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Tagliaferro M, Marino M, Basile V, Pocino K, Rapaccini GL, Ciasca G, Basile U, Carnazzo V. New Biomarkers in Liver Fibrosis: A Pass through the Quicksand? J Pers Med 2024; 14:798. [PMID: 39201990 PMCID: PMC11355846 DOI: 10.3390/jpm14080798] [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: 06/08/2024] [Revised: 07/12/2024] [Accepted: 07/27/2024] [Indexed: 09/03/2024] Open
Abstract
Chronic liver diseases (CLD) stem from various causes and lead to a gradual progression that ultimately may result in fibrosis and eventually cirrhosis. This process is typically prolonged and asymptomatic, characterized by the complex interplay among various cell types, signaling pathways, extracellular matrix components, and immune responses. With the prevalence of CLD increasing, diagnoses are often delayed, which leads to poor prognoses and in some cases, the need for liver transplants. Consequently, there is an urgent need for the development of novel, non-invasive methods for the diagnosis and monitoring of CLD. In this context, serum biomarkers-safer, repeatable, and more acceptable alternatives to tissue biopsies-are attracting significant research interest, although their clinical implementation is not yet widespread. This review summarizes the latest advancements in serum biomarkers for detecting hepatic fibrogenesis and advocates for concerted efforts to consolidate current knowledge, thereby providing patients with early, effective, and accessible diagnoses that facilitate personalized therapeutic strategies.
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Affiliation(s)
- Marzia Tagliaferro
- Dipartimento di Patologia Clinica, Ospedale Santa Maria Goretti, A.U.S.L. Latina, 04100 Latina, Italy; (M.T.); (V.C.)
| | - Mariapaola Marino
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.M.); (G.L.R.)
- Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | - Valerio Basile
- Clinical Pathology Unit and Cancer Biobank, Department of Research and Advanced Technologies, I.R.C.C.S. Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Krizia Pocino
- Clinical Pathology Unit, San Pietro Fatebenefratelli Hospital, 00189 Rome, Italy;
| | - Gian Ludovico Rapaccini
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (M.M.); (G.L.R.)
| | - Gabriele Ciasca
- Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Umberto Basile
- Dipartimento di Patologia Clinica, Ospedale Santa Maria Goretti, A.U.S.L. Latina, 04100 Latina, Italy; (M.T.); (V.C.)
| | - Valeria Carnazzo
- Dipartimento di Patologia Clinica, Ospedale Santa Maria Goretti, A.U.S.L. Latina, 04100 Latina, Italy; (M.T.); (V.C.)
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Velliou RI, Legaki AI, Nikolakopoulou P, Vlachogiannis NI, Chatzigeorgiou A. Liver endothelial cells in NAFLD and transition to NASH and HCC. Cell Mol Life Sci 2023; 80:314. [PMID: 37798474 PMCID: PMC11072568 DOI: 10.1007/s00018-023-04966-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/04/2023] [Accepted: 09/15/2023] [Indexed: 10/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome, which is characterised by obesity, insulin resistance, hypercholesterolemia and hypertension. NAFLD is the most frequent liver disease worldwide and more than 10% of NAFLD patients progress to the inflammatory and fibrotic stage of non-alcoholic steatohepatitis (NASH), which can lead to end-stage liver disease including hepatocellular carcinoma (HCC), the most frequent primary malignant liver tumor. Liver sinusoidal endothelial cells (LSEC) are strategically positioned at the interface between blood and hepatic parenchyma. LSECs are highly specialized cells, characterised by the presence of transcellular pores, called fenestrae, and exhibit anti-inflammatory and anti-fibrotic characteristics under physiological conditions. However, during NAFLD development they undergo capillarisation and acquire a phenotype similar to vascular endothelial cells, actively promoting all pathophysiological aspects of NAFLD, including steatosis, inflammation, and fibrosis. LSEC dysfunction is critical for the progression to NASH and HCC while restoring LSEC homeostasis appears to be a promising approach to prevent NAFLD progression and its complications and even reverse tissue damage. In this review we present current information on the role of LSEC throughout the progressive phases of NAFLD, summarising in vitro and in vivo experimental evidence and data from human studies.
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Affiliation(s)
- Rallia-Iliana Velliou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece
| | - Aigli-Ioanna Legaki
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece
| | - Polyxeni Nikolakopoulou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece
| | - Nikolaos I Vlachogiannis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece.
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
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Roshani M, Molavizadeh D, Sadeghi S, Jafari A, Dashti F, Mirazimi SMA, Ahmadi Asouri S, Rajabi A, Hamblin MR, Anoushirvani AA, Mirzaei H. Emerging roles of miR-145 in gastrointestinal cancers: A new paradigm. Biomed Pharmacother 2023; 166:115264. [PMID: 37619484 DOI: 10.1016/j.biopha.2023.115264] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
Gastrointestinal (GI) carcinomas are a group of cancers affecting the GI tract and digestive organs, such as the gastric, liver, bile ducts, pancreas, small intestine, esophagus, colon, and rectum. MicroRNAs (miRNAs) are small functional non-coding RNAs (ncRNAs) which are involved in regulating the expression of multiple target genes; mainly at the post-transcriptional level, via complementary binding to their 3'-untranslated region (3'-UTR). Increasing evidence has shown that miRNAs have critical roles in modulating of various physiological and pathological cellular processes and regulating the occurrence and development of human malignancies. Among them, miR-145 is recognized for its anti-oncogenic properties in various cancers, including GI cancers. MiR-145 has been implicated in diverse biological processes of cancers through the regulation of target genes or signaling, including, proliferation, differentiation, tumorigenesis, angiogenesis, apoptosis, metastasis, and therapy resistance. In this review, we have summarized the role of miR-145 in selected GI cancers and also its downstream molecules and cellular processes targets, which could lead to a better understanding of the miR-145 in these cancers. In conclusion, we reveal the potential diagnostic, prognostic, and therapeutic value of miR-145 in GI cancer, and hope to provide new ideas for its application as a biomarker as well as a therapeutic target for the treatment of these cancer.
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Affiliation(s)
- Mohammad Roshani
- Internal Medicine and Gastroenterology, Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Danial Molavizadeh
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sara Sadeghi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sahar Ahmadi Asouri
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for BasicSciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Rajabi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Ali Arash Anoushirvani
- Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Stechele M, Wildgruber M, Markezana A, Kästle S, Öcal E, Kimm MA, Alunni-Fabbroni M, Paldor M, Haixing L, Salvermoser L, Pech M, Powerski M, Galun E, Ricke J, Goldberg SN. Prediction of Protumorigenic Effects after Image-Guided Radiofrequency Ablation of Hepatocellular Carcinoma Using Biomarkers. J Vasc Interv Radiol 2023; 34:1528-1537.e1. [PMID: 36442741 DOI: 10.1016/j.jvir.2022.11.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 11/01/2022] [Accepted: 11/19/2022] [Indexed: 11/26/2022] Open
Abstract
PURPOSE To perform radiofrequency (RF) ablation of hepatocellular carcinoma (HCC) and to assess serological and histopathological markers of tumorigenesis in distant untreated tumors to determine whether these were associated with unfavorable outcomes such as early relapse and increased biological aggressiveness. MATERIALS AND METHODS The study cohort comprised 13 patients from a prospective single-arm study. All patients underwent 2 ablation sessions of multifocal HCC nodules 14 days apart. Core biopsy samples of untreated tumors were acquired at baseline and at the time of the second ablation session. Samples were stained immunohistochemically with Ki-67 (proliferation) and CD34 (microvasculature). Blood plasma was obtained at baseline and 2 days after the initial ablation session and analyzed for hepatocyte growth factor (HGF), vascular endothelial growth factor C, and angiopoietin-2 using an enzyme-linked immunosorbent assay. The clinical follow-up period ranged from 7 to 25 months. Patients were stratified as responders (complete remission or limited and delayed recurrence at >6 months; n = 6) or nonresponders (any recurrence within 6 months or >3 new tumors or any new tumor of >3 cm thereafter; n = 7). RESULTS In 3 of 7 nonresponders, the Ki-67 index markedly increased in untreated tumors, whereas Ki-67 was stable in all responders. Microvascular density strongly increased in a single nonresponder only. HGF and angiopoietin-2 increased by >30% in 3 of 7 and 4 of 7 nonresponders, respectively, whereas they were stable or decreased in responders. Overall, ≥2 biomarkers were elevated in 6 of 7 (85.7%) nonresponders, whereas 4 of 6 responders demonstrated no increased biomarker and 2 patients demonstrated increase in 1 biomarker only (P = .002). CONCLUSIONS RF ablation of HCC can produce protumorigenic factors that induce effects in distant untreated tumors. These may potentially function as biomarkers of clinical outcome.
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Affiliation(s)
- Matthias Stechele
- Department of Radiology, University Hospital, Ludwig Maximilians University Munich, Munich, Germany.
| | - Moritz Wildgruber
- Department of Radiology, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Aurelia Markezana
- Goldyne Savad Institute of Gene Therapy and Division of Image-Guided Therapy and Interventional Oncology, Department of Radiology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Sophia Kästle
- Department of Radiology, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Elif Öcal
- Department of Radiology, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Melanie A Kimm
- Department of Radiology, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Marianna Alunni-Fabbroni
- Department of Radiology, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Mor Paldor
- Goldyne Savad Institute of Gene Therapy and Division of Image-Guided Therapy and Interventional Oncology, Department of Radiology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Liao Haixing
- Department of Radiology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Lukas Salvermoser
- Department of Radiology, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Maciej Pech
- Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg, Germany
| | - Maciej Powerski
- Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg, Germany
| | - Eithan Galun
- Goldyne Savad Institute of Gene Therapy and Division of Image-Guided Therapy and Interventional Oncology, Department of Radiology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Jens Ricke
- Department of Radiology, University Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Shraga Nahum Goldberg
- Goldyne Savad Institute of Gene Therapy and Division of Image-Guided Therapy and Interventional Oncology, Department of Radiology, Hadassah Hebrew University Hospital, Jerusalem, Israel
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Xu M, Xu K, Yin S, Chang C, Sun W, Wang G, Zhang K, Mu J, Wu M, Xing B, Zhang X, Han J, Zhao X, Wang Y, Xu D, Yu X. In-Depth Serum Proteomics Reveals the Trajectory of Hallmarks of Cancer in Hepatitis B Virus-Related Liver Diseases. Mol Cell Proteomics 2023; 22:100574. [PMID: 37209815 PMCID: PMC10316086 DOI: 10.1016/j.mcpro.2023.100574] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 04/25/2023] [Accepted: 05/16/2023] [Indexed: 05/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent cancer in China, with chronic hepatitis B (CHB) and liver cirrhosis (LC) being high-risk factors for developing HCC. Here, we determined the serum proteomes (762 proteins) of 125 healthy controls and Hepatitis B virus-infected CHB, LC, and HCC patients and constructed the first cancerous trajectory of liver diseases. The results not only reveal that the majority of altered biological processes were involved in the hallmarks of cancer (inflammation, metastasis, metabolism, vasculature, and coagulation) but also identify potential therapeutic targets in cancerous pathways (i.e., IL17 signaling pathway). Notably, the biomarker panels for detecting HCC in CHB and LC high-risk populations were further developed using machine learning in two cohorts comprised of 200 samples (discovery cohort = 125 and validation cohort = 75). The protein signatures significantly improved the area under the receiver operating characteristic curve of HCC (CHB discovery and validation cohort = 0.953 and 0.891, respectively; LC discovery and validation cohort = 0.966 and 0.818, respectively) compared to using the traditional biomarker, alpha-fetoprotein, alone. Finally, selected biomarkers were validated with parallel reaction monitoring mass spectrometry in an additional cohort (n = 120). Altogether, our results provide fundamental insights into the continuous changes of cancer biology processes in liver diseases and identify candidate protein targets for early detection and intervention.
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Affiliation(s)
- Meng Xu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Kaikun Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China; Research Unit of Proteomics Driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Shangqi Yin
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Cheng Chang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China; Research Unit of Proteomics Driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Sun
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Guibin Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Kai Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Jinsong Mu
- Department of Critical Care Medicine, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Miantao Wu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Baocai Xing
- Department of Hepato-Pancreato-Biliary Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xiaomei Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Jinyu Han
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, China; State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yajie Wang
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Danke Xu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
| | - Xiaobo Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China.
