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1
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Li JJ, Mao JX, Zhong HX, Zhao YY, Teng F, Lu XY, Zhu LY, Gao Y, Fu H, Guo WY. Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review. World J Hepatol 2024; 16:537-549. [PMID: 38689749 PMCID: PMC11056903 DOI: 10.4254/wjh.v16.i4.537] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/11/2024] [Accepted: 03/18/2024] [Indexed: 04/24/2024] Open
Abstract
The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.
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Affiliation(s)
- Jing-Jing Li
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Jia-Xi Mao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Han-Xiang Zhong
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yuan-Yu Zhao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xin-Yi Lu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Li-Ye Zhu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yang Gao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wen-Yuan Guo
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
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Bhardwaj V, Zhang X, Pandey V, Garg M. Neo-vascularization-based therapeutic perspectives in advanced ovarian cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188888. [PMID: 37001618 DOI: 10.1016/j.bbcan.2023.188888] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/23/2023] [Accepted: 03/02/2023] [Indexed: 03/30/2023]
Abstract
The process of angiogenesis is well described for its potential role in the development of normal ovaries, and physiological functions as well as in the initiation, progression, and metastasis of ovarian cancer (OC). In advanced stages of OC, cancer cells spread outside the ovary to the pelvic, abdomen, lung, or multiple secondary sites. This seriously limits the efficacy of therapeutic options contributing to fatal clinical outcomes. Notably, a variety of angiogenic effectors are produced by the tumor cells to initiate angiogenic processes leading to the development of new blood vessels, which provide essential resources for tumor survival, dissemination, and dormant micro-metastasis of tumor cells. Multiple proangiogenic effectors and their signaling axis have been discovered and functionally characterized for potential clinical utility in OC. In this review, we have provided the current updates on classical and emerging proangiogenic effectors, their signaling axis, and the immune microenvironment contributing to the pathogenesis of OC. Moreover, we have comprehensively reviewed and discussed the significance of the preclinical strategies, drug repurposing, and clinical trials targeting the angiogenic processes that hold promising perspectives for the better management of patients with OC.
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Affiliation(s)
- Vipul Bhardwaj
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Institute of Biopharmaceutical and Bioengineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China
| | - Xi Zhang
- Shenzhen Bay Laboratory, Shenzhen 518055, PR China
| | - Vijay Pandey
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; Institute of Biopharmaceutical and Bioengineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China.
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Sector-125, Noida 201301, India.
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Bustos G, Ahumada-Castro U, Silva-Pavez E, Puebla A, Lovy A, Cesar Cardenas J. The ER-mitochondria Ca 2+ signaling in cancer progression: Fueling the monster. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 363:49-121. [PMID: 34392932 DOI: 10.1016/bs.ircmb.2021.03.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer is a leading cause of death worldwide. All major tumor suppressors and oncogenes are now recognized to have fundamental connections with metabolic pathways. A hallmark feature of cancer cells is a reprogramming of their metabolism even when nutrients are available. Increasing evidence indicates that most cancer cells rely on mitochondrial metabolism to sustain their energetic and biosynthetic demands. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca2+) storage organelle in mammalian cells, through special domains known as mitochondria-ER contact sites (MERCS). In this domain, the release of Ca2+ from the ER is mainly regulated by inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), a family of Ca2+ release channels activated by the ligand IP3. IP3R mediated Ca2+ release is transferred to mitochondria through the mitochondrial Ca2+ uniporter (MCU). Once in the mitochondrial matrix, Ca2+ activates several proteins that stimulate mitochondrial performance. The role of IP3R and MCU in cancer, as well as the other proteins that enable the Ca2+ communication between these two organelles is just beginning to be understood. Here, we describe the function of the main players of the ER mitochondrial Ca2+ communication and discuss how this particular signal may contribute to the rise and development of cancer traits.
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Affiliation(s)
- Galdo Bustos
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Ulises Ahumada-Castro
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Eduardo Silva-Pavez
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Andrea Puebla
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile
| | - Alenka Lovy
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile; Department of Neuroscience, Center for Neuroscience Research, Tufts School of Medicine, Boston, MA, United States.
| | - J Cesar Cardenas
- Faculty of Sciences, Universidad Mayor, Center for Integrative Biology, Santiago, Chile; Geroscience Center for Brain Health and Metabolism, Santiago, Chile; Buck Institute for Research on Aging, Novato, CA, United States; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, United States.
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Sabra M, Karbasiafshar C, Aboulgheit A, Raj S, Abid MR, Sellke FW. Clinical Application of Novel Therapies for Coronary Angiogenesis: Overview, Challenges, and Prospects. Int J Mol Sci 2021; 22:3722. [PMID: 33918396 PMCID: PMC8038234 DOI: 10.3390/ijms22073722] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 03/30/2021] [Accepted: 03/31/2021] [Indexed: 01/26/2023] Open
Abstract
Cardiovascular diseases continue to be the leading cause of death worldwide, with ischemic heart disease as the most significant contributor. Pharmacological and surgical interventions have improved clinical outcomes, but are unable to ameliorate advanced stages of end-heart failure. Successful preclinical studies of new therapeutic modalities aimed at revascularization have shown short lasting to no effects in the clinical practice. This lack of success may be attributed to current challenges in patient selection, endpoint measurements, comorbidities, and delivery systems. Although challenges remain, the field of therapeutic angiogenesis is evolving, as novel strategies and bioengineering approaches emerge to optimize delivery and efficacy. Here, we describe the structure, vascularization, and regulation of the vascular system with particular attention to the endothelium. We proceed to discuss preclinical and clinical findings and present challenges and future prospects in the field.
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Affiliation(s)
- Mohamed Sabra
- Cardiovascular Research Center, Rhode Island Hospital, Providence, RI 02903, USA; (M.S.); (C.K.); (A.A.); ; (M.R.A.)
| | - Catherine Karbasiafshar
- Cardiovascular Research Center, Rhode Island Hospital, Providence, RI 02903, USA; (M.S.); (C.K.); (A.A.); ; (M.R.A.)
| | - Ahmed Aboulgheit
- Cardiovascular Research Center, Rhode Island Hospital, Providence, RI 02903, USA; (M.S.); (C.K.); (A.A.); ; (M.R.A.)
