antibody and antagonists of VEGF receptors in suppressing hepatocarcinogenesis and growth of HCC. Antiangiogenic therapy has already entered clinical trials in HCC patients and holds the promise of providing an effective novel treatment for HCC, which is of great clinical significance because there is no existing effective systemic therapy for HCC.
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Affiliation(s)
- Roberta Pang
- Department of Medicine, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
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Chi-Man Tang T, Tung-Ping Poon R, Fan ST. The significance of cyclooxygenase-2 expression in human hepatocellular carcinoma. Biomed Pharmacother 2006; 59 Suppl 2:S311-6. [PMID: 16507400 DOI: 10.1016/s0753-3322(05)80053-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the five most common malignancies in the world and is the second leading cause of death in Hong Kong. Previous studies have shown increased levels of cyclooxygenase-2 (COX-2) in a variety of human malignancies including HCC, suggesting that abnormal COX-2 expression plays an important role in carcinogenesis. In addition, some evidence suggests that selective COX-2 inhibitors suppress the formation of tumors in experimental models. However, there are no data in the literature on using COX-2 as an inhibitor target in HCC. The main objective of this article was to give a brief summary of the recent findings of the role of COX-2 in HCC. We briefly reviewed the significance of COX-2 in varies cancers, and then focused on the recent findings of the significance of COX-2 in HCC. Finally, we further evaluated the possibility of using COX-2 as a therapeutic target in HCC.
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Affiliation(s)
- T Chi-Man Tang
- Center for the Study of Liver Disease, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, China
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Nikfarjam M, Muralidharan V, Christophi C. Altered growth patterns of colorectal liver metastases after thermal ablation. Surgery 2006; 139:73-81. [PMID: 16364720 DOI: 10.1016/j.surg.2005.07.030] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2004] [Revised: 07/23/2005] [Accepted: 07/23/2005] [Indexed: 01/19/2023]
Abstract
BACKGROUND Thermal ablation by radiofrequency or laser is used increasingly for the treatment of colorectal liver metastases. Recurrence after thermal ablation is common and occurs both locally and at distant sites. One possible cause of this recurrence may be a result of growth stimulation of micrometastases in the remaining liver. This study examined the impact of thermal ablation on growth patterns of hepatic micrometastases. METHODS Colorectal liver metastases were induced in male CBA-strain mice via an intrasplenic injection of a murine-derived cancer cell line. Subtotal thermal ablation of the left posterior lobe of the liver (30% of total liver volume) was performed by neodymium yttrium-aluminum-garnet laser 7 days after induction of metastases. The distribution, number, cross-sectional diameter, volume, and proliferation rate of established neoplasms were compared with controls at 21 days after tumor induction. The effect of thermal ablation of 7% of the total liver volume by laser on the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor 2 (FGF-2), transforming growth factor beta, and cellular proliferation (Ki-67 antigen) adjacent to the ablated site was assessed by immunohistochemistry in separate groups of animals at specific time points after therapy. RESULTS Thermal ablation did not alter the overall volume, number, size, and proliferation rate of neoplasms 21 days after laser ablation. There were no extrahepatic metastases after therapy. The number of neoplasms in the regenerated posterior lobe was equivalent to control despite subtotal ablation (29 +/- 2 vs 27 +/- 2; P = NS). A greater amount of metastases occupied the regenerated thermal-ablated lobe compared with controls (55% +/- 4% vs 29% +/- 3%; P < .04). Thermal ablation stimulated liver proliferation adjacent to the treatment site at 12 hours compared with untreated controls. Stimulation peaked at 72 hours (20% +/- 1% vs 1% +/- 1%; P < .001) and persisted to 21 days after therapy. FGF-2 and VEGF expression increased in liver tissue adjacent to the ablation site compared with baseline, peaking at 12 hours (112% +/- 2% vs 102% +/- 1%; P < .001) and 72 hours (114% +/- 2% vs 101% +/- 1%; P < .001), respectively. CONCLUSIONS Thermal ablation promotes the progression of micrometastases to form macroscopically detectable neoplasms in treated regenerating liver. This effect may relate to an increased expression of VEGF and FGF-2 adjacent to the treatment site.
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Affiliation(s)
- Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Austin Hospital, Lance Townsend Building Level 8, Studley Road, Heldelberg, Melbourne, Victoria 3084, Australia.
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Ho JWY, Man K, Sun CK, Lee TK, Poon RTP, Fan ST. Effects of a novel immunomodulating agent, FTY720, on tumor growth and angiogenesis in hepatocellular carcinoma. Mol Cancer Ther 2006; 4:1430-8. [PMID: 16170036 DOI: 10.1158/1535-7163.mct-05-0021] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In this study, we aimed to evaluate the potential anticancer and antiangiogenic effects of FTY720 on hepatocellular carcinoma. In vitro, chemosensitivity was tested on hepatoma cells, nontumorigenic, immortalized hepatocyte cells, as well as human umbilical vein endothelial cells (HUVEC). Moreover, effect of FTY720 on cell cycle and apoptosis was analyzed. In addition, a number of angiogenesis-associated assays were carried out. The in vivo effect of the drug on hepatocellular carcinoma tumor growth on nude mice was studied. Tissues obtained were analyzed in terms of proliferation, apoptosis, tumor microvessel density, and tumor vascular permeability. Compared with the MIHA cells, the hepatoma cell lines as well as HUVECs were found to be highly sensitive to the drugs in the aspect that FTY720 could induce G(1) arrest and apoptosis in the hepatoma cells. Furthermore, FTY720 significantly decreased invasion, migration, and capillary tube formation of HUVECs at very low doses. In vivo study showed that tumor growth was significantly suppressed in the FTY720-treated animals, and staining of the tissue sections showed decreased tumor cell proliferation and increased tumor cell apoptosis in the treatment groups. Interestingly, significant reductions in tumor microvessel density and tumor vascular permeability were also found in the FTY720-treated groups. In conclusion, FTY720 not only shows potent antiangiogenic effects but is also cytotoxic toward hepatoma cells. Results from our preclinical study suggest that FTY720 can be selected as a good candidate for the treatment of hepatocellular carcinoma.