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Kohlhepp MS, Liu H, Tacke F, Guillot A. The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer-Challenges and opportunities. Front Mol Biosci 2023; 10:1129831. [PMID: 36845555 PMCID: PMC9950415 DOI: 10.3389/fmolb.2023.1129831] [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: 12/22/2022] [Accepted: 01/31/2023] [Indexed: 02/12/2023] Open
Abstract
Chronic liver diseases from varying etiologies generally lead to liver fibrosis and cirrhosis. Among them, non-alcoholic fatty liver disease (NAFLD) affects roughly one-quarter of the world population, thus representing a major and increasing public health burden. Chronic hepatocyte injury, inflammation (non-alcoholic steatohepatitis, NASH) and liver fibrosis are recognized soils for primary liver cancer, particularly hepatocellular carcinoma (HCC), being the third most common cause for cancer-related deaths worldwide. Despite recent advances in liver disease understanding, therapeutic options on pre-malignant and malignant stages remain limited. Thus, there is an urgent need to identify targetable liver disease-driving mechanisms for the development of novel therapeutics. Monocytes and macrophages comprise a central, yet versatile component of the inflammatory response, fueling chronic liver disease initiation and progression. Recent proteomic and transcriptomic studies performed at singular cell levels revealed a previously overlooked diversity of macrophage subpopulations and functions. Indeed, liver macrophages that encompass liver resident macrophages (also named Kupffer cells) and monocyte-derived macrophages, can acquire a variety of phenotypes depending on microenvironmental cues, and thus exert manifold and sometimes contradictory functions. Those functions range from modulating and exacerbating tissue inflammation to promoting and exaggerating tissue repair mechanisms (i.e., parenchymal regeneration, cancer cell proliferation, angiogenesis, fibrosis). Due to these central functions, liver macrophages represent an attractive target for the treatment of liver diseases. In this review, we discuss the multifaceted and contrary roles of macrophages in chronic liver diseases, with a particular focus on NAFLD/NASH and HCC. Moreover, we discuss potential therapeutic approaches targeting liver macrophages.
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Balaziova E, Vymola P, Hrabal P, Mateu R, Zubal M, Tomas R, Netuka D, Kramar F, Zemanova Z, Svobodova K, Brabec M, Sedo A, Busek P. Fibroblast Activation Protein Expressing Mesenchymal Cells Promote Glioblastoma Angiogenesis. Cancers (Basel) 2021; 13:cancers13133304. [PMID: 34282761 PMCID: PMC8267680 DOI: 10.3390/cancers13133304] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/25/2021] [Accepted: 06/26/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary The perivascular niche in glioblastoma is crucial for maintaining a tumour- permissive microenvironment. In various extracranial cancers, mesenchymal cells that express fibroblast activation protein (FAP) are an important stromal component and a potential therapeutic target. In this study, we examine their functions in the glioblastoma microenvironment where their role is so far largely unexplored. Glioblastoma-associated FAP+ mesenchymal cells are localised around activated endothelial cells and their presence positively correlates with vascular density. They represent a subpopulation of stromal, non-tumorigenic cells which mostly lack the chromosomal aberrations characteristic of glioma cells. By soluble factors they induce angiogenic sprouting, chemotaxis of endothelial cells, contribute to destabilisation of blood vessels, and increase the migration and growth of glioma cells. Taken together, we identified a subpopulation of FAP+ mesenchymal cells in the perivascular niche in glioblastoma that may contribute to tumour progression by promoting angiogenesis and supporting dissemination of transformed cells into the surrounding tissue. Abstract Fibroblast activation protein (FAP) is a membrane-bound protease that is upregulated in a wide range of tumours and viewed as a marker of tumour-promoting stroma. Previously, we demonstrated increased FAP expression in glioblastomas and described its localisation in cancer and stromal cells. In this study, we show that FAP+ stromal cells are mostly localised in the vicinity of activated CD105+ endothelial cells and their quantity positively correlates with glioblastoma vascularisation. FAP+ mesenchymal cells derived from human glioblastomas are non-tumorigenic and mostly lack the cytogenetic aberrations characteristic of glioblastomas. Conditioned media from these cells induce angiogenic sprouting and chemotaxis of endothelial cells and promote migration and growth of glioma cells. In a chorioallantoic membrane assay, co-application of FAP+ mesenchymal cells with glioma cells was associated with enhanced abnormal angiogenesis, as evidenced by an increased number of erythrocytes in vessel-like structures and higher occurrence of haemorrhages. FAP+ mesenchymal cells express proangiogenic factors, but in comparison to normal pericytes exhibit decreased levels of antiangiogenic molecules and an increased Angiopoietin 2/1 ratio. Our results show that FAP+ mesenchymal cells promote angiogenesis and glioma cell migration and growth by paracrine communication and in this manner, they may thus contribute to glioblastoma progression.
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Affiliation(s)
- Eva Balaziova
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (E.B.); (P.V.); (R.M.); (M.Z.)
| | - Petr Vymola
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (E.B.); (P.V.); (R.M.); (M.Z.)
| | - Petr Hrabal
- Department of Pathology, Military University Hospital, 169 02 Prague, Czech Republic;
| | - Rosana Mateu
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (E.B.); (P.V.); (R.M.); (M.Z.)
| | - Michal Zubal
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (E.B.); (P.V.); (R.M.); (M.Z.)
| | - Robert Tomas
- Departments of Neurosurgery, Na Homolce Hospital, 150 00 Prague, Czech Republic;
| | - David Netuka
- Department of Neurosurgery and Neurooncology, First Faculty of Medicine, Charles University and Military University Hospital, 168 02 Prague, Czech Republic; (D.N.); (F.K.)
| | - Filip Kramar
- Department of Neurosurgery and Neurooncology, First Faculty of Medicine, Charles University and Military University Hospital, 168 02 Prague, Czech Republic; (D.N.); (F.K.)
| | - Zuzana Zemanova
- Center of Oncocytogenomics, Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (Z.Z.); (K.S.)
| | - Karla Svobodova
- Center of Oncocytogenomics, Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (Z.Z.); (K.S.)
| | - Marek Brabec
- Institute of Computer Science, The Czech Academy of Sciences, 128 00 Prague, Czech Republic;
| | - Aleksi Sedo
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (E.B.); (P.V.); (R.M.); (M.Z.)
- Correspondence: (A.S.); (P.B.)
| | - Petr Busek
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; (E.B.); (P.V.); (R.M.); (M.Z.)
- Correspondence: (A.S.); (P.B.)
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Kawasaki J, Toshima T, Yoshizumi T, Itoh S, Mano Y, Wang H, Iseda N, Harada N, Oda Y, Mori M. Prognostic Impact of Vessels that Encapsulate Tumor Cluster (VETC) in Patients who Underwent Liver Transplantation for Hepatocellular Carcinoma. Ann Surg Oncol 2021; 28:8186-8195. [PMID: 34091774 DOI: 10.1245/s10434-021-10209-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/29/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND There is limited published information about prognostic value of vessels that encapsulate tumor cluster (VETC) based on their involvement with immune cells in hepatocellular carcinoma (HCC). Our goal was to evaluate prognostic impact of VETC in patients who underwent living-donor liver transplantation (LDLT) for HCC, focusing on the involvement of VETC with immune status in tumor microenvironment (TME). METHODS Using a database of 150 patients who underwent LDLT for HCC, immunohistochemical staining of CD34 for VETC, angiopoietin-2 (Ang-2), CD3, and CD68, was reviewed with patients' clinicopathological factors. RESULTS A strong correlation between VETC pattern and malignant potential in HCC was observed; larger tumor size (P < 0.001), more numbers of tumors (P = 0.003), higher α-fetoprotein levels (P = 0.001), higher des-γ-carboxy prothrombin levels (P = 0.022), microvascular invasion (P < 0.001), and poor differentiation (P = 0.010). Overall survival (OS) of patients with VETC(+) was significantly lower than those with VETC(-) (P = 0.021; 5-year OS rates, 72.0% vs. 87.1%). Furthermore, the ratio of CD3(+) cells was significantly lower in VETC(+) group (P = 0.001), indicating that VETC activity may be strongly correlated with lymphocyte activity. Moreover, combination status of VETC(+)/CD3low was an independent risk factor for mortality (hazard ratio 2.760, 95% confidence interval 1.183-6.439, P = 0.019). Additionally, the combination of VETC expression with immune status (low CD3 levels) enabled further classification of patients based on their clinical outcome. CONCLUSIONS Our results show the prognostic impact of VETC expression, tumor-infiltrating lymphocytes (TILs), and their combination in the setting of LDLT for HCC, which can be a novel prognostic biomarker for mortality after LDLT.
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Affiliation(s)
- Junji Kawasaki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yohei Mano
- Department of Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Huanlin Wang
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Norifumi Iseda
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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9
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Koshkin SA, Anatskaya OV, Vinogradov AE, Uversky VN, Dayhoff GW, Bystriakova MA, Pospelov VA, Tolkunova EN. Isolation and Characterization of Human Colon Adenocarcinoma Stem-Like Cells Based on the Endogenous Expression of the Stem Markers. Int J Mol Sci 2021; 22:4682. [PMID: 33925224 PMCID: PMC8124683 DOI: 10.3390/ijms22094682] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cancer stem cells' (CSCs) self-maintenance is regulated via the pluripotency pathways promoting the most aggressive tumor phenotype. This study aimed to use the activity of these pathways for the CSCs' subpopulation enrichment and separating cells characterized by the OCT4 and SOX2 expression. METHODS To select and analyze CSCs, we used the SORE6x lentiviral reporter plasmid for viral transduction of colon adenocarcinoma cells. Additionally, we assessed cell chemoresistance, clonogenic, invasive and migratory activity and the data of mRNA-seq and intrinsic disorder predisposition protein analysis (IDPPA). RESULTS We obtained the line of CSC-like cells selected on the basis of the expression of the OCT4 and SOX2 stem cell factors. The enriched CSC-like subpopulation had increased chemoresistance as well as clonogenic and migration activities. The bioinformatic analysis of mRNA seq data identified the up-regulation of pluripotency, development, drug resistance and phototransduction pathways, and the downregulation of pathways related to proliferation, cell cycle, aging, and differentiation. IDPPA indicated that CSC-like cells are predisposed to increased intrinsic protein disorder. CONCLUSION The use of the SORE6x reporter construct for CSCs enrichment allows us to obtain CSC-like population that can be used as a model to search for the new prognostic factors and potential therapeutic targets for colon cancer treatment.
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Affiliation(s)
- Sergei A. Koshkin
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1015 Walnut Street, Ste. 1024, Philadelphia, PA 19107, USA
| | - Olga V. Anatskaya
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
| | - Alexander E. Vinogradov
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
| | - Vladimir N. Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Guy W. Dayhoff
- Department of Chemistry, College of Art and Sciences, University of South Florida, Tampa, FL 33620, USA;
| | - Margarita A. Bystriakova
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
| | - Valery A. Pospelov
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
| | - Elena N. Tolkunova
- Institute of Cytology of the Russian Academy of Science, 194064 St-Petersburg, Russia; (M.A.B.); (V.A.P.)
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10
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Abdel Ghafar MT, Elkhouly RA, Elnaggar MH, Mabrouk MM, Darwish SA, Younis RL, Elkholy RA. Utility of serum neuropilin-1 and angiopoietin-2 as markers of hepatocellular carcinoma. J Investig Med 2021; 69:1222-1229. [PMID: 33833047 DOI: 10.1136/jim-2020-001744] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2021] [Indexed: 12/24/2022]
Abstract
This study aimed to assess the diagnostic value of two serum angiogenetic markers neuropilin-1 (NRP-1) and angiopoietin-2 (ANG-2) in patients with hepatocellular carcinoma (HCC) and their relation to tumor characteristics. 149 subjects were recruited and divided into 50 patients with recently diagnosed HCC, 49 patients with cirrhosis on top of hepatitis C virus infection, and 50 healthy subjects. Serum NRP-1 and ANG-2 were estimated by ELISA. Alpha-fetoprotein (AFP) levels were measured using fluorescence immunoassay. Serum NRP-1 and ANG-2 levels were significantly higher in patients with HCC (2221.8±1056.6 pg/mL and 3018.5±841.4 pg/mL) than healthy subjects (219.3±61.8 pg/mL and 2007.7±904.8 pg/mL) and patients with cirrhosis (1108.9±526.6 pg/mL and 2179.1±599.2 pg/mL), respectively. In multivariate logistic regression analysis, NRP-1 and AFP were the only independent factors of HCC development and correlated positively with each other (r=0.781, p<0.001). Receiver operating characteristic curve analysis showed that the area under the curve (AUC) of NRP-1 was higher than that of ANG-2 in discriminating HCC from patients with cirrhosis (0.801 vs 0.748, p=0.250) and healthy subjects (0.992 vs 0.809, p<0.001). The AUC of NRP-1 was detected to be increased (0.994) when combined estimation with AFP was performed. Elevated serum NRP-1 and ANG-2 levels were detected in patients with HCC with tumor numbers >3, tumor size ≥5 cm, tumor stages B/C according to the Barcelona Clinic Liver Cancer staging system, vascular invasion, and distant metastasis. In conclusion, NRP-1 is a potential serological marker for HCC diagnosis and is better than ANG-2. It is feasible to be estimated in combination with AFP to enhance its diagnostic power. High serum NRP-1 and ANG-2 levels are associated with advanced HCC tumor characteristics.