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | - Sidharth Raj
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | - M. Ruhul Abid
- Cardiovascular Research Center, Rhode Island Hospital, Providence, RI 02903, USA; (M.S.); (C.K.); (A.A.); ; (M.R.A.)
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | - Frank W. Sellke
- Cardiovascular Research Center, Rhode Island Hospital, Providence, RI 02903, USA; (M.S.); (C.K.); (A.A.); ; (M.R.A.)
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University, Providence, RI 02903, USA;
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Tumor Endothelial Cell-A Biological Tool for Translational Cancer Research. Int J Mol Sci 2020; 21:ijms21093238. [PMID: 32375250 PMCID: PMC7247330 DOI: 10.3390/ijms21093238] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 12/14/2022] Open
Abstract
Going from bench to bedside is a simplified description of translational research, with the ultimate goal being to improve the health status of mankind. Tumor endothelial cells (TECs) perform angiogenesis to support the growth, establishment, and dissemination of tumors to distant organs. TECs have various features that distinguish them from normal endothelial cells, which include alterations in gene expression patterns, higher angiogenic and metabolic activities, and drug resistance tendencies. The special characteristics of TECs enhance the vulnerability of tumor blood vessels toward antiangiogenic therapeutic strategies. Therefore, apart from being a viable therapeutic target, TECs would act as a better mediator between the bench (i.e., angiogenesis research) and the bedside (i.e., clinical application of drugs discovered through research). Exploitation of TEC characteristics could reveal unidentified strategies of enhancing and monitoring antiangiogenic therapy in the treatment of cancer, which are discussed in this review.
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Sinha UK, Kundra A, Scalia P, Smith DL, Parsa B, Masood R, Gill PS. Expression of EphB4 in Head and Neck Squamous Cell Carcinoma. EAR, NOSE & THROAT JOURNAL 2019. [DOI: 10.1177/014556130308201113] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Uttam K. Sinha
- From the Department of Otolaryngology–Head and Neck Surgery, University of Southern California, Los Angeles
| | - Ajay Kundra
- The Department of Medicine, University of Southern California, Los Angeles
| | - Pierluigi Scalia
- The Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles
| | - Diane L. Smith
- The Department of Medicine, University of Southern California, Los Angeles
| | - Behdad Parsa
- From the Department of Otolaryngology–Head and Neck Surgery, University of Southern California, Los Angeles
| | - Rizwan Masood
- The Department of Medicine, University of Southern California, Los Angeles
| | - Parkash S. Gill
- The Department of Medicine, University of Southern California, Los Angeles
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Li T, Kang G, Wang T, Huang H. Tumor angiogenesis and anti-angiogenic gene therapy for cancer. Oncol Lett 2018; 16:687-702. [PMID: 29963134 PMCID: PMC6019900 DOI: 10.3892/ol.2018.8733] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 07/11/2017] [Indexed: 12/22/2022] Open
Abstract
When Folkman first suggested a theory about the association between angiogenesis and tumor growth in 1971, the hypothesis of targeting angiogenesis to treat cancer was formed. Since then, various studies conducted across the world have additionally confirmed the theory of Folkman, and numerous efforts have been made to explore the possibilities of curing cancer by targeting angiogenesis. Among them, anti-angiogenic gene therapy has received attention due to its apparent advantages. Although specific problems remain prior to cancer being fully curable using anti-angiogenic gene therapy, several methods have been explored, and progress has been made in pre-clinical and clinical settings over previous decades. The present review aimed to provide up-to-date information concerning tumor angiogenesis and gene delivery systems in anti-angiogenic gene therapy, with a focus on recent developments in the study and application of the most commonly studied and newly identified anti-angiogenic candidates for anti-angiogenesis gene therapy, including interleukin-12, angiostatin, endostatin, tumstatin, anti-angiogenic metargidin peptide and endoglin silencing.
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Affiliation(s)
- Tinglu Li
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
- Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin 300072, P.R. China
- Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, P.R. China
| | - Guangbo Kang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
- Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin 300072, P.R. China
- Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, P.R. China
| | - Tingyue Wang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
- Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin 300072, P.R. China
- Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, P.R. China
| | - He Huang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
- Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin University, Tianjin 300072, P.R. China
- Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, P.R. China
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8
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Park-Windhol C, D'Amore PA. Disorders of Vascular Permeability. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2016; 11:251-81. [PMID: 26907525 DOI: 10.1146/annurev-pathol-012615-044506] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The endothelial barrier maintains vascular and tissue homeostasis and modulates many physiological processes, such as angiogenesis. Vascular barrier integrity can be disrupted by a variety of soluble permeability factors, and changes in barrier function can exacerbate tissue damage during disease progression. Understanding endothelial barrier function is critical for vascular homeostasis. Many of the signaling pathways promoting vascular permeability can also be triggered during disease, resulting in prolonged or uncontrolled vascular leak. It is believed that recovery of the normal vasculature requires diminishing this hyperpermeable state. Although the molecular mechanisms governing vascular leak have been studied over the last few decades, recent advances have identified new therapeutic targets that have begun to show preclinical and clinical promise. These approaches have been successfully applied to an increasing number of disease conditions. New perspectives regarding how vascular leak impacts the progression of various diseases are highlighted in this review.