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MESH Headings
- Animals
- Antineoplastic Agents, Hormonal/pharmacology
- Apoptosis/drug effects
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/immunology
- Cell Proliferation/drug effects
- Endothelium, Vascular/cytology
- Endothelium, Vascular/drug effects
- Fingolimod Hydrochloride
- Flow Cytometry
- G1 Phase/drug effects
- Humans
- Liver Neoplasms/blood supply
- Liver Neoplasms/drug therapy
- Liver Neoplasms/immunology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Microcirculation
- Neovascularization, Pathologic/prevention & control
- Propylene Glycols/therapeutic use
- Sphingosine/analogs & derivatives
- Transplantation, Heterologous
- Umbilical Veins/cytology
- Umbilical Veins/drug effects
- Wounds and Injuries
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Affiliation(s)
- Joanna W Y Ho
- Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Queen Mary Hospital, China
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Mross K, Drevs J, Müller M, Medinger M, Marmé D, Hennig J, Morgan B, Lebwohl D, Masson E, Ho YY, Günther C, Laurent D, Unger C. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer 2005; 41:1291-9. [PMID: 15939265 DOI: 10.1016/j.ejca.2005.03.005] [Citation(s) in RCA: 126] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2005] [Accepted: 03/01/2005] [Indexed: 11/20/2022]
Abstract
The family of VEGF receptors are important mediators of angiogenesis, which is essential for tumour growth and metastasis. PTK/ZK is a multiple VEGF receptor inhibitor that blocks the activity of all known VEGF receptor tyrosine kinases. This phase I/II trial evaluated the safety, pharmacokinetics and efficacy of PTK/ZK in patients with liver metastases from solid tumours. Patients were administered oral PTK/ZK monotherapy once daily at doses of 300-1200 mg/day in 28-day cycles until unacceptable toxicity or tumour progression occurred. Twenty-seven patients were enrolled and treatment with PTK/ZK was generally well tolerated. The most frequently reported adverse events were fatigue, nausea, dizziness, and vomiting (mostly National Cancer Institute Common Toxicity Criteria grade 1 or 2). The area under the concentration-time curve (AUC) of PTK/ZK increased between 300 and 1000 mg/day with no further increase from 1000 to 1200 mg/day; the AUC decreased by 50% between day 1 and day 15. The DCE-MRI showed a statistically significant early reduction of tumour blood supply (measured as Ki) at day 2 at doses > or = 750 mg/day. Disease progression was significantly correlated with percent change from baseline Ki. Thirteen patients had stable disease for at least two cycles (56 days). Median overall survival was 11.8 months (95% CI = 6.6, 17.1 months). Long-term therapy with PTK/ZK demonstrated predictable pharmacokinetics, was safe and feasible in patients with metastatic disease, and showed promising clinical activity. The minimum biologically active dose was established at 750 mg/day whereas the recommended dose for phase III studies is 1200 mg/day.
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Affiliation(s)
- Klaus Mross
- Tumour Biology Center at the Albert-Ludwigs-University Freiburg, Breisacher Strasse 117, D-79106 Freiburg i. Br., Germany.
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Abstract
Docetaxel is a semisynthetic taxane that acts primarily by promoting microtubule assembly and preventing the depolymerization of assembled microtubules, thereby inducing mitotic block and inhibition of cell proliferation. This agent also induces apoptosis and appears to prevent angiogenesis. Although docetaxel has shown efficacy in a wide variety of tumors, it has only recently been evaluated in the treatment of gastrointestinal cancers. Data from preclinical studies have shown that docetaxel has substantial in vitro and in vivo activity against gastric, esophageal, and pancreatic tumors. The cytotoxic activity of docetaxel is generally time- and dose-dependent, and greater than that produced by other chemotherapeutic agents, including paclitaxel and anthracyclines. Studies evaluating combination regimens suggest that docetaxel has additive-to-synergistic antitumor activity against gastrointestinal cancers over that produced by the individual agents, and the increased antitumor activity appears to be schedule-dependent. These data suggest that docetaxel has promising therapeutic activity in the treatment of gastrointestinal cancers and provides a rationale for its inclusion in therapeutic protocols either as a single agent or in combination regimens. In addition to combination regimens with conventional chemotherapeutic agents, early studies with a number of novel molecularly targeted therapies in combination with docetaxel have shown encouraging results. These studies provide a basis for pursuing future clinical trials with docetaxel-based combinations of novel therapies for improving response rates in the treatment of gastrointestinal cancers.
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Affiliation(s)
- Tanios S Bekaii-Saab
- Department of Medicine at The Ohio State University College of Medicine and Public Health, Columbus 43210-1240, USA
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