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Affiliation(s)
| | - Reham A Elkhouly
- Tropical Medicine, Tanta University Faculty of Medicine, Tanta, Egypt
| | | | - Mohamed M Mabrouk
- Internal Medicine, Tanta University Faculty of Medicine, Tanta, Egypt
| | - Sara A Darwish
- Clinical Oncology and Nuclear Medicine, Tanta University Faculty of Medicine, Tanta, Egypt
| | - Reham L Younis
- Physiology, Tanta University Faculty of Medicine, Tanta, Egypt
| | - Rasha A Elkholy
- Clinical Pathology, Tanta University Faculty of Medicine, Tanta, Egypt
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11
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Ao J, Chiba T, Kanzaki H, Kanayama K, Shibata S, Kurosugi A, Iwanaga T, Kan M, Sakuma T, Qiang N, Ma Y, Kojima R, Kusakabe Y, Nakamura M, Kobayashi K, Kiyono S, Kanogawa N, Saito T, Nakagawa R, Kondo T, Ogasawara S, Suzuki E, Nakamoto S, Muroyama R, Tawada A, Kato J, Kanda T, Maruyama H, Kato N. Serum Angiopoietin 2 acts as a diagnostic and prognostic biomarker in hepatocellular carcinoma. J Cancer 2021; 12:2694-2701. [PMID: 33854629 PMCID: PMC8040723 DOI: 10.7150/jca.56436] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/17/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is typically accompanied by abundant arterial blood flow. Although angiogenic growth factors such as Angiopoietin 2 (Ang2) play a central role in tumor angiogenesis in HCC, the role of serum Ang2 as a biomarker in HCC remains unclear. In this study, we aimed to investigate the potential of Ang2 as a diagnostic and prognostic biomarker in HCC using a sandwich enzyme-linked immunosorbent assay (ELISA). The median Ang2 levels in controls (n=20), chronic liver disease patients (n=98), and HCC patients (n=275) were 1.58, 2.33, and 3.53 ng/mL, respectively. The optimal cut-off value of Ang2 was determined as 3.5 ng/mL by receiver operating curve analysis. The sensitivity, specificity, and accuracy of Ang2 for HCC detection were 50.9, 83.7, and 59.5%, respectively. Spearman's rank correlation coefficient analysis demonstrated only a weak correlation between Ang2 serum levels and alpha-fetoprotein (AFP) or des-gamma-carboxy prothrombin (DCP) serum levels. The diagnostic value of Ang2 was comparable to those of other existing markers. In addition, 24 out of 73 patients with normal AFP and DCP levels (32.9%) demonstrated abnormally high Ang2 levels (≥3.5 ng/mL). Although no significant difference in overall survival was found between Ang2high and Ang2low patients with curative ablation therapy, recurrence-free survival (RFS) in Ang2high patients was observed to be significantly shorter than those in Ang2low patients. Multivariate analysis demonstrated that high serum Ang2 levels (≥3.5 ng/mL) and the presence of multiple tumors were poor prognostic factors. In conclusion, our findings indicate that serum Ang2 is a potential novel biomarker for both diagnosis and prognosis in HCC.
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Affiliation(s)
- Junjie Ao
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Kengo Kanayama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Shuhei Shibata
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Akane Kurosugi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Terunao Iwanaga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Motoyasu Kan
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Takafumi Sakuma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Na Qiang
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Yaojia Ma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Ryuta Kojima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Yuko Kusakabe
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Akinobu Tawada
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
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12
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Yoodee S, Peerapen P, Plumworasawat S, Thongboonkerd V. ARID1A knockdown in human endothelial cells directly induces angiogenesis by regulating angiopoietin-2 secretion and endothelial cell activity. Int J Biol Macromol 2021; 180:1-13. [PMID: 33675830 DOI: 10.1016/j.ijbiomac.2021.02.218] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 02/10/2021] [Accepted: 02/24/2021] [Indexed: 12/29/2022]
Abstract
AT-rich interactive domain 1A (ARID1A) is a novel tumor suppressor gene found in several human cells and its loss/defect is commonly observed in many cancers. However, its roles in angiogenesis, which is one of the hallmarks for tumor progression, remained unclear. Herein, we demonstrated the direct effects of ARID1A knockdown in human endothelial cells by lentivirus-based short-hairpin RNA (shRNA) (shARID1A) on angiogenesis. Functional assays revealed that shARID1A significantly enhanced cell proliferation and migration/invasion and endothelial tube formation compared with the control cells transfected with scramble shRNA (shControl). Additionally, the shARID1A-transfected cells had significantly increased podosome formation and secretion of angiopoietin-2 (ANG2), a key angiogenic factor. Moreover, neutralization of ANG2 with monoclonal anti-ANG2 antibody strongly reduced cell proliferation and migration/invasion and endothelial tube formation in the shARID1A-transfected cells. These findings indicate that down-regulation of ARID1A in human endothelial cells directly induces angiogenesis by regulating angiopoietin-2 secretion and endothelial cell activity.
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Affiliation(s)
- Sunisa Yoodee
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Paleerath Peerapen
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Sirikanya Plumworasawat
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Visith Thongboonkerd
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
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13
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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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14
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Zheng J, Gong XQ, Tao YY, Wang R, Yang G, Li JD, Ren T, Li ZM, Yang C, Wang WC, Yang L, Zhang XM. A Correlative Study Between IVIM-DWI Parameters and the Expression Levels of Ang-2 and TKT in Hepatocellular Carcinoma. Front Oncol 2021; 10:594366. [PMID: 33520706 PMCID: PMC7845759 DOI: 10.3389/fonc.2020.594366] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 11/23/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Noninvasive evaluation of the expression of angiopoietin-2 (Ang-2) and transketolase (TKT) in hepatocellular carcinoma (HCC) is of great significance for the clinical development of individualized treatment plans. However, the correlation between intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) and the expression of Ang-2 and TKT has not been reported. We sought to investigate the correlations between IVIM-DWI parameters and Ang-2 and TKT expression levels in HCCs. METHODS Conventional non-enhanced magnetic resonance imaging (MRI) and IVIM-DWI and dynamic contrast MRI were performed for 61 patients with HCC before surgical treatment. Various IVIM-DWI parameters, such as apparent diffusion coefficient (ADC), slow apparent diffusion coefficient (D), fast apparent diffusion coefficient (D*) and fraction of fast apparent diffusion coefficient (f), were calculated using Function-MADC software. Expression levels of Ang-2 and TKT in HCC were detected via immunohistochemical staining and classified into two grades. Independent sample t tests were used to compare differences in parameters between the two groups. The Spearman rank correlation test was used to analyze the correlations between IVIM-DWI parameters and Ang-2 and TKT expression levels in HCCs. RESULTS The D* and f values were significantly higher in the high Ang-2 group than in the low Ang-2 group; there were no obvious between-group differences in ADC and D. Ang-2 expression was positively correlated with D* and f but not with ADC and D. The ADC and D values were significantly lower in the high TKT group than in the low TKT group, whereas the between-group differences for D* and f were not significant. TKT expression was negatively correlated with ADC and D but not with D* and f. CONCLUSIONS IVIM-DWI can be used to evaluate Ang-2 and TKT expression in HCC.
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Affiliation(s)
- Jing Zheng
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Xue Qin Gong
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Yun Yun Tao
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Ran Wang
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Gang Yang
- Institute of Hepato-Biliary-Intestinal Disease, Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Jing Dong Li
- Institute of Hepato-Biliary-Intestinal Disease, Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Tian Ren
- Department of Medical Record Statistics, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Zu Mao Li
- Department of Pathology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Cui Yang
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Wei Cheng Wang
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Lin Yang
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Xiao Ming Zhang
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
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15
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Isaji T, Osuka K, Ohmichi Y, Ohmichi M, Naito M, Nakano T, Iwami K, Miyachi S. Expression of Angiopoietins and Angiogenic Signaling Pathway Molecules in Chronic Subdural Hematomas. J Neurotrauma 2020; 37:2493-2498. [DOI: 10.1089/neu.2020.7042] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Taiki Isaji
- Department of Neurosurgery, Aichi Medical University, Nagakute, Aichi, Japan
| | - Koji Osuka
- Department of Neurosurgery, Aichi Medical University, Nagakute, Aichi, Japan
| | - Yusuke Ohmichi
- Department of Anatomy, Aichi Medical University, Nagakute, Aichi, Japan
| | - Mika Ohmichi
- Department of Anatomy, Aichi Medical University, Nagakute, Aichi, Japan
| | - Munekazu Naito
- Department of Anatomy, Aichi Medical University, Nagakute, Aichi, Japan
| | - Takashi Nakano
- Department of Anatomy, Aichi Medical University, Nagakute, Aichi, Japan
| | - Kenichiro Iwami
- Department of Neurosurgery, Aichi Medical University, Nagakute, Aichi, Japan
| | - Shigeru Miyachi
- Department of Neurosurgery, Aichi Medical University, Nagakute, Aichi, Japan
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16
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Current perspectives on the tumor microenvironment in hepatocellular carcinoma. Hepatol Int 2020; 14:947-957. [PMID: 33188512 DOI: 10.1007/s12072-020-10104-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 10/22/2020] [Indexed: 12/24/2022]
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17
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Vanderborght B, Lefere S, Vlierberghe HV, Devisscher L. The Angiopoietin/Tie2 Pathway in Hepatocellular Carcinoma. Cells 2020; 9:cells9112382. [PMID: 33143149 PMCID: PMC7693961 DOI: 10.3390/cells9112382] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/23/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
Due to the usually late diagnosis and lack of effective therapies, hepatocellular carcinoma (HCC), which poses a growing global health problem, is characterized by a poor prognosis. Angiogenesis plays an important role in HCC progression, and vascular endothelial growth factor (VEGF) and angiopoietins (Angs) are key drivers of HCC angiogenesis. VEGF-targeting strategies already represent an important component of today’s systemic treatment landscape of HCC, whereas targeting the Ang/Tie2 signaling pathway may harbor future potential in this context due to reported beneficial anticancer effects when targeting this pathway. In addition, a better understanding of the relation between Angs and HCC angiogenesis and progression may reveal their potential as predictive factors for post-treatment disease progression and prognosis. In this review, we give a comprehensive overview of the complex role of Ang/Tie2 signaling in HCC, pinpointing its potential value as biomarker and target for HCC treatments, aiding HCC diagnosis and therapy.
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Affiliation(s)
- Bart Vanderborght
- Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, B-9000 Ghent, Belgium; (B.V.); (S.L.); (H.V.V.)
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, B-9000 Ghent, Belgium
| | - Sander Lefere
- Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, B-9000 Ghent, Belgium; (B.V.); (S.L.); (H.V.V.)
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, B-9000 Ghent, Belgium
| | - Hans Van Vlierberghe
- Department of Internal Medicine and Pediatrics, Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, B-9000 Ghent, Belgium; (B.V.); (S.L.); (H.V.V.)
| | - Lindsey Devisscher
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, B-9000 Ghent, Belgium
- Correspondence: ; Tel.: +32-9-332-56-65
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18
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MiR-145-5p suppresses the proliferation, migration and invasion of gastric cancer epithelial cells via the ANGPT2/NOD_LIKE_RECEPTOR axis. Cancer Cell Int 2020; 20:416. [PMID: 32874130 PMCID: PMC7456024 DOI: 10.1186/s12935-020-01483-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 02/06/2023] Open
Abstract
Objective This study aimed to investigate the relationship among miR-145-5p, ANGPT2 and the NOD_LIKE_RECEPTOR pathway, thereby revealing the molecular mechanism of these three factors underlying the proliferation, migration and invasion of gastric cancer (GC) epithelial cells. Methods qRT-PCR was carried out to detect the expression of miR-145-5p and ANGPT2 mRNA. Western blot was performed to test the protein levels of ANGPT2 as well as NOD1, NOD2 and NF-κB in the NOD_LIKE_RECEPTOR pathway. The targeting relationship between miR-145-5p and ANGPT2 was verified via a dual-luciferase reporter gene assay. The proliferation, migration and invasion of GC cells were detected through MTT and Transwell assays, respectively. Results The expression of miR-145-5p was significantly down-regulated in GC cells, while that of ANGPT2 was notably up-regulated. MiR-145-5p directly bound with the 3′-UTR of ANGPT2 mRNA, thereby targeting ANGPT2 after transcription. Overexpression of miR-145-5p inhibited the proliferation, migration and invasion of GC cells by suppressing ANGPT2. Moreover, low expression of ANGPT2 affected the protein levels of NOD1, NOD2 and NF-κB in the NOD_LIKE_RECEPTOR pathway, thus weakening the abilities of cell proliferation, migration and invasion. Conclusions MiR-145-5p plays an important role in GC epithelial cells, and it can affect cell proliferation, migration and invasion of GC cells by targeting ANGPT2 and regulating the NOD_LIKE_RECEPTOR pathway. Overall, our study further elucidates the molecular mechanism underlying the malignant progression of GC.