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Affiliation(s)
- Cindy Park-Windhol
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts 02114; , .,Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02115
| | - Patricia A D'Amore
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts 02114; , .,Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02115.,Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
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9
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Townley-Tilson WHD, Wu Y, Ferguson JE, Patterson C. The ubiquitin ligase ASB4 promotes trophoblast differentiation through the degradation of ID2. PLoS One 2014; 9:e89451. [PMID: 24586788 PMCID: PMC3931756 DOI: 10.1371/journal.pone.0089451] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 01/21/2014] [Indexed: 01/22/2023] Open
Abstract
Vascularization of the placenta is a critical developmental process that ensures fetal viability. Although the vascular health of the placenta affects both maternal and fetal well being, relatively little is known about the early stages of placental vascular development. The ubiquitin ligase Ankyrin repeat, SOCS box-containing 4 (ASB4) promotes embryonic stem cell differentiation to vascular lineages and is highly expressed early in placental development. The transcriptional regulator Inhibitor of DNA binding 2 (ID2) negatively regulates vascular differentiation during development and is a target of many ubiquitin ligases. Due to their overlapping spatiotemporal expression pattern in the placenta and contrasting effects on vascular differentiation, we investigated whether ASB4 regulates ID2 through its ligase activity in the placenta and whether this activity mediates vascular differentiation. In mouse placentas, ASB4 expression is restricted to a subset of cells that express both stem cell and endothelial markers. Placentas that lack Asb4 display immature vascular patterning and retain expression of placental progenitor markers, including ID2 expression. Using JAR placental cells, we determined that ASB4 ubiquitinates and represses ID2 expression in a proteasome-dependent fashion. Expression of ASB4 in JAR cells and primary isolated trophoblast stem cells promotes the expression of differentiation markers. In functional endothelial co-culture assays, JAR cells ectopically expressing ASB4 increased endothelial cell turnover and stabilized endothelial tube formation, both of which are hallmarks of vascular differentiation within the placenta. Co-transfection of a degradation-resistant Id2 mutant with Asb4 inhibits both differentiation and functional responses. Lastly, deletion of Asb4 in mice induces a pathology that phenocopies human pre-eclampsia, including hypertension and proteinuria in late-stage pregnant females. These results indicate that ASB4 mediates vascular differentiation in the placenta via its degradation of ID2.
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Affiliation(s)
- W. H. Davin Townley-Tilson
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Yaxu Wu
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - James E. Ferguson
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Cam Patterson
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- * E-mail:
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Middleton K, Jones J, Lwin Z, Coward JIG. Interleukin-6: an angiogenic target in solid tumours. Crit Rev Oncol Hematol 2013; 89:129-39. [PMID: 24029605 DOI: 10.1016/j.critrevonc.2013.08.004] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 07/29/2013] [Accepted: 08/13/2013] [Indexed: 12/18/2022] Open
Abstract
During the past decade, incorporating anti-angiogenic agents into the therapeutic management of a myriad of malignancies has in certain cases made a significant impact on survival. However, the development of resistance to these drugs is inevitable and swift disease progression on their cessation often ensues. Hence, there is a drive to devise strategies that aim to enhance response to anti-angiogenic therapies by combining them with other targeted agents that facilitate evasion from resistance. The pleiotropic cytokine, interleukin-6 (IL-6), exerts pro-angiogenic effects in the tumour microenvironment of several solid malignancies and there is emerging evidence that reveals significant relationships between IL-6 signalling and treatment failure with antibodies directed against vascular endothelial growth factor (VEGF). This review summarises the role of IL-6 in pivotal angiogenic processes and preclinical/clinical research to support the future introduction of anti-IL-6 therapies to be utilised either in combination with other anti-angiogenic drugs or as a salvage therapy for patients with diseases that become refractory to these approaches.
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Affiliation(s)
- Kathryn Middleton
- Mater Adult Hospital, Department of Medical Oncology, Raymond Terrace, Brisbane, QLD 4101, Australia
| | - Joanna Jones
- Mater Adult Hospital, Department of Medical Oncology, Raymond Terrace, Brisbane, QLD 4101, Australia
| | - Zarnie Lwin
- Mater Adult Hospital, Department of Medical Oncology, Raymond Terrace, Brisbane, QLD 4101, Australia
| | - Jermaine I G Coward
- Mater Adult Hospital, Department of Medical Oncology, Raymond Terrace, Brisbane, QLD 4101, Australia; Inflammation & Cancer Therapeutics Group, Mater Research, Level 4, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, QLD 4102, Australia; School of Medicine, University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
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Dewing D, Emmett M, Pritchard Jones R. The Roles of Angiogenesis in Malignant Melanoma: Trends in Basic Science Research over the Last 100 Years. ISRN ONCOLOGY 2012; 2012:546927. [PMID: 22720169 PMCID: PMC3376762 DOI: 10.5402/2012/546927] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Accepted: 04/28/2012] [Indexed: 12/13/2022]
Abstract
Blood vessels arose during evolution carrying oxygen and nutrients to distant organs via complex networks of blood vessels penetrating organs and tissues. Mammalian cells require oxygen and nutrients for survival, of which oxygen has a diffusion limit of 100 to 200 μm between cell and blood vessel. For growth beyond this margin, cells must recruit new blood vessels, first by vasculogenesis, where embryonic vessels form from endothelial precursors, then angiogenesis which is the sprouting of interstitial tissue columns into the lumen of preexisting blood vessels. Angiogenesis occurs in many inflammatory diseases and in many malignant disease states, including over 90% of solid tumours. Malignant melanoma (MM) is the most lethal skin cancer, highly angiogenic, highly metastatic, and refractory to all treatments. Raised serum levels of vascular endothelial growth factor (VEGF) strongly correlate MM disease progression and poor prognosis. Melanoma cells secrete several proangiogenic cytokines including VEGF-A, fibroblast growth factor (FGF-2), platelet growth factor (PGF-1), interleukin-8 (IL-8), and transforming growth factor (TGF-1) that modulate the angiogenic switch, changing expression levels during tumour transition from radial to invasive vertical and then metastatic growth. We highlight modern and historical lines of research and development that are driving this exciting area of research currently.