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19
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Urosevic J, Blasco MT, Llorente A, Bellmunt A, Berenguer-Llergo A, Guiu M, Cañellas A, Fernandez E, Burkov I, Clapés M, Cartanà M, Figueras-Puig C, Batlle E, Nebreda AR, Gomis RR. ERK1/2 Signaling Induces Upregulation of ANGPT2 and CXCR4 to Mediate Liver Metastasis in Colon Cancer. Cancer Res 2020; 80:4668-4680. [PMID: 32816905 DOI: 10.1158/0008-5472.can-19-4028] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 06/23/2020] [Accepted: 08/12/2020] [Indexed: 11/16/2022]
Abstract
Carcinoma development in colorectal cancer is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of colorectal cancer metastatic disease, yet how RAS-ERK signaling regulates colorectal cancer metastasis remains unknown. In this study, we used an unbiased screening approach based on selection of highly liver metastatic colorectal cancer cells in vivo to determine genes associated with metastasis. From this, an ERK1/2-controlled metastatic gene set (EMGS) was defined. EMGS was associated with increased recurrence and reduced survival in patients with colorectal cancer tumors. Higher levels of EMGS expression were detected in the colorectal cancer subsets consensus molecular subtype (CMS)1 and CMS4. ANGPT2 and CXCR4, two genes within the EMGS, were subjected to gain-of-function and loss-of-function studies in several colorectal cancer cell lines and then tested in clinical samples. The RAS-ERK1/2 axis controlled expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in colorectal cancer cells, which facilitated development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are important for metastatic outgrowth in the liver. CXCR4 controlled the expression of cytokines IL10 and CXCL1, providing evidence for a causal role of IL10 in supporting liver colonization. In summary, these studies demonstrate that amplification of ERK1/2 signaling in KRAS-mutated colorectal cancer cells affects the cytokine milieu of the tumors, possibly affecting tumor-stroma interactions and favoring liver metastasis formation. SIGNIFICANCE: These findings identify amplified ERK1/2 signaling in KRAS-mutated colorectal cancer cells as a driver of tumor-stroma interactions that favor formation of metastases in the liver.
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Affiliation(s)
- Jelena Urosevic
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBERONC, Spain
| | - María Teresa Blasco
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBERONC, Spain
| | - Alicia Llorente
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Anna Bellmunt
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Antoni Berenguer-Llergo
- Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Marc Guiu
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Adrià Cañellas
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBERONC, Spain
| | - Esther Fernandez
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Ivan Burkov
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Maria Clapés
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Mireia Cartanà
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Cristina Figueras-Puig
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Eduard Batlle
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBERONC, Spain.,ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Angel R Nebreda
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.,ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Roger R Gomis
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. .,CIBERONC, Spain.,ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.,School of Medicine, Universitat de Barcelona, Barcelona, Spain
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20
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Caveolin-1 Knockdown Decreases SMMC7721 Human Hepatocellular Carcinoma Cell Invasiveness by Inhibiting Vascular Endothelial Growth Factor-Induced Angiogenesis. Can J Gastroenterol Hepatol 2020; 2020:8880888. [PMID: 32676485 PMCID: PMC7336196 DOI: 10.1155/2020/8880888] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/03/2020] [Accepted: 06/08/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Recently, several studies have demonstrated that caveolin-1 overexpression is involved in apoptosis resistance, angiogenesis, and invasiveness in hepatocellular carcinoma (HCC). However, the mechanisms underlying caveolin-1-mediated tumor progression remain unclear. Methodogy. Lentiviral vectors were used to construct caveolin-1 small interfering RNA- (siRNA-) expressing cells. Secreted VEGF levels in SMMC7721 cells were evaluated by enzyme-linked immunosorbent assay (ELISA). SMMC7721 cell proliferation, cycle, apoptosis, and invasiveness were detected by MTT, flow cytometry, Annexin V-FITC/PI, and invasion assay, respectively. Phospho-eNOS levels in human umbilical vein endothelial cells (HUVECs) cocultured with SMMC7721 cell supernatants were analyzed by Western blot. Capillary-like tubule formation assay was performed to analyze endothelial tubular structure formation in HUVECs treated with supernatants from caveolin-1 siRNA-expressing SMMC7721 cells. SMMC7721 implantation and growth in nude mice were observed. Angiogenesis in vivo was analyzed by immunohistochemical angiogenesis assay. RESULTS Caveolin-1 siRNA-expressing SMMC7721 cells secreted reduced levels of VEGF. Caveolin-1 RNAi also caused an inhibition of SMMC7721 cell proliferation and cell cycle progression that was accompanied by increased apoptosis. Supernatants from caveolin-1 siRNA-expressing SMMC7721 cells inhibited cell cycle progression and decreased phospho-eNOS levels in HUVECs. Endothelial tubular structure formation in HUVECs treated with supernatants from caveolin-1 siRNA-expressing SMMC7721 cells was considerably reduced. Caveolin-1 siRNA-expressing SMMC7721 cells also showed reduced tumorigenicity and angiogenesis induction in vivo. CONCLUSION Our results reveal a novel mechanism, whereby caveolin-1 positively regulates human HCC cell invasiveness by coordinating VEGF-induced angiogenesis.
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21
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Moawad AW, Szklaruk J, Lall C, Blair KJ, Kaseb AO, Kamath A, Rohren SA, Elsayes KM. Angiogenesis in Hepatocellular Carcinoma; Pathophysiology, Targeted Therapy, and Role of Imaging. J Hepatocell Carcinoma 2020; 7:77-89. [PMID: 32426302 PMCID: PMC7188073 DOI: 10.2147/jhc.s224471] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/24/2019] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, usually occurring on a background of liver cirrhosis. HCC is a highly vascular tumor in which angiogenesis plays a major role in tumor growth and spread. Tumor-induced angiogenesis is usually related to a complex interplay between multiple factors and pathways, with vascular endothelial growth factor being a major player in angiogenesis. In the past decade, understanding of tumor-induced angiogenesis has led to the emergence of novel anti-angiogenic therapies, which act by reducing neo-angiogenesis, and improving patient survival. Currently, Sorafenib and Lenvatinib are being used as the first-line treatment for advanced unresectable HCC. However, a disadvantage of these agents is the presence of numerous side effects. A major challenge in the management of HCC patients being treated with anti-angiogenic therapy is effective monitoring of treatment response, which decides whether to continue treatment or to seek second-line treatment. Several criteria can be used to assess response to treatment, such as quantitative perfusion on cross-sectional imaging and novel/emerging MRI techniques, including a host of known and emerging biomarkers and radiogenomics. This review addresses the pathophysiology of angiogenesis in HCC, accurate imaging assessment of angiogenesis, monitoring effects of anti-angiogenic therapy to guide future treatment and assessing prognosis.
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Affiliation(s)
- Ahmed W Moawad
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Janio Szklaruk
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Chandana Lall
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Katherine J Blair
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Amita Kamath
- Department of Radiology, Icahn School of Medicine at Mount Sinai West, New York, NY, USA
| | - Scott A Rohren
- School of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Khaled M Elsayes
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
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22
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Juengpanich S, Topatana W, Lu C, Staiculescu D, Li S, Cao J, Lin J, Hu J, Chen M, Chen J, Cai X. Role of cellular, molecular and tumor microenvironment in hepatocellular carcinoma: Possible targets and future directions in the regorafenib era. Int J Cancer 2020; 147:1778-1792. [PMID: 32162677 DOI: 10.1002/ijc.32970] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 03/02/2020] [Accepted: 03/09/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) remains as one of the major causes of cancer-related mortality, despite the recent development of new therapeutic options. Regorafenib, an oral multikinase inhibitor, is the first systemic therapy that has a survival benefit for patients with advanced HCC that have a poor response to sorafenib. Even though regorafenib has been approved by the FDA, the clinical trial for regorafenib treatment does not show significant improvement in overall survival. The impaired efficacy of regorafenib caused by various resistance mechanisms, including epithelial-mesenchymal transitions, inflammation, angiogenesis, hypoxia, oxidative stress, fibrosis and autophagy, still needs to be resolved. In this review, we provide insight on regorafenib microenvironmental, molecular and cellular mechanisms and interactions in HCC treatment. The aim of this review is to help physicians select patients that would obtain the maximal benefits from regorafenib in HCC therapy.
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Affiliation(s)
- Sarun Juengpanich
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.,School of Medicine, Zhejiang University, Hangzhou, China
| | - Win Topatana
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.,School of Medicine, Zhejiang University, Hangzhou, China
| | - Chen Lu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.,School of Medicine, Zhejiang University, Hangzhou, China
| | - Daniel Staiculescu
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Shijie Li
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Jiasheng Cao
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Jiacheng Lin
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiahao Hu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Mingyu Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.,School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiang Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.,Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Xiujun Cai
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, China.,School of Medicine, Zhejiang University, Hangzhou, China
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23
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Liu J, Xu W, Li S, Sun R, Cheng W. Multi-omics analysis of tumor mutational burden combined with prognostic assessment in epithelial ovarian cancer based on TCGA database. Int J Med Sci 2020; 17:3200-3213. [PMID: 33173439 PMCID: PMC7646107 DOI: 10.7150/ijms.50491] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 10/07/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Tumor mutation burden (TMB) is considered as a novel biomarker of response to immunotherapy and correlated with survival outcomes in various malignancies. Here, TMB-related genes (TRGs) expression signatures were constructed to investigate the association between TMB and prognosis in epithelial ovarian cancer (EOC), and the potential mechanism in immunoregulation was also explored. Methods: Based on somatic mutation data of 436 EOC samples from The Cancer Genome Atlas database, we examined the relationship between TMB level and overall survival (OS), as well as disease-free survival (DFS). Next, the TRGs signatures were constructed and validated. Differential abundance of immune cell infiltration, expression levels of immunomodulators and functional enrichment in high- and low-risk groups were also analyzed. Results: Higher TMB level revealed better OS and DFS, and correlated with earlier clinical stages in EOCs (P = 2.796e-04). The OS-related prognostic model constructed based on seven TRGs (B3GALT1, LIN7B, ANGPT2, D2HGDH, TAF13, PFDN4 and DNAJC19) significantly stratified EOC patients into high- and low-risk groups (P < 0.001). The AUC values of the seven-gene prognostic signature at 1 year, 3 years, and 5 years were 0.703, 0.758 and 0.777. While the DFS-related prognostic model was constructed based on the 4 TRGs (LPIN3, PXYLP1, IGSF23 and B3GALT1), with AUCs of 0.617, 0.756, and 0.731, respectively. Functional analysis indicated that immune-related pathways were enriched in low-risk groups. When considering the infiltration patterns of immune cells, we found higher proportions of follicular helper T (Tfh) cell and M1 macrophage, while lower infiltration of M0 macrophage in low-risk groups (P < 0.05). Accordingly, TMB levels of low-risk patients were significantly higher both in OS and DFS model (P < 0.01). Conclusions: Our TRGs-based models are reliable predictive tools for OS and DFS. High TMB may confer with an immunogenic microenvironment and predict favorable outcomes in EOCs.