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Affiliation(s)
- D Dewing
- Department of Molecular and Clinical Cancer Medicine, Mersey Academic Plastic Surgery Group, Liverpool Cancer Research UK Centre, The Duncan Building, Daulby Street, Liverpool L69 3GA, UK
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Hemocyte-secreted type IV collagen enhances BMP signaling to guide renal tubule morphogenesis in Drosophila. Dev Cell 2010; 19:296-306. [PMID: 20708591 PMCID: PMC2941037 DOI: 10.1016/j.devcel.2010.07.019] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Revised: 07/09/2010] [Accepted: 07/28/2010] [Indexed: 12/17/2022]
Abstract
Details of the mechanisms that determine the shape and positioning of organs in the body cavity remain largely obscure. We show that stereotypic positioning of outgrowing Drosophila renal tubules depends on signaling in a subset of tubule cells and results from enhanced sensitivity to guidance signals by targeted matrix deposition. VEGF/PDGF ligands from the tubules attract hemocytes, which secrete components of the basement membrane to ensheath them. Collagen IV sensitizes tubule cells to localized BMP guidance cues. Signaling results in pathway activation in a subset of tubule cells that lead outgrowth through the body cavity. Failure of hemocyte migration, loss of collagen IV, or abrogation of BMP signaling results in tubule misrouting and defective organ shape and positioning. Such regulated interplay between cell-cell and cell-matrix interactions is likely to have wide relevance in organogenesis and congenital disease.
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Kim C, Yu HG, Sohn J. The anti-angiogenic effect of chlorogenic acid on choroidal neovascularization. KOREAN JOURNAL OF OPHTHALMOLOGY 2010; 24:163-8. [PMID: 20532143 PMCID: PMC2882080 DOI: 10.3341/kjo.2010.24.3.163] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2009] [Accepted: 05/07/2010] [Indexed: 11/23/2022] Open
Abstract
PURPOSE To evaluate the inhibitory effect of chlorogenic acid on laser-induced choroidal neovascularization (CNV) in a rat model. METHODS Intraperitoneal injection of chlorogenic acid (10 mg/kg) was initiated one day prior to laser photocoagulation and continued for eight days. Eyes were removed 14 days after laser photocoagulation. Fluorescein angiography was employed at seven and 14 days to assess the CNV lesions, and histological examination was performed. Quantification of CNV size and leakage were performed both in histological sections and fluorescein angiography in order to compare the inhibitory effects of chlorogenic acid on CNV with the results of the control. RESULTS Histological analysis showed no significant difference in CNV size between the treated and control groups. However, CNV leakage on fluorescein angiography had significantly decreased in the chlorogenic acid-treated group at 14 days after laser photocoagulation compared with that of the control group. In addition, CNV size on fluorescein angiography had significantly decreased in the treated group at seven and 14 days. CONCLUSIONS These results suggest that chlorogenic acid has anti-angiogenic effects on CNV and may be useful as an inhibitor in the treatment or prevention of neovascular age-related macular degeneration.
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Affiliation(s)
- Cinoo Kim
- Department of Ophthalmology, Incheon Medical Center, Incheon, Korea
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14
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Angiogenesis inhibition in cancer therapy: platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) and their receptors: biological functions and role in malignancy. Recent Results Cancer Res 2010; 180:51-81. [PMID: 20033378 DOI: 10.1007/978-3-540-78281-0_5] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. VEGF gene transcription is induced in particular in hypoxic cells. In developmental angiogenesis, the role of VEGF is demonstrated by the finding that the loss of a single VEGF allele results in defective vascularization and early embryonic lethality. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Platelet-derived growth factor (PDGF) is mainly believed to be an important mitogen for connective tissue, and also has important roles during embryonal development. Its overexpression has been linked to different types of malignancies. Thus, it is important to understand the physiology of VEGF and PDGF and their receptors as well as their roles in malignancies in order to develop antiangiogenic strategies for the treatment of malignant disease.
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Woolard J, Bevan HS, Harper SJ, Bates DO. Molecular diversity of VEGF-A as a regulator of its biological activity. Microcirculation 2009; 16:572-92. [PMID: 19521900 PMCID: PMC2929464 DOI: 10.1080/10739680902997333] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The vascular endothelial growth factor (VEGF) family of proteins regulates blood flow, growth, and function in both normal physiology and disease processes. VEGF-A is alternatively spliced to form multiple isoforms, in two subfamilies, that have specific, novel functions. Alternative splicing of exons 5-7 of the VEGF gene generates forms with differing bioavailability and activities, whereas alternative splice-site selection in exon 8 generates proangiogenic, termed VEGF(xxx), or antiangiogenic proteins, termed VEGF(xxx)b. Despite its name, emerging roles for VEGF isoforms on cell types other than endothelium have now been identified. Although VEGF-A has conventionally been considered to be a family of proangiogenic, propermeability vasodilators, the identification of effects on nonendothelial cells, and the discovery of the antiangiogenic subfamily of splice isoforms, has added further complexity to their regulation of microvascular function. The distally spliced antiangiogenic isoforms are expressed in normal human tissue, but downregulated in angiogenic diseases, such as cancer and proliferative retinopathy, and in developmental pathologies, such as Denys Drash syndrome and preeclampsia. Here, we examine the molecular diversity of VEGF-A as a regulator of its biological activity and compare the role of the pro- and antiangiogenic VEGF-A splice isoforms in both normal and pathophysiological processes.
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Affiliation(s)
- Jeanette Woolard
- Department of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Sciences, University of Bristol, Bristol, UK.
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16
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Affiliation(s)
- D. Stavrou
- Department of Plastic and Reconstructive Surgery, Sheba Medical Center, Tel-Hashomer, Tel-Aviv, Israel
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17
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Similarities Between Angiogenesis and Neural Development: What Small Animal Models Can Tell Us. Curr Top Dev Biol 2007; 80:1-55. [DOI: 10.1016/s0070-2153(07)80001-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Fischer C, Schneider M, Carmeliet P. Principles and therapeutic implications of angiogenesis, vasculogenesis and arteriogenesis. Handb Exp Pharmacol 2006:157-212. [PMID: 16999228 DOI: 10.1007/3-540-36028-x_6] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The vasculature is the first organ to arise during development. Blood vessels run through virtually every organ in the body (except the avascular cornea and the cartilage), assuring metabolic homeostasis by supplying oxygen and nutrients and removing waste products. Not surprisingly therefore, vessels are critical for organ growth in the embryo and for repair of wounded tissue in the adult. Notably, however, an imbalance in angiogenesis (the growth of blood vessels) contributes to the pathogenesis of numerous malignant, inflammatory, ischaemic, infectious and immune disorders. During the last two decades, an explosive interest in angiogenesis research has generated the necessary insights to develop the first clinically approved anti-angiogenic agents for cancer and blindness. This novel treatment is likely to change the face of medicine in the next decade, as over 500 million people worldwide are estimated to benefit from pro- or anti-angiogenesis treatment. In this following chapter, we discuss general key angiogenic mechanisms in health and disease, and highlight recent developments and perspectives of anti-angiogenic therapeutic strategies.