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Affiliation(s)
- Jinhui Liu
- Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Wei Xu
- Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Siyue Li
- Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Rui Sun
- Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Wenjun Cheng
- Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
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24
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Pirouzpanah S, Varshosaz P, Fakhrjou A, Montazeri V. The contribution of dietary and plasma folate and cobalamin to levels of angiopoietin-1, angiopoietin-2 and Tie-2 receptors depend on vascular endothelial growth factor status of primary breast cancer patients. Sci Rep 2019; 9:14851. [PMID: 31619709 PMCID: PMC6795805 DOI: 10.1038/s41598-019-51050-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 09/20/2019] [Indexed: 12/12/2022] Open
Abstract
The aim of this study was to determine the association of dietary folate and cobalamin with plasma levels of Angiopoietins (ANG), vascular endothelial growth factor-C (VEGF-C) and tyrosine kinase receptor-2 (Tie-2) of primary breast cancer patients. Women (n = 177), aged 30 to 75 years diagnosed with breast cancer were recruited from an ongoing case series study. Dietary intake of nutrients was estimated by using a validated food frequency questionnaire. Enzyme-linked immunosorbent assay was applied to measure biomarkers. MCF-7 cell cultures were supplemented with folic acid (0–40 μM) for 24 h to measure cell viability and fold change of expression by the real-time reverse transcriptase-polymerase chain reaction. Structural equation modeling was applied to analyze the structural relationships between the measured variables of nutrients and Angiopoietins. Dietary intake of folate and cobalamin showed a significant inverse correlation with plasma ANG-1 and ANG-2 (P < 0.05), particularly in subjects with estrogen-receptor positive tumors or low plasma VEGF-C. Plasma folate was positively associated with the ratio of ANG-1/ANG-2 (P < 0.05). Residual intake levels of total cobalamin were inversely associated with plasma ANG-1 when plasma stratum of VEGF-C was high (P < 0.05). Structural equation modeling identified a significant inverse contribution of folate profiles on the latent variable of Angiopoietins (coefficient β = −0.99, P < 0.05). Folic acid treatment resulted in dose-dependent down-regulations on ANGPT1 and ANGPT1/ANGPT2 ratio but VEGF and ANGPT2/VEGF were upregulated at folic acid >20 μM. Studying the contributing role of dietary folate to pro-angiogenic biomarkers in breast cancer patients can infer the preventive role of folate in the ANGs/VEGF-C-dependent cascade of tumor metastasis. By contrast, high concentrations of folic acid in vitro supported VEGF-C-dependent ANGPT2 overexpression might potentiate micro-lymphatic vessel development to support malignant cell dissemination.
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Affiliation(s)
- Saeed Pirouzpanah
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, 5166614711, Iran.
| | - Parisa Varshosaz
- Drug Applied Research Center/ and also Department of Biochemistry and Dietetics, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, 5166614711, Iran.,Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, 5165665811, Iran
| | - Ashraf Fakhrjou
- Department of Pathology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, 5156913193, Iran
| | - Vahid Montazeri
- Department of Thoracic Surgery, Faculty of Medicine, Surgery Ward, Tabriz University of Medical Sciences, and also Nour-Nejat Hospital, Tabriz, 5138665793, Iran
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The Evaluation of Angiogenesis Markers in Hepatocellular Carcinoma and Precursor Lesions in Liver Explants From a Single Institution. Appl Immunohistochem Mol Morphol 2019; 26:330-336. [PMID: 27556821 DOI: 10.1097/pai.0000000000000426] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. Precursor lesions are described, and the correct diagnosis of liver nodules is paramount when considering liver transplantation. We evaluated the immunohistochemical expression of vascular endothelial growth factor (VEGF) and angiopoietin-2 in HCC and precursors lesion in a single institution series of whole liver explants between 2013 and 2015, evaluating morphologic and clinical variables. The study comprised 67 patients (32.8% female) and 107 nodules. The mean age of the patients was 52.7 years (29 to 70 y). There were no significant epidemiologic differences among malignant lesions, dysplastic nodules, and regenerative nodules. Angiopoietin-2 expression was significantly more expressed in carcinoma when compared with regenerative lesions (P<0.0001). A statistically significant relationship was noted between the expression of VEGF in hepatocytes and Ang-2 expression in the small vasculature (P=0.006). VEGF expression also correlated significantly with the number of nonpaired arteries (P=0.03), although it was not useful in separating benign from malignant cases. We identified a sensitivity of 54% and a specificity of 96% using angiopoietin-2, and a sensitivity of 68.7% and a specificity of 31.2% when using VEGF for the diagnosis of HCC. There was no significant correlation between the immunohistochemical parameters and the clinical staging, the number of gross lesions, and the histologic grade in cases of HCC. Angiopoietin-2 may be a candidate biomarker in assessing liver nodules in transplant patients, and may assist in the diagnosis of difficult lesions and in small biopsies pretransplant.
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Teufel M, Seidel H, Köchert K, Meinhardt G, Finn RS, Llovet JM, Bruix J. Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma. Gastroenterology 2019; 156:1731-1741. [PMID: 30738047 DOI: 10.1053/j.gastro.2019.01.261] [Citation(s) in RCA: 155] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS In a phase 3 trial (RESORCE), regorafenib increased overall survival compared with placebo in patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. In an exploratory study, we analyzed plasma and tumor samples from study participants to identify genetic, microRNA (miRNA), and protein biomarkers associated with response to regorafenib. METHODS We obtained archived tumor tissues and baseline plasma samples from patients with HCC given regorafenib in the RESORCE trial. Baseline plasma samples from 499 patients were analyzed for expression of 294 proteins (DiscoveryMAP) and plasma samples from 349 patients were analyzed for levels of 750 miRNAs (miRCURY miRNA PCR). Tumor tissues from 7 responders and 10 patients who did not respond (progressors) were analyzed by next-generation sequencing (FoundationOne). Forty-six tumor tissues were analyzed for expression patterns of 770 genes involved in oncogenic and inflammatory pathways (PanCancer Immune Profiling). Associations between plasma levels of proteins and miRNAs and response to treatment (overall survival and time to progression) were evaluated using a Cox proportional hazards model. RESULTS Decreased baseline plasma concentrations of 5 of 266 evaluable proteins (angiopoietin 1, cystatin B, the latency-associated peptide of transforming growth factor beta 1, oxidized low-density lipoprotein receptor 1, and C-C motif chemokine ligand 3; adjusted P ≤ .05) were significantly associated with increased overall survival time after regorafenib treatment. Levels of these 5 proteins, which have roles in inflammation and/or HCC pathogenesis, were not associated with survival independently of treatment. Only 20 of 499 patients had high levels and a reduced survival time. Plasma levels of α-fetoprotein and c-MET were associated with poor outcome (overall survival) independently of regorafenib treatment only. We identified 9 plasma miRNAs (MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645) whose levels significantly associated with overall survival time with regorafenib (adjusted P ≤ .05). Functional analyses of these miRNAs indicated that their expression level associated with increased overall survival of patients with tumors of the Hoshida S3 subtype. Next-generation sequencing analyses of tumor tissues revealed 49 variants in 27 oncogenes or tumor suppressor genes. Mutations in CTNNB1 were detected in 3 of 10 progressors and VEGFA amplification in 1 of 7 responders. CONCLUSION We identified expression patterns of plasma proteins and miRNAs that associated with increased overall survival times of patients with HCC following treatment with regorafenib in the RESORCE trial. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with HCC most likely to respond to regorafenib. ClinicalTrials.gov number NCT01774344. NCBI GEO accession numbers: mRNA data (NanoString): GSE119220; miRNA data (Exiqon): GSE119221.
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Affiliation(s)
| | | | | | | | - Richard S Finn
- David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Josep M Llovet
- BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain; Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Jordi Bruix
- BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain
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27
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Huang W, Skanderup AJ, Lee CG. Advances in genomic hepatocellular carcinoma research. Gigascience 2018; 7:5232228. [PMID: 30521023 PMCID: PMC6335342 DOI: 10.1093/gigascience/giy135] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 11/01/2018] [Indexed: 12/14/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the cancer with the second highest mortality in the world due to its late presentation and limited treatment options. As such, there is an urgent need to identify novel biomarkers for early diagnosis and to develop novel therapies. The availability of next-generation sequencing (NGS) data from tumors of liver cancer patients has provided us with invaluable resources to better understand HCC through the integration of data from different sources to facilitate the identification of promising biomarkers or therapeutic targets. Findings Here, we review key insights gleaned from more than 20 NGS studies of HCC tumor samples, comprising approximately 582 whole genomes and 1,211 whole exomes mainly from the East Asian population. Through consolidation of reported somatic mutations from multiple studies, we identified genes with different types of somatic mutations, including single nucleotide variations, insertion/deletions, structural variations, and copy number alterations as well as genes with multiple frequent viral integration. Pathway analysis showed that this curated list of somatic mutations is critically involved in cancer-related pathways, viral carcinogenesis, and signaling pathways. Lastly, we addressed the future directions of HCC research as more NGS datasets become available. Conclusions Our review is a comprehensive resource for the current NGS research in HCC, consolidating published articles, potential gene candidates, and their related biological pathways.
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Affiliation(s)
- Weitai Huang
- Computational and Systems Biology, Agency for Science Technology and Research, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.,Graduate School of Integrative Sciences and Engineering, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 117456, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Anders Jacobsen Skanderup
- Computational and Systems Biology, Agency for Science Technology and Research, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore
| | - Caroline G Lee
- Graduate School of Integrative Sciences and Engineering, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 117456, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.,Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Center Singapore, Singapore 169610, Singapore.,Duke-NUS Graduate Medical School Singapore, Singapore 169547, Singapore
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Chen Y, Wu Y, Zhang X, Zeng H, Liu Y, Wu Q, Chen Y, Zhu G, Pan Q, Jin L, Guo L, Sun F. Angiopoietin-2 (Ang-2) is a useful serum tumor marker for liver cancer in the Chinese population. Clin Chim Acta 2018; 478:18-27. [PMID: 29253494 DOI: 10.1016/j.cca.2017.12.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 11/22/2017] [Accepted: 12/12/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND We estimated the diagnostic and prognostic value of serum angiopoietin-2 (Ang-2) in liver cancer patients. METHODS Tissue Ang-2 was measured using immunohistochemistry (IHC). Cell localization of Ang-2 was tested using immunofluorescence (IF). Cell viability and apoptosis were evaluated using MTT and caspase3/7 assays, respectively. Colony-formation was measured using a soft agar assay. Serum Ang-2 was examined using enzyme-linked immunosorbent assay (ELISA) and Western blotting. RESULTS Ang-2 was up-regulated in liver cancer compared to the levels in normal tissues. Serum Ang-2 concentrations were much higher in liver cancer patients than in healthy individuals and those with chronic liver disease (CLD). Inhibitions of Ang-2 using specific shRNA decreased cell proliferation. Serum Ang-2 decreased significantly after surgery. Serum Ang-2 was positively correlated with serum alpha-fetoprotein (AFP; R=0.375, P=0.005). Receiver operating characteristic (ROC) curves suggested that serum Ang-2 could be used with relatively high sensitivity and specificity in differentiating liver cancer patients from CLD patients or healthy controls, with corresponding AUC values of 0.742 and 0.924, respectively. Serum Ang-2 was negatively correlated with overall survival. Subgroup analysis also showed that Ang-2 retained its prognostic value in overall survival prediction in different risk subgroups. CONCLUSION Serum Ang-2 may be a useful tumor marker in predicting liver cancer prognosis.
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Affiliation(s)
- Yuxin Chen
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China
| | - Yanping Wu
- Department of Geriatrics, Zhong Da Hospital of Southeast University, Nanjing 210009, China
| | - Xiao Zhang
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China
| | - Hong Zeng
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Ya Liu
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China
| | - Qi Wu
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China
| | - Yan Chen
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China
| | - GuoQing Zhu
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China
| | - Qiuhui Pan
- Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127,China
| | - Lei Jin
- College of Allied Health Professions, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Highway, Pudong New Area, Shanghai 201318, China.
| | - Lin Guo
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, China; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai 200032, China..
| | - Fenyong Sun
- Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
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Lv Q, Zhong W, Ye X, Lv Y, Liu H, Yan G, Chen D. Expression of Angiopoietin and VEGF in Cervical Cancer and its Clinical Significance. Open Life Sci 2018; 13:527-532. [PMID: 33817123 PMCID: PMC7874711 DOI: 10.1515/biol-2018-0063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/01/2018] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The aim of this study was to evaluate the expression of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) in cervical cancer and its clinical significance. METHODS Immunohistochemical assay was used to examine the expression of Ang-1/2 and VEGF in tumor tissue from 56 cervical squamous cell carcinoma patients treated with operation only (SCC-O group), as well as 51 subjects with cervical squamous cell carcinoma treated with neoadjuvant radiotherapy (SCC-RCO group, n=28) or neoadjuvant chemotherapy (SCC-CO group, n=23). Both microvessel density (MVD) and lymphatic vessel density (LVD) were examined in the three groups through detection of CD34 and D2-40 expression in respective tissue samples. RESULTS With the progression of cervical cancer, the positive expression scores of Ang-2 and VEGF were significantly increased (p<0.05). Compared with surgical intervention, neoadjuvant chemoradiotherapy significantly reduced the positive expression scores of Ang-1, Ang-2, and VEGF in cervical cancer tissues (p<0.05). The MVD values of the SCC-CO and SCC-RO groups were significantly reduced as compared to the SCC-O group (p<0.05). Similarly, the LVD values of the SCC-CO and SCC-RO groups were also significantly reduced when compared to those of the SCC-O group (p<0.05). However, LVD values of the SCC-CO and SCC-RO groups were not statistical different (p>0.05). CONCLUSION Ang-1, Ang-2 and VEGF may play an important role in the development of cervical cancer. Mutual synergism of Ang-2 and VEGF demonstrated a close relationship with the generation of cervical blood and lymphatic vessels. Cervical cancer radiotherapy and chemotherapy could significantly inhibit the formation of blood vessels and lymphatic vessels in tumor tissue.
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Affiliation(s)
- Qingyuan Lv
- Department of Obstetrics and Gynecology, LishuiPeople’s Hospital Zhejiang Province 323000PR China
| | - Weijuan Zhong
- No. 15 Dazhong Road Liandu DistrictLishui CityZhejiang Province 323000PR China
| | - Xiabin Ye
- Department of Obstetrics and Gynecology, LishuiPeople’s Hospital Zhejiang Province 323000PR China
| | - Yang Lv
- Department of Obstetrics and Gynecology, LishuiPeople’s Hospital Zhejiang Province 323000PR China
| | - Haiying Liu
- Department of Obstetrics and Gynecology, LishuiPeople’s Hospital Zhejiang Province 323000PR China
| | - Guizhen Yan
- Department of Obstetrics and Gynecology, LishuiPeople’s Hospital Zhejiang Province 323000PR China
| | - Diwen Chen
- Department of Obstetrics and Gynecology, LishuiPeople’s Hospital Zhejiang Province 323000PR China
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Ali MM, H Borai I, Ghanem HM, H Abdel-Halim A, Mousa FM. The prophylactic and therapeutic effects of Momordica charantia methanol extract through controlling different hallmarks of the hepatocarcinogenesis. Biomed Pharmacother 2017; 98:491-498. [PMID: 29287196 DOI: 10.1016/j.biopha.2017.12.096] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/17/2017] [Accepted: 12/19/2017] [Indexed: 02/08/2023] Open
Abstract
Inspite of the wide facilities for controlling cancer growth, there are little drugs to inhibit its metastasis or prevent its angiogenesis. Discovering such natural or synthetic multi-targeted agent that might strike different targets is considered as a vital goal for tumor controlling. In a previous study, the chemoprotective effect of methanol extract of Momordicacharantia (MEMC) on albino western rats bearing hepatocarcinogenesis was evaluated. The mechanism by which MEMC exert its anticancer properties was unknown. Therefore, we aimed in this study to investigate the possible role of MEMC as anti-proliferative, anti-angiogenic and anti-metastatic agent to exert its chemoprotective effect. The study was conducted on sixty albino western rats divided into six groups, 10 rats each. Diethylnitrosamine (DENA) was injected intraperitoneally (i.p.) at a dose of 200 mg/kg body weight once, 2 weeks later rats were received carbon tetrachloride (CCl4) subcutaneously (3 ml/kg/week) continued for 10 weeks. MEMC was orally produced to rats (40 mg/kg) alone, as well as before, at the same time and after DENA injection. Cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), caspase-3,-8 (Casp-3,-8), histone deacetylase (HDAC) and matrixmetalloproteinases-2,-9 (MMP-2,-9) were evaluated. MEMC treatment significantly decreased Cox-2, VEGF, HDAC and MMP-2,-9 and increased Casp-3,-8 as compared to DENAgroup,which demonstrated that the anticancer effect of MEMC may be through the inhibition of angiogenesis, proliferation and metastasis and the activation of apoptosis. The improvement in before-treated group was more pronounced than that in after- and simultaneous-treated groups, indicating thatMEMC may act as a prophylactic agent more than being a therapeutic agent.
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Affiliation(s)
- Mamdouh M Ali
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt.
| | - Ibrahim H Borai
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hala M Ghanem
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Abeer H Abdel-Halim
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt
| | - Fatma M Mousa
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt
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A Review of Anti-Angiogenic Targets for Monoclonal Antibody Cancer Therapy. Int J Mol Sci 2017; 18:ijms18081786. [PMID: 28817103 PMCID: PMC5578174 DOI: 10.3390/ijms18081786] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 08/11/2017] [Accepted: 08/14/2017] [Indexed: 12/13/2022] Open
Abstract
Tumor angiogenesis is a key event that governs tumor progression and metastasis. It is controlled by the complicated and coordinated actions of pro-angiogenic factors and their receptors that become upregulated during tumorigenesis. Over the past several decades, vascular endothelial growth factor (VEGF) signaling has been identified as a central axis in tumor angiogenesis. The remarkable advent of recombinant antibody technology has led to the development of bevacizumab, a humanized antibody that targets VEGF and is a leading clinical therapy to suppress tumor angiogenesis. However, despite the clinical efficacy of bevacizumab, its significant side effects and drug resistance have raised concerns necessitating the identification of novel drug targets and development of novel therapeutics to combat tumor angiogenesis. This review will highlight the role and relevance of VEGF and other potential therapeutic targets and their receptors in angiogenesis. Simultaneously, we will also cover the current status of monoclonal antibodies being developed to target these candidates for cancer therapy.
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Hernández-Bartolomé Á, López-Rodríguez R, García-Buey L, Martín-Vílchez S, Rodríguez-Muñoz Y, Borque MJ, González-Moreno L, Real-Martínez Y, Mendoza-Ridruejo J, Martín-Pérez E, Moreno-Otero R, Sanz-Cameno P. Intrahepatic angiopoietin-2 correlates with chronic hepatitis C progression and is induced in hepatitis C virus replicon systems. Liver Int 2017; 37:1148-1156. [PMID: 28027429 DOI: 10.1111/liv.13352] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 12/13/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis C (CHC) is a major cause of cirrhosis and hepatocellular carcinoma and angiogenesis is closely related to the pathogenesis and progression of different chronic liver diseases (CLD). Thus, the intrahepatic expression of angiopoietins 1 and 2 (Ang1 and Ang2), as relevant mediators of pathological angiogenesis in several CLD, was investigated. In addition, the differential influence of structural and non-structural genomic regions of HCV on the expression of angiopoietins and the possible signalling involved were studied. METHODS Ang1 and Ang2 expression was evaluated by western blotting and enzyme-linked immunosorbent assay (ELISA) in liver homogenates of CHC patients (n=47) and uninfected subjects (n=8). Their association with disease progression (according to METAVIR classification) was assessed by Spearman's correlation. Statistical differences among the expression of angiopoietins at different CHC stages were calculated by Mann-Whitney U-test. Finally, the in vitro expression of Angiopoietins in HCV replicons (complete or non-structural subgenomic) and the main signalling pathways involved were also examined. RESULTS Ang2 levels were significantly higher in the liver of CHC patients compared to controls and significantly correlated with inflammation and fibrosis. Accordingly, an increased expression of Ang2 was found in all HCV replicons tested. Interestingly, the inhibition of MEK and PI3K signalling pathways exerted differential effects on Ang2 expression concerning to the genomic region of HCV. CONCLUSIONS Hepatitis C virus induces Ang2 expression in hepatocytes through different signalling routes which may lead to the disregulation of vascular homeostasis in the liver. Thus, pharmacologic intervention on Ang2 signalling might constitute an important therapeutic tool.
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Affiliation(s)
| | | | - Luisa García-Buey
- Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.,CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain
| | | | | | - María Jesús Borque
- Molecular Biology Unit, Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | | | | | | | - Elena Martín-Pérez
- Digestive Surgery Service, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain
| | - Ricardo Moreno-Otero
- Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.,CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain
| | - Paloma Sanz-Cameno
- Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.,CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain
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Tang S, Wang D, Zhang Q, Li L. miR-218 suppresses gastric cancer cell proliferation and invasion via regulation of angiopoietin-2. Exp Ther Med 2016; 12:3837-3842. [PMID: 28105117 PMCID: PMC5228446 DOI: 10.3892/etm.2016.3893] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Accepted: 09/01/2016] [Indexed: 12/14/2022] Open
Abstract
Novel targeted therapies need to be developed for gastric cancer, the third most common cancer type and the second most common cause of cancer-related mortality in China. Previous studies indicate that angiopoietin (Ang)-2 serves a role in the proliferation, migration, invasion and adhesion of malignant cells. The present study identified, using functional studies, that exogenous expression of miR-218 increased migration of NCI-87 and HGC-27 gastric cancer cells, which coincided with a reduction in the expression of Ang-2. In addition, intratumoral delivery of miR-218 inhibited proliferation and angiogenesis of gastric cancer cells in vivo, with a corresponding decreased in Ang-2 expression. These results indicate that miR-218 serves an important role in gastric cancer tumorigenesis through regulating the expression of Ang-2. Therefore, components of miR-218/Ang-2 signaling could provide novel therapeutic targets for the treatment of gastric cancer.
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Affiliation(s)
- Sifeng Tang
- Department of Gastrointestinal Surgery, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China; Department of General Surgery, Laiwu People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Deyou Wang
- Department of General Surgery, Laiwu People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Qiwen Zhang
- Department of General Surgery, Laiwu People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Leping Li
- Department of Gastrointestinal Surgery, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China; Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Zhou HC, Fang JH, Shang LR, Zhang ZJ, Sang Y, Xu L, Yuan Y, Chen MS, Zheng L, Zhang Y, Zhuang SM. MicroRNAs miR-125b and miR-100 suppress metastasis of hepatocellular carcinoma by disrupting the formation of vessels that encapsulate tumour clusters. J Pathol 2016; 240:450-460. [DOI: 10.1002/path.4804] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 07/25/2016] [Accepted: 08/17/2016] [Indexed: 01/06/2023]
Affiliation(s)
- Hui-Chao Zhou
- Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital; Sun Yat-sen University; Guangzhou PR China
| | - Jian-Hong Fang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Centre for Cancer Medicine, School of Life Sciences; Sun Yat-sen University; Guangzhou PR China
| | - Li-Ru Shang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Centre for Cancer Medicine, School of Life Sciences; Sun Yat-sen University; Guangzhou PR China
| | - Zi-Jun Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Centre for Cancer Medicine, School of Life Sciences; Sun Yat-sen University; Guangzhou PR China
| | - Ye Sang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Centre for Cancer Medicine, School of Life Sciences; Sun Yat-sen University; Guangzhou PR China
| | - Li Xu
- State Key Laboratory of Oncology in South China, Cancer Centre; Sun Yat-sen University; Guangzhou PR China
- Department of Hepatobiliary Oncology, Cancer Centre; Sun Yat-sen University; Guangzhou PR China
| | - Yunfei Yuan
- State Key Laboratory of Oncology in South China, Cancer Centre; Sun Yat-sen University; Guangzhou PR China
- Department of Hepatobiliary Oncology, Cancer Centre; Sun Yat-sen University; Guangzhou PR China
| | - Min-Shan Chen
- State Key Laboratory of Oncology in South China, Cancer Centre; Sun Yat-sen University; Guangzhou PR China
- Department of Hepatobiliary Oncology, Cancer Centre; Sun Yat-sen University; Guangzhou PR China
| | - Limin Zheng
- State Key Laboratory of Oncology in South China, Cancer Centre; Sun Yat-sen University; Guangzhou PR China
| | - Yaojun Zhang
- State Key Laboratory of Oncology in South China, Cancer Centre; Sun Yat-sen University; Guangzhou PR China
- Department of Hepatobiliary Oncology, Cancer Centre; Sun Yat-sen University; Guangzhou PR China
| | - Shi-Mei Zhuang
- Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital; Sun Yat-sen University; Guangzhou PR China
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Centre for Cancer Medicine, School of Life Sciences; Sun Yat-sen University; Guangzhou PR China
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Cai Z, Zhao B, Deng Y, Shangguan S, Zhou F, Zhou W, Li X, Li Y, Chen G. Notch signaling in cerebrovascular diseases (Review). Mol Med Rep 2016; 14:2883-98. [PMID: 27574001 PMCID: PMC5042775 DOI: 10.3892/mmr.2016.5641] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Accepted: 07/22/2016] [Indexed: 12/30/2022] Open
Abstract
The Notch signaling pathway is a crucial regulator of numerous fundamental cellular processes. Increasing evidence suggests that Notch signaling is involved in inflammation and oxidative stress, and thus in the progress of cerebrovascular diseases. In addition, Notch signaling in cerebrovascular diseases is associated with apoptosis, angiogenesis and the function of blood-brain barrier. Despite the contradictory results obtained to date as to whether Notch signaling is harmful or beneficial, the regulation of Notch signaling may provide a novel strategy for the treatment of cerebrovascular diseases.