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Affiliation(s)
- C Fischer
- Centre for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium
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19
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Ladomery MR, Harper SJ, Bates DO. Alternative splicing in angiogenesis: the vascular endothelial growth factor paradigm. Cancer Lett 2006; 249:133-42. [PMID: 17027147 DOI: 10.1016/j.canlet.2006.08.015] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2006] [Accepted: 08/14/2006] [Indexed: 12/14/2022]
Abstract
Alternative splicing, first discovered in the 1970s, has emerged as one of the key generators of proteomic diversity. Not surprisingly, alternative splicing is increasingly linked to the etiology of cancer. This is illustrated by vascular endothelial growth factor (VEGF), the dominant angiogenic factor. Recently, an antiangiogenic family of VEGF isoforms was discovered, and termed VEGF(xxx)b. VEGF(xxx)b isoforms arise from an alternative 3' splice site in exon 8, and differ by a mere six amino acids at the C-terminus. These alternative six amino acids radically change the functional properties of VEGF. VEGF(xxx)b isoform expression is regulated in human tissues and development, and disregulated in many pathological states including cancer. Understanding what regulates VEGF(xxx)b alternative splicing, and therefore the balance of pro- and antiangiogenic isoforms is of great importance and will be explored in detail over the next few years.
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Affiliation(s)
- Michael R Ladomery
- Centre for Research in Biomedicine, Bristol Genomics Research Institute, Faculty of Applied Sciences, University of the West of England, Coldharbour Lane, Bristol BS16 1QY, UK.
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Wu Q, Du Y, Yang N, Liang Y, Li Y. Microvasculature change and placenta growth factor expression in the early stage of a rat remnant kidney model. Am J Nephrol 2006; 26:97-104. [PMID: 16543713 DOI: 10.1159/000092032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2005] [Accepted: 02/13/2006] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIM There is significant loss of microvasculature and impaired angiogenesis in rat remnant kidney (RK). Placenta growth factor (PlGF) is a potential angiogenic growth factor. In this study, we investigate the changes of microvasculature and expression of PlGF in the first 4 weeks of the early stage of a rat RK model. METHOD RK was induced by right nephrectomy and ligation of two of the three branches of the left renal arteries (equivalent to 5/6 subtotal nephrectomy). Blood urea nitrogen (BUN), serum creatinine (Scr), and blood pressure (BP) were measured. Proliferation of endothelial cells was identified by double staining of two antibodies, anti-rat endothelial cell (RECA-1) and antiproliferating cell nuclear antigen (PCNA). RT-PCR and Western blot were used for PlGF analysis. RESULTS BUN, Scr and BP remained stable after rising within the first week. An angiogenic response occurred in RKs, with an increase in the proliferation of peritubular and glomerular endothelial cells. Both PlGF protein and mRNA expression were significantly upregulated 2- to 3-fold in RK at week 1 and week 2, compared to the sham-operated group (p < 0.05). CONCLUSION The expression of PlGF is upregulated and coincident with an early angiogenic response in rat RK, suggesting that PlGF may be involved in angiogenesis in progressive renal injury.
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Affiliation(s)
- Qingqing Wu
- Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou China
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21
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Silva EA, Mooney DJ. Synthetic extracellular matrices for tissue engineering and regeneration. Curr Top Dev Biol 2005; 64:181-205. [PMID: 15563948 DOI: 10.1016/s0070-2153(04)64008-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The need for replacement tissues or organs requires a tissue supply that cannot be satisfied by the donor supply. The tissue engineering and regeneration field is focused on the development of biological tissue and organ substitutes and may provide functional tissues to restore, maintain, or improve tissue formation. This field is already providing new therapeutic options to bypass the limitations of organ?tissue transplantation and will likely increase in medical importance in the future. This interdisciplinary field accommodates principles of life sciences and engineering and encompasses three major strategies. The first, guided tissue regeneration, relies on synthetic matrices that are conductive to host cells populating a tissue defect site and reforming the lost tissue. The second approach, inductive strategy, involves the delivery of growth factors, typically using drug delivery strategies, which are targeted to specific cell populations in the tissues surrounding the tissue defect. In the third approach, specific cell populations, typically multiplied in culture, are directly delivered to the site at which one desires to create a new tissue or organ. In all of these approaches, the knowledge acquired from developmental studies often serves as a template for the tissue engineering approach for a specific tissue or organ. This article overviews the development of synthetic extracellular matrices (ECMs) for use in tissue engineering that aim to mimic functions of the native ECM of developing and regenerating tissues. In addition to the potential therapeutic uses of these materials, they also provide model systems for basic studies that may shed light on developmental processes.
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Affiliation(s)
- Eduardo A Silva
- Division of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA
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22
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Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 2004; 105:1383-95. [PMID: 15471951 DOI: 10.1182/blood-2004-07-2909] [Citation(s) in RCA: 242] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Besides its role as an essential regulator of physiologic and pathologic angiogenesis, vascular endothelial growth factor (VEGF) triggers growth, survival, and migration of leukemia and multiple myeloma cells; plays a pivotal role in hematopoiesis; inhibits maturation of dendritic cells; and increases osteoclastic bone-resorbing activity as well as osteoclast chemotaxis. Dysregulation of VEGF expression and signaling pathways therefore plays an important role in the pathogenesis and clinical features of hematologic malignancies, in particular multiple myeloma. Direct and indirect targeting of VEGF and its receptors therefore may provide a potent novel therapeutic approach to overcome resistance to therapies and thereby improve patient outcome.