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Affiliation(s)
- Zhiyou Cai
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Bin Zhao
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Yanqing Deng
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Shouqin Shangguan
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Faming Zhou
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Wenqing Zhou
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Xiaoli Li
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Yanfeng Li
- Department of Neurology, Peking Union Medical College Hospital, Beijing 100730, P.R. China
| | - Guanghui Chen
- Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
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Abstract
Hepatocellular cancer (HCC) is a leading cause of cancer death worldwide, and most patients who are diagnosed with HCC are ineligible for curative local therapy. The targeted agent sorafenib provides modest survival benefits in the setting of advanced disease. Novel systemic treatment options for HCC are sorely needed. In this review, we identify and categorize the drugs and targets that are in various phases of testing for use against HCC. We also focus on the potential for combining these agents with radiotherapy. This would help identify directions for future study that are likely to yield positive findings and improve outcomes for patients with HCC.
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Affiliation(s)
- Nitin Ohri
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
| | - Andreas Kaubisch
- Department of Medical Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
| | - Madhur Garg
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
| | - Chandan Guha
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
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Chen Z, Zhu S, Hong J, Soutto M, Peng D, Belkhiri A, Xu Z, El-Rifai W. Gastric tumour-derived ANGPT2 regulation by DARPP-32 promotes angiogenesis. Gut 2016; 65:925-34. [PMID: 25779598 PMCID: PMC4573388 DOI: 10.1136/gutjnl-2014-308416] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 02/27/2015] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Overexpression of dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32), and its truncated isoform (t-DARPP) are associated with gastric tumorigenesis. Herein, we investigated the role of DARPP-32 proteins in regulating angiopoietin 2 (ANGPT2) and promoting tumour angiogenesis. DESIGN Quantitative real-time RT-PCR, immunoblotting, luciferase reporter, immunofluorescence, immunohistochemistry and angiogenesis assays were applied to investigate the regulation of angiogenesis by DARPP-32 proteins. RESULTS Overexpression of DARPP-32 significantly increased the mRNA and protein levels of ANGPT2 in gastric cancer cells. The overexpression of DARPP-32 T34A mutant or the N-terminal truncated isoform, t-DARPP, led to similar effects ruling out the T34-dependent regulation of protein phosphatase 1 activity in regulating ANGPT2. DARPP-32 proteins induced a secreted form of ANGPT2, which was detectable in the media, functionally active, and able to induce angiogenesis, measured by the human umbilical vein endothelial cells tube formation assay. Antibody blocking of the secreted ANGPT2 abrogated its function. To identify the mechanism by which DARPP-32 regulates ANGPT2, we examined the activities of NF-κB and signal transducer and activator of transcription 3 (STAT3), known regulators of angiogenesis. The results ruled out NF-κB and showed induction of STAT3 phosphorylation, activation and nuclear localisation. Inhibition or knockdown of STAT3 significantly attenuated the induction of ANGPT2 by DARPP-32 proteins. In vivo xenograft models demonstrated that overexpression of DARPP-32 promotes angiogenesis and tumour growth. Analyses of human gastric cancer tissues showed a strong correlation between DARPP-32 and ANGPT2. CONCLUSIONS Our novel findings establish the role of DARPP-32-STAT3 axis in regulating ANGPT2 in cancer cells to promote angiogenesis and tumorigenesis.
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Affiliation(s)
- Zheng Chen
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shoumin Zhu
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jun Hong
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mohammed Soutto
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - DunFa Peng
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Abbes Belkhiri
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wael El-Rifai
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee
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Shinoda K, Kuboki S, Shimizu H, Ohtsuka M, Kato A, Yoshitomi H, Furukawa K, Miyazaki M. Pin1 facilitates NF-κB activation and promotes tumour progression in human hepatocellular carcinoma. Br J Cancer 2015; 113:1323-31. [PMID: 26461058 PMCID: PMC4815797 DOI: 10.1038/bjc.2015.272] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 06/14/2015] [Accepted: 07/01/2015] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND NF-κB promotes HCC progression; however, therapies targeting NF-κB are not used due to severe adverse reactions. Pin1 is reported to induce tumour progression in vitro. However, the role of Pin1 in HCC is unclear. Moreover, little is known about the mechanism of Pin1-mediated NF-κB activation. METHODS Fresh surgical specimens were collected from 144 HCC patients. Pin1 and NF-κB-p65 expression was evaluated by immunohistochemistry and western blotting. NF-κB activation was assessed by EMSA. RESULTS Pin1 was increased in HCC compared to adjacent liver tissue. The multivariate analysis revealed that high Pin1 expression was an independent factor for poor prognosis. In HCC with high Pin1 expression, tumour size was larger and portal vein invasion was increased. Pin1 expression was correlated with phosphorylated (p-) NF-κB-p65(Thr254) and p-NF-κB-p65(Ser276), and thereby NF-κB activation. Pin1-induced NF-κB activation accelerated cell cycle progression, induced angiogenesis, and inhibited apoptosis. Pin1 knockdown in HCC cells inhibited the phosphorylation of NF-κB-p65(Ser276), and reduced NF-κB activation, which resulted in inhibiting tumour cell progression. When HCC cells were treated with the Pin1 inhibitors, p-NF-κB-p65(Ser276) expression and NF-κB activation was reduced, and cell proliferation was inhibited. CONCLUSIONS Pin1 is associated with aggressive tumour progression and poor prognosis in HCC by mediating NF-κB activation.
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Affiliation(s)
- Kimio Shinoda
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan
| | - Hiroaki Shimizu
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan
| | - Atsushi Kato
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan
| | - Hideyuki Yoshitomi
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan
| | - Masaru Miyazaki
- Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-0856, Japan
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Bouattour M, Payancé A, Wassermann J. Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging. World J Hepatol 2015; 7:2245-2263. [PMID: 26380650 PMCID: PMC4568486 DOI: 10.4254/wjh.v7.i20.2245] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 05/16/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimizing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.
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Affiliation(s)
- Mohamed Bouattour
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Audrey Payancé
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Johanna Wassermann
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
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Fang JH, Zhou HC, Zhang C, Shang LR, Zhang L, Xu J, Zheng L, Yuan Y, Guo RP, Jia WH, Yun JP, Chen MS, Zhang Y, Zhuang SM. A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial-mesenchymal transition-independent manner. Hepatology 2015; 62:452-65. [PMID: 25711742 DOI: 10.1002/hep.27760] [Citation(s) in RCA: 172] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Accepted: 02/21/2015] [Indexed: 12/15/2022]
Abstract
UNLABELLED Early metastasis is responsible for frequent relapse and high mortality of hepatocellular carcinoma (HCC), but its underlying mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) has been considered a key event in metastasis. Based on histological examination of serial HCC sections and three-dimensional reconstruction, we found a novel and prevalent vascular pattern, vessels that encapsulated tumor clusters (VETC) and formed cobweb-like networks. The presence of VETC (VETC(+) ) predicted higher metastasis and recurrence rates of HCC. Using clinical samples and mouse xenograft models, we further showed that VETC was composed of functional vessels with blood perfusion and induced by tumor cells at the early stage of HCC. Subsequent investigations revealed that HCC cell-derived angiopoietin-2 was a prerequisite for VETC formation and that the VETC pattern was a critical factor promoting HCC metastasis as knockdown of angiopoietin-2 abolished this vascular pattern and consequently attenuated in vivo tumor metastasis. Interestingly, abrogation of EMT by knockdown of Snail or Slug significantly diminished in vivo metastasis of VETC(-) xenografts but did not affect that of VETC(+) ones, although silencing of Snail or Slug substantially reduced the in vitro migration of both VETC(+) and VETC(-) HCC cells. In contrast to human VETC(-) cases, EMT signatures were rarely observed in VETC(+) cases with metastatic potential. Further analysis revealed that VETC provided an efficient metastasis mode by facilitating the release of whole tumor clusters into the bloodstream. CONCLUSION Our findings identify a novel metastasis mechanism that relies on vascular pattern but is independent of EMT, which may provide new targets for antimetastasis therapy and offer a basis for selecting patients who may benefit from certain molecularly targeted drugs.
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MESH Headings
- Analysis of Variance
- Angiopoietin-2/metabolism
- Animals
- Biopsy, Needle
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/physiopathology
- Chi-Square Distribution
- Disease Models, Animal
- Epithelial-Mesenchymal Transition/physiology
- Female
- Heterografts
- Humans
- Liver Neoplasms/pathology
- Liver Neoplasms/physiopathology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Neoplasm Metastasis/pathology
- Neoplasm Metastasis/physiopathology
- Neoplastic Cells, Circulating/pathology
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/physiopathology
- Random Allocation
- Real-Time Polymerase Chain Reaction
- Tumor Cells, Cultured
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Affiliation(s)
- Jian-Hong Fang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Hui-Chao Zhou
- Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chong Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Li-Ru Shang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lei Zhang
- Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing Xu
- Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Limin Zheng
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yunfei Yuan
- Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Rong-Ping Guo
- Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Wei-Hua Jia
- Bank of Tumor Resources, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Jing-Ping Yun
- Department of Pathology, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Min-Shan Chen
- Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Yaojun Zhang
- Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Shi-Mei Zhuang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Pauta M, Ribera J, Melgar-Lesmes P, Casals G, Rodríguez-Vita J, Reichenbach V, Fernandez-Varo G, Morales-Romero B, Bataller R, Michelena J, Altamirano J, Jiménez W, Morales-Ruiz M. Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition. Liver Int 2015; 35:1383-92. [PMID: 24612347 DOI: 10.1111/liv.12505] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 02/12/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Studies in experimental models of cirrhosis showed that anti-angiogenic treatments may be effective for the treatment of liver fibrosis. In this context, angiopoietins are potential therapeutic targets as they are involved in the maintenance and stabilization of newly formed blood vessels. In addition, angiopoietin-2 is expressed in fibrotic livers and its inhibition in tumours results in vessel stability. Therefore, our study was aimed to assess the therapeutic utility of inhibiting angiopoietin-2. METHODS Circulating levels of angiopoietin-1 and angiopoietin-2 were quantified by ELISA in CCl4 -treated rats and in patients with cirrhosis. In vivo blockade of angiopoietin-2 in rats with liver fibrosis was performed with a chemically programmed antibody, CVX-060. RESULTS High levels of angiopoietin-2 were found in the systemic and suprahepatic circulation of cirrhotic patients and the ratio angiopoietin-1/angiopoietin-2 inversely correlated with prognostic models for alcoholic liver disease. Chronic treatment of CCl4 -treated rats with CVX-060 was associated with a significant decrease in inflammatory infiltrate, normalization of the hepatic microvasculature and reduction in VCAM-1 vascular expression. The anti-angiopoietin-2 treatment was also associated with less liver fibrosis and with lower levels of circulating transaminases. CVX-060 treatment was not associated with either vascular pruning in healthy tissue or compensatory overexpression of VEGF. CONCLUSIONS Inhibition of angiopoietin-2 is an effective and safe treatment for liver fibrosis in CCl4 -treated rats, acting mainly through the induction of vessel normalization and the attenuation of hepatic inflammatory infiltrate. Therefore, inhibition of angiopoietin-2 offers a therapeutic alternative for liver fibrosis.
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Affiliation(s)
- Montse Pauta
- Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS) and CIBERehd, Barcelona, Spain
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Muto J, Shirabe K, Sugimachi K, Maehara Y. Review of angiogenesis in hepatocellular carcinoma. Hepatol Res 2015; 45:1-9. [PMID: 24533487 DOI: 10.1111/hepr.12310] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 01/27/2014] [Accepted: 02/03/2014] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular tumor, and its vascularity is unique and greatly different from peripheral parenchyma of liver. Afferent and efferent vessels of HCC lesions come to differ as the lesion develops. The characteristic of the flow regulates the common style of metastasis. The portal tract of the HCC lesion is the first site of the intrahepatic metastasis, because cancer cells roll into the portal vein via efferent flow. On microscopic observation, HCC displays marked vascular abnormalities, arteriogenesis and capillarization. Arteriogenesis is defined as the growth of functional collateral arteries covered with smooth muscle cells from pre-existing arteries. Sinusoidal capillarization involves the transformation of fenestrated hepatic sinusoids into continuous capillaries. Several angiogenic factors have been reported, and some of them are studied as prognostic factors or target molecules of chemotherapeutic reagents. However, the mechanism of neovascularization during HCC development is still unclear. This review discusses the characteristics of angiogenesis in HCC and known angiogenic factors of HCC.
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Affiliation(s)
- Jun Muto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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44
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Hara M, Kono H, Furuya S, Hirayama K, Tsuchiya M, Fujii H. Macrophage colony-stimulating factor plays a pivotal role in chemically induced hepatocellular carcinoma in mice. Hepatol Res 2014; 44:798-811. [PMID: 23710613 DOI: 10.1111/hepr.12174] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 04/23/2013] [Accepted: 05/21/2013] [Indexed: 12/13/2022]
Abstract
AIM The specific purpose of this study was to investigate the role of macrophage colony-stimulating factor (M-CSF) in initiation and progression of hepatocellular carcinoma using M-CSF-deficient mice. METHODS M-CSF-deficient (osteopetrotic: op/op) and their littermate (LM) mice were i.p. injected with diethylnitrosamine (DEN) to induce hepatocellular carcinoma. Twenty-eight weeks after DEN administration, the tumor incidence rate and serum M-CSF levels were assessed. Furthermore, distribution of the activated macrophages and the mRNA expression of CD163 and CD204 were evaluated. Moreover, angiogenesis was analyzed in tumors. In another set of experiments, apoptosis and proliferation of the hepatocytes were examined in the acute phase after DEN administration. Isolated hepatic macrophages were cultured with or without M-CSF, and vascular endothelial growth factor (VEGF) production was assessed by enzyme-linked immunoassay. RESULTS Tumor incidence was significantly reduced in the op/op compared with the LM mice. Serum M-CSF levels were increased in the carcinogenesis models of the LM mice. Hepatic macrophages were found only in tumors in the op/op but in both normal liver tissue and tumors in the LM mice. In the op/op group, the mRNA expression of inflammatory cytokines was significantly lower compared with the LM mice. Furthermore, apoptosis was significantly increased in the op/op than the LM mice. Angiogenesis increased in liver tumors from the LM compared with the op/op mice. Production of VEGF was greater in the hepatic macrophages incubated with M-CSF compared with those without M-CSF. CONCLUSION Thus, M-CSF is involved in the progression of chemically induced hepatocarcinogenesis.
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Affiliation(s)
- Michio Hara
- First Department of Surgery, University of Yamanashi, Chuo, Japan
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45
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Runge A, Hu J, Wieland M, Bergeest JP, Mogler C, Neumann A, Géraud C, Arnold B, Rohr K, Komljenovic D, Schirmacher P, Goerdt S, Augustin HG. An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice. Cancer Res 2014; 74:4157-69. [PMID: 24906623 DOI: 10.1158/0008-5472.can-13-2311] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase-mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen-positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies.
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Affiliation(s)
- Anja Runge
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Junhao Hu
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Matthias Wieland
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Jan-Philip Bergeest
- Division of Bioinformatics and Functional Genomics, BioQuant Center, Heidelberg University, Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Carolin Mogler
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Pathology, Heidelberg University, Heidelberg, Germany
| | - André Neumann
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Cyrill Géraud
- Department for Dermatology, Venerology, and Allergy, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Bernd Arnold
- Division of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Karl Rohr
- Division of Bioinformatics and Functional Genomics, BioQuant Center, Heidelberg University, Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dorde Komljenovic
- Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Sergij Goerdt
- Department for Dermatology, Venerology, and Allergy, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany. German Cancer Consortium, Heidelberg, Germany.
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Fujita N, Nishie A, Aishima S, Kubo Y, Asayama Y, Ishigami K, Kakihara D, Ushijima Y, Takayama Y, Shirabe K, Oda Y, Honda H. Role of tumor-associated macrophages in the angiogenesis of well-differentiated hepatocellular carcinoma: pathological-radiological correlation. Oncol Rep 2014; 31:2499-505. [PMID: 24737173 DOI: 10.3892/or.2014.3138] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 03/04/2014] [Indexed: 11/06/2022] Open
Abstract
The role of tumor-associated macrophages (TAMs) in hepatocellular carcinoma (HCC) has not been fully investigated. The aim of the present study was to clarify whether TAMs are associated with the angiogenesis of HCC during its multistep development, especially at an early stage. Forty‑three well-differentiated HCCs and 30 well- to moderately differentiated HCCs (nodule-in-nodule lesion) were used. We immunohistochemically assessed microvessel density (by CD34) and macrophage count (by CD68 or CD163). Computed tomography hepatic angiography (CTHA) was performed for 26 well-differentiated HCCs and all 30 well- to moderately differentiated HCCs. The pathological analysis of the 43 well-differentiated HCCs revealed a positive correlation between microvessel density and macrophage count (p=0.0026, r=0.4486). Based on the CTHA findings, 26 well-differentiated HCCs classified into a hyperattenuation group (n=14) and a hypo- or isoattenuation group (n=12). The microvessel density and macrophage count of the hyperattenuation group were significantly higher than those of the hypo- or isoattenuation group (p=0.0372 and p=0.0476). In the 30 well- to moderately differentiated HCCs, microvessel density of the moderately differentiated components was significantly higher than that of the well-differentiated components (p<0.0001). However, the macrophage count of the moderately differentiated component was significantly lower than that of the well-differentiated component (p<0.0001). All the moderately differentiated components showed marked hyperattenuation on CTHA. Tumor vascularity was correlated with macrophage count in the tumor when limited to well-differentiated HCCs. TAMs may have a role in promoting angiogenesis of HCC at an early stage during its multistep development.
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Affiliation(s)
- Nobuhiro Fujita
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Akihiro Nishie
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Shinichi Aishima
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yuichiro Kubo
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshiki Asayama
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kousei Ishigami
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Daisuke Kakihara
- Department of Molecular Imaging and Diagnosis, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yasuhiro Ushijima
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yukihisa Takayama
- Department of Molecular Imaging and Diagnosis, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Hiroshi Honda
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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ZHANG ZHONGLIN, ZHANG JIFA, YUAN YUFENG, HE YUEMING, LIU QUANYAN, MAO XIAOWEN, AI YONGBIAO, LIU ZHISU. Suppression of angiogenesis and tumor growth in vitro and in vivo using an anti-angiopoietin-2 single-chain antibody. Exp Ther Med 2014; 7:543-552. [PMID: 24520243 PMCID: PMC3919851 DOI: 10.3892/etm.2014.1476] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Accepted: 12/11/2013] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinomas (HCCs) are tumors with a highly developed vascular architecture. HCC cells require access to blood vessels for growth and metastasis; therefore, the inhibition of angiogenesis represents a potential therapeutic target for HCC that may reduce the mortality and morbidity from HCC. Various attempts to develop an anti-angiogenic therapy have been made in past decades; however, modest results have been achieved in clinical trials and the challenge of HCC treatment remains. Single-chain antibodies (scFv) are characterized by low molecular weight, low immunogenicity, high penetration and a short half-life, and are easy to produce on a large scale by genetic engineering. Accordingly, an scFv against a specific angiogenic regulator, such as angiopoietin (Ang), may be a promising anti-angiogenic therapy for HCC. Our previous study indicated that an imbalanced expression of angiopoietin-2 (Ang-2) vs. angiopoietin-1 (Ang-1) in HCCs contributes to initiation of neovascularization and promotes the angiogenesis and progression of HCCs. Therefore, we suggest that specific Ang-2-targeting interventions may be valuable in the treatment of HCC via remodeling the neovascular network and changing the tumor microenvironment. In this study, a prokaryotic expression vector of Ang-2 was constructed and purified human Ang-2 protein was isolated. An scFv against human Ang-2 (scFv-Ang2) was identified and purified via phage display technology, and the effects of scFv-Ang2 in vitro and in vivo on HCC in nude mice were evaluated. The results show that scFv-Ang2 inhibits vascular endothelial growth factor (VEGF) and Ang-2 induces the proliferation, migration and tubule formation of human umbilical vein endothelial cells (HUVECs) in vitro. In the in vivo assay, statistical indices, including tumor weight and volume, metastases to lungs, CD31 expression and the microvessel density (MVD) count in the scFv-Ang2-treated group of mice were significantly lower than those in the control group (P<0.05). In conclusion, the successfully generated scFv-Ang2 showed significant inhibitory effects on the angiogenesis and tumor growth of human HCC in vitro and in vivo.
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Affiliation(s)
- ZHONG-LIN ZHANG
- Hepatobiliary & Pancreatic Unit, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - JI-FA ZHANG
- Department of General Surgery, Branch Hospital in Fengxian of Shanghai No. 6 People’s Hospital, Shanghai 201406, P.R. China
| | - YU-FENG YUAN
- Hepatobiliary & Pancreatic Unit, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - YUE-MING HE
- Hepatobiliary & Pancreatic Unit, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - QUAN-YAN LIU
- Hepatobiliary & Pancreatic Unit, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - XIAO-WEN MAO
- Hepatobiliary & Pancreatic Unit, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - YONG-BIAO AI
- Hepatobiliary & Pancreatic Unit, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - ZHI-SU LIU
- Hepatobiliary & Pancreatic Unit, Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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Raeisossadati R, Abbaszadegan MR, Moghbeli M, Tavassoli A, Kihara AH, Forghanifard MM. Aberrant expression of DPPA2 and HIWI genes in colorectal cancer and their impacts on poor prognosis. Tumour Biol 2014; 35:5299-305. [PMID: 24532429 DOI: 10.1007/s13277-014-1690-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 01/23/2014] [Indexed: 02/06/2023] Open
Abstract
Cancer cells have countless behaviors of pluripotent embryonic stem cells and germ line cells, such as unlimited proliferation, self-renewal, and migration. Expression of specific germ line and embryonic genes in tumor cells may be associated with indefinite growth and invasiveness of such cells. Developmental pluripotency factor 2 (DPPA2) and HIWI are two important developmental genes which are involved in embryonic and germ line stem cell properties. Deciphering the role of these genes seems to be necessary for understanding cancer initiation and progression. Tumoral and normal tissues from 46 colorectal cancer (CRC) patients were subjected to gene expression analysis using quantitative real-time reverse transcription-polymerase chain reaction, prior to any therapeutic intervention. Overexpression of DPPA2 and HIWI was detected in 26.1 and 34.8 % of specimens, respectively. Significant correlation between DPPA2 overexpression and lymph node metastasis of the tumor cells (P=0.049) was seen in the samples with advanced stages (III/IV) of the tumor development. HIWI mRNA expression was significantly associated to the depth of tumor invasion (P=0.020) and the stage of tumorigenesis progression (P=0.030). In samples with overexpression of at least one gene, DPPA2 mRNA expression was significantly correlated to the stage of tumor (P=0.017). In the same samples, a significant correlation was observed between mRNA expression of HIWI and the stage of tumor cells (P=0.034). These results documented the important role of HIWI and DPPA2 in tumorigenesis and also in lymph node metastasis of tumor cells. Further evaluation is required to uncover the detailed role of HIWI and DPPA2 and their interactions in tumorigenesis of CRC.
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Affiliation(s)
- Reza Raeisossadati
- Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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Ranieri G, Marech I, Lorusso V, Goffredo V, Paradiso A, Ribatti D, Gadaleta CD. Molecular targeting agents associated with transarterial chemoembolization or radiofrequency ablation in hepatocarcinoma treatment. World J Gastroenterol 2014; 20:486-497. [PMID: 24574717 PMCID: PMC3923023 DOI: 10.3748/wjg.v20.i2.486] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer in the world. According to Barcelona Clinic Liver Cancer modified criteria, patients with early stage disease are candidate to radiofrequency ablation (RFA), while patients with intermediate stage HCC are usually treated by transarterial chemoembolization (TACE). TACE and RFA induce a transient devascularisation effect followed by strong neo-angiogenic stimulus. In fact, after these procedures, it has been demonstrated an up-regulation of pro-angiogenic and growth factors such as vascular endothelial growth factor-A, which might contribute to accelerated progression in patients with incomplete response. Several studies have demonstrated that MAP-kinase and AKT pathways, in addition to neo-angiogenesis, have an important role in the development of HCC. In advanced HCC, anti-angiogenic therapy and tyrosine kinases inhibitors showed potential clinical benefit. Actually, a number of clinical studies are ongoing testing these agents in combination with TACE or RFA. In this paper, we have reviewed the most recent preclinical and clinical results of such trials.
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Zacharoulis D, Hatzitheofilou C, Athanasiou E, Zacharoulis S. Antiangiogenic strategies in hepatocellular carcinoma: current status. Expert Rev Anticancer Ther 2014; 5:645-56. [PMID: 16111465 DOI: 10.1586/14737140.5.4.645] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma is a leading cause of cancer death worldwide in both adult and pediatric patients. Despite many options, no ideal treatment exists for this highly malignant tumor, and management strategies have varied accordingly. Angiogenesis, the formation of new blood vessels, is an essential component of hepatocellular carcinoma biology. Innovative approaches such as targeting the nontransformed, less resistant, tumor-supporting endothelial cells are currently under investigation in hepatocellular carcinoma. This review will focus on the current knowledge of the pathophysiology of hepatocellular carcinoma angiogenesis, as well as the reported data with angiogenesis inhibitors against hepatocellular carcinoma.
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