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Affiliation(s)
- Klaus Podar
- Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Boston, MA 02115, USA
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23
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Luttun A, Autiero M, Tjwa M, Carmeliet P. Genetic dissection of tumor angiogenesis: are PlGF and VEGFR-1 novel anti-cancer targets? Biochim Biophys Acta Rev Cancer 2004; 1654:79-94. [PMID: 14984769 DOI: 10.1016/j.bbcan.2003.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2003] [Revised: 09/19/2003] [Accepted: 09/19/2003] [Indexed: 02/06/2023]
Abstract
Many proliferative diseases, most typically cancer, are driven by uncontrolled blood vessel growth. Genetic studies have been very helpful in unraveling the cellular and molecular players in pathological blood vessel formation and have provided opportunities to reduce tumor growth and metastasis. The fact that tumor vessels and normal blood vessels have distinct properties may help in designing more specific--and therefore safer--anti-angiogenic strategies. Such strategies may interfere with angiogenesis at the cellular or molecular level. Possible molecular targets include angiogenic growth factors and their receptors, proteinases, coagulation factors, junctional/adhesion molecules and extracellular matrix (ECM) components. Some anti-angiogenic drugs, i.e., vascular endothelial growth factor (VEGF) antibodies and VEGF receptor-2 (VEGFR-2) inhibitors, have progressed into clinical cancer trials. While the results of these trials support the potential of anti-angiogenic therapy to treat cancer, they also demonstrate the need for more effective and safer alternatives. Targeting placental growth factor (PlGF) or VEGFR-1 may constitute such an alternative since animal studies have proven their pleiotropic working mechanism and attractive safety profile. Together, these insights may bring anti-angiogenic drugs closer from bench to bedside.
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Affiliation(s)
- Aernout Luttun
- The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
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24
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Abstract
Blood vessels nourish organs with vital nutrients and oxygen and, thus, new vessels form when the embryo needs to grow or wounds are to heal. However, forming new blood vessels is a complex and delicate process, which, unfortunately, is often derailed. Thus, when insufficient vessels form, the tissue becomes ischaemic and stops to function adequately. Conversely, when vessels grow excessively, malignant and inflamed tissues grow faster. It is now becoming increasingly evident that abnormal vessel growth contributes to the pathogenesis of numerous malignant, ischaemic, inflammatory, infectious and immune disorders. With an in-depth molecular understanding, we should be better armamented to combat such angiogenic disorders in the future. That such therapeutic strategies might change the face of medicine is witnessed by initial evidence of success in the clinic.
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Affiliation(s)
- Peter Carmeliet
- Center for Transgene Technology and Gene Therapy, Flanders Interuniversitary Institute for Biotechnology, KU Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
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25
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Goerges AL, Nugent MA. pH Regulates Vascular Endothelial Growth Factor Binding to Fibronectin. J Biol Chem 2004; 279:2307-15. [PMID: 14570917 DOI: 10.1074/jbc.m308482200] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Hypoxia is one of the major signals that induces angiogenesis. Hypoxic conditions lead to reduced extracellular pH. Vascular endothelial growth factor (VEGF) binding to endothelial cells and the extracellular matrix (ECM) increases at acidic pH (7.0-5.5). These interactions are dependent on heparan sulfate proteoglycans, but do not depend on the presence of VEGF receptors. Here we report that VEGF(165) and VEGF(121) binding to fibronectin also increased at acidic pH, and that these interactions are further enhanced by the addition of heparin. These results reveal that the accepted non-heparin-binding isoform of VEGF (VEGF(121)) is converted into a heparin-binding growth factor under acidic conditions. Interestingly, we did not observe increased binding of VEGF to collagen type I at acidic pH in the presence or absence of heparin, indicating that this effect is not a general property of all heparin-binding ECM proteins. The high level of VEGF binding at acidic pH was also rapidly reversed as demonstrated by increased rates of VEGF dissociation from fibronectin and fibronectin-heparin matrices as the pH was raised. The VEGF released from fibronectin retained its ability to stimulate the activation of extracellular-regulated kinase 1/2 in endothelial cells. These results suggest that VEGF may be stored in the extracellular matrix via interactions with fibronectin and heparan sulfate in tissues that are in need of vascularization so that it can aid in directing the dynamic process of growth and migration of new blood vessels.
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Affiliation(s)
- Adrienne L Goerges
- Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
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26
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Abstract
Angiogenesis is a term that describes the formation of new capillaries from a pre-existing vasculature. This process is very important in physiologic conditions because it helps healing injured tissues, and in female populations it helps forming the placenta after fertilization and reconstructs the inside layer of the uterus after menstruation. Angiogenesis is the result of an intricate balance between proangiogenic and antiangiogenic factors and is now very well recognized as a powerful control point in tumor development. In this particular environment, the fine modulation among proangiogenic and antiangiogenic factors is disrupted, leading to inappropriate vessels growth. In this review, we discuss the molecular basis of angiogenesis during tumor growth and we also illustrate some of the molecules that are involved in this angiogenic switch.
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Affiliation(s)
- Tiziana Tonini
- Department of Biotechnology, Temple University, Philadelphia, PA 19122, USA
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27
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Abstract
Both blood vessels and nerves are vital channels to and from tissues. Recent genetic insights show that they have much more in common than was originally anticipated. They use similar signals and principles to differentiate, grow and navigate towards their targets. Moreover, the vascular and nervous systems cross-talk and, when dysregulated, this contributes to medically important diseases. The realization that both systems use common genetic pathways should not only form links between vascular biology and neuroscience, but also promises to accelerate the discovery of new mechanistic insights and therapeutic opportunities.
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Affiliation(s)
- Peter Carmeliet
- Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium.
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28
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Pralhad T, Madhusudan S, Rajendrakumar K. Concept, mechanisms and therapeutics of angiogenesis in cancer and other diseases. J Pharm Pharmacol 2003; 55:1045-53. [PMID: 12956893 DOI: 10.1211/0022357021819] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Angiogenesis supports normal physiology as well as contributing to the progression of various diseases including cancer. Determination of the key role of angiogenesis in cancer has led to much optimism for the development of targeted drugs without cytotoxic side-effects. Currently, research in angiogenesis therapy is robust, with the discovery of a growing number of pro- and anti-angiogenic molecules. More time, however, is required to be able to elucidate the complex interactions among these molecules, how they affect vasculature and their functions in different environments. As we learn more about the molecular mechanisms of angiogenesis, a number of effective methods to treat cancer and other diseases will be developed.
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Affiliation(s)
- Tayade Pralhad
- Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai-400 098, India.
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29
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Wasserman SM, Mehraban F, Komuves LG, Yang RB, Tomlinson JE, Zhang Y, Spriggs F, Topper JN. Gene expression profile of human endothelial cells exposed to sustained fluid shear stress. Physiol Genomics 2002; 12:13-23. [PMID: 12419857 DOI: 10.1152/physiolgenomics.00102.2002] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Biomechanical forces can modulate endothelial phenotype through changes in gene expression. We hypothesized that physiological laminar shear stresses (LSS) act as differentiative stimuli on endothelial cells (EC) to alter gene expression, creating an antioxidant, anti-apoptotic and anti-proliferative environment. The transcriptional profile of cultured human umbilical vein endothelial cells (HUVEC) exposed to LSS was evaluated by GeneCalling; 107 genes demonstrated at least a twofold change in expression at 24 h (LSS vs. static). These flow-responsive genes represent a limited number of functional clusters that include transcription factors, antioxidants, signaling molecules, cell cycle regulators, and genes involved in cellular differentiation. Immunohistochemistry and in situ hybridization confirmed that many of these flow-responsive genes, including the novel basic helix-loop-helix transcription factor Hath6, are expressed in EC in vivo. Thus these data identify a limited set of flow-responsive genes expressed in the endothelium that may be responsible for the establishment and maintenance of the flow-adapted endothelial phenotype in vivo.
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30
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Gururaj AE, Belakavadi M, Venkatesh DA, Marmé D, Salimath BP. Molecular mechanisms of anti-angiogenic effect of curcumin. Biochem Biophys Res Commun 2002; 297:934-42. [PMID: 12359244 DOI: 10.1016/s0006-291x(02)02306-9] [Citation(s) in RCA: 193] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Modulation of pathological angiogenesis by curcumin (diferuloylmethane), the active principle of turmeric, seems to be an important possibility meriting mechanistic investigations. In this report, we have studied the effect of curcumin on the growth of Ehrlich ascites tumor cells and endothelial cells in vitro. Further, regulation of tumor angiogenesis by modulation of angiogenic ligands and their receptor gene expression in tumor and endothelial cells, respectively, by curcumin was investigated. Curcumin, when injected intraperitoneally (i.p) into mice, effectively decreased the formation of ascites fluid by 66% in EAT bearing mice in vivo. Reduction in the number of EAT cells and human umbelical vein endothelial cells (HUVECs) in vitro by curcumin, without being cytotoxic to these cells, is attributed to induction of apoptosis by curcumin, as is evident by an increase in cells with fractional DNA content seen in our results on FACS analysis. However, curcumin had no effect on the growth of NIH3T3 cells. Curcumin proved to be a potent angioinhibitory compound, as demonstrated by inhibition of angiogenesis in two in vivo angiogenesis assay systems, viz. peritoneal angiogenesis and chorioallantoic membrane assay. The angioinhibitory effect of curcumin in vivo was corroborated by the results on down-regulation of the expression of proangiogenic genes, in EAT, NIH3T3, and endothelial cells by curcumin. Our results on Northern blot analysis clearly indicated a time-dependent (0-24h) inhibition by curcumin of VEGF, angiopoietin 1 and 2 gene expression in EAT cells, VEGF and angiopoietin 1 gene expression in NIH3T3 cells, and KDR gene expression in HUVECs. Further, decreased VEGF levels in conditioned media from cells treated with various doses of curcumin (1 microM-1mM) for various time periods (0-24h) confirm its angioinhibitory action at the level of gene expression. Because of its non-toxic nature, curcumin could be further developed to treat chronic diseases that are associated with extensive neovascularization.
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Affiliation(s)
- Anupama E Gururaj
- Department of Applied Botany and Biotechnology, University of Mysore, Mysore 570 006, India
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31
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Abstract
Ovarian cancer claims the lives of more women in North America each year than all other gynecologic malignancies combined. Despite the high initial response rates of patients with advanced ovarian cancer to aggressive primary surgical debulking followed by combination chemotherapy, the majority of patients will ultimately develop disease recurrence. The high risk of relapse and nearly guaranteed incurability after relapse is due to genetic instability and a high mutation rate of neoplastic cells that together allow for a high risk of selection for drug resistance. Given the seemingly insurmountable obstacle that acquired drug resistance presents in a setting of minimal, often undetectable, residual tumor burden in women with ovarian cancer, antiangiogenic-targeted therapies offer an attractive strategy for enhanced long-term disease-free survival. The past decade has witnessed a substantial proliferation in our knowledge regarding tumor angiogenesis, which has spurred interest in antiangiogenesis drug development. Current clinical trials are evaluating these agents in a variety of solid tumors, including ovarian cancer. Preliminary work has provided hope that the addition of antiangiogenic therapies may be incorporated into the treatment of women afflicted with ovarian cancer and may translate into enhanced survival.
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Affiliation(s)
- Pamela J Paley
- Department of Obstetrics and Gynecology, University of Washington School of Medicine, Box 356460, Seattle, WA 98195, USA.
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32
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Abstract
Research into areas as divergent as hemangiopoiesis and cardiogenesis as well as investigations of diseases such as cancer and diabetic retinopathy have converged to form the face of research in vascular development today. This convergence of disparate topics has resulted in rapid advances in many areas of vascular research. The focus of this review has been the role of cell-cell interactions in the development of the vascular system, but we have included discussions of pathology where the mechanism of disease progression may have parallels with developmental processes. A number of intriguing questions remain unanswered. For example, what triggers abnormal angiogenesis in the disease state? Are the mechanisms similar to those that control developmental neovascularization? Perhaps the difference in development in angiogenesis versus in disease is context driven, that is, an adult versus an embryonic organism. If this is the case, can the controls that curtail developmental vessel formation be applied in pathologies? Can cell-cell interactions be targeted as a control point for new vessel formation? For instance, can perivascular cells be stimulated or eliminated to result in increased vessel stability or instability, respectively? If the hypothesis that mural cell association is required for vessel stabilization is accurate, are there mechanisms to promote or inhibit mural cell recruitment and differentiation as needed? These and other questions lie in wait for the next generation of approaches to discern the mechanisms and the nature of the cell-cell interactions and the influence of the microenvironment on vascular development.
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Affiliation(s)
- D C Darland
- Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA
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33
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Couffinhal T, Dufourcq P, Daret D, Duplaà C. [The mechanisms of angiogenesis. Medical and therapeutic applications]. Rev Med Interne 2001; 22:1064-82. [PMID: 11817119 DOI: 10.1016/s0248-8663(01)00472-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE Endothelial and smooth muscle cells interact with each other to form new blood vessels. In this review, the cellular and molecular mechanism underlying the formation of the primary vascular plexus (vasculogenesis), the sprouting of further blood vessels (angiogenesis) and their maturation via recruitment of smooth muscle cells (arteriogenesis) during physiological and pathological conditions are summarized. CURRENT KNOWLEDGE AND KEY POINT The concept of angiogenesis is studied in tumoral and cardiovascular pathology. Promoting the formation of new collateral vessels in ischemic tissues using angiogenic growth factors (therapeutic angiogenesis) is a promising approach in cardiovascular diseases. Conversely, inhibition of the action of key regulators of angiogenesis is a new pathway for the treatment of solid tumors and metastasis. FUTURE PROSPECTS AND PROJECTS These concepts are being tested now in clinical trials in the oncology or cardiovascular fields. Some trials are reported in this review with their potential adverse effects, limits and developments in the future.
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Affiliation(s)
- T Couffinhal
- Service de cardiologie et de maladies vasculaires, hôpital cardiologique, avenue de Magellan, 33604 Pessac, France.
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Moser TL, Kenan DJ, Ashley TA, Roy JA, Goodman MD, Misra UK, Cheek DJ, Pizzo SV. Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci U S A 2001; 98:6656-61. [PMID: 11381144 PMCID: PMC34409 DOI: 10.1073/pnas.131067798] [Citation(s) in RCA: 245] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2001] [Indexed: 12/22/2022] Open
Abstract
Angiostatin blocks tumor angiogenesis in vivo, almost certainly through its demonstrated ability to block endothelial cell migration and proliferation. Although the mechanism of angiostatin action remains unknown, identification of F(1)-F(O) ATP synthase as the major angiostatin-binding site on the endothelial cell surface suggests that ATP metabolism may play a role in the angiostatin response. Previous studies noting the presence of F(1) ATP synthase subunits on endothelial cells and certain cancer cells did not determine whether this enzyme was functional in ATP synthesis. We now demonstrate that all components of the F(1) ATP synthase catalytic core are present on the endothelial cell surface, where they colocalize into discrete punctate structures. The surface-associated enzyme is active in ATP synthesis as shown by dual-label TLC and bioluminescence assays. Both ATP synthase and ATPase activities of the enzyme are inhibited by angiostatin as well as by antibodies directed against the alpha- and beta-subunits of ATP synthase in cell-based and biochemical assays. Our data suggest that angiostatin inhibits vascularization by suppression of endothelial-surface ATP metabolism, which, in turn, may regulate vascular physiology by established mechanisms. We now have shown that antibodies directed against subunits of ATP synthase exhibit endothelial cell-inhibitory activities comparable to that of angiostatin, indicating that these antibodies function as angiostatin mimetics.
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Affiliation(s)
- T L Moser
- Department of Pathology and Duke University School of Nursing, Duke University Medical Center, Durham, NC 27710, USA
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35
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Abstract
Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials. The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated. This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases. But owing to several unanswered questions, caution is needed.
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Affiliation(s)
- P Carmeliet
- The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium.
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36
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Abstract
Endothelial and smooth muscle cells interact with each other to form new blood vessels. In this review, the cellular and molecular mechanisms underlying the formation of endothelium-lined channels (angiogenesis) and their maturation via recruitment of smooth muscle cells (arteriogenesis) during physiological and pathological conditions are summarized, alongside with possible therapeutic applications.
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Affiliation(s)
- P Carmeliet
- The Center for Transgene Technology and Gene Therapy Flanders Interuniversity Institute for Biotechnology KU Leuven, Leuven, B-3000, Belgium.
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37
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Zhong TP, Rosenberg M, Mohideen MA, Weinstein B, Fishman MC. gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science 2000; 287:1820-4. [PMID: 10710309 DOI: 10.1126/science.287.5459.1820] [Citation(s) in RCA: 295] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The first artery and vein of the vertebrate embryo assemble in the trunk by migration and coalescence of angioblasts to form endothelial tubes. The gridlock (grl) mutation in zebrafish selectively perturbs assembly of the artery (the aorta). Here it is shown that grl encodes a basic helix-loop-helix (bHLH) protein belonging to the Hairy/Enhancer of the split family of bHLH proteins. The grl gene is expressed in lateral plate mesoderm before vessel formation, and thereafter in the aorta and not in the vein. These results suggest that the arterial endothelial identity is established even before the onset of blood flow and implicate the grl gene in assignment of vessel-specific cell fate.
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Affiliation(s)
- T P Zhong
- Cardiovascular Research Center, Massachusetts General Hospital-Harvard Medical School, 149 13th Street, 4th floor, Charlestown, MA 02129, USA
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