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Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct Target Ther 2025; 10:170. [PMID: 40383803 PMCID: PMC12086256 DOI: 10.1038/s41392-025-02249-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/09/2025] [Accepted: 04/21/2025] [Indexed: 05/20/2025] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.
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Affiliation(s)
- Chunsik Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea.
| | - Myung-Jin Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea
| | - Anil Kumar
- Center for Research and Innovations, Adichunchanagiri University, Mandya, Karnataka, India
| | - Han-Woong Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yonghwan Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea.
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Zinellu A, Mangoni AA. Vascular endothelial growth factor as a potential biomarker in systemic sclerosis: a systematic review and meta-analysis. Front Immunol 2024; 15:1442913. [PMID: 39669565 PMCID: PMC11634811 DOI: 10.3389/fimmu.2024.1442913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 11/12/2024] [Indexed: 12/14/2024] Open
Abstract
Introduction Systemic sclerosis (SSc), a chronic autoimmune condition, is characterized by microvascular dysfunction, ineffective angiogenesis, and fibrosis. The identification of robust biomarkers reflecting these processes may assist in clinical management and lead to the discovery of new therapies. We sought to address this issue by conducting a systematic review and meta-analysis of studies investigating one such biomarker, vascular endothelial growth factor (VEGF), in SSc patients and healthy controls and in SSc patients with localized or diffuse disease, different video capillaroscopy patterns (early, active, or late), and presence or absence of complications. Methods We searched PubMed, Scopus, and Web of Science from inception to 15 May 2024. We assessed the risk of bias and the certainty of evidence using the JBI checklist for analytical studies and GRADE, respectively. Results In 42 eligible studies, compared to controls, patients with SSc had significantly higher plasma or serum VEGF concentrations (standard mean difference, SMD=0.93, 95% CI 0.71 to 1.15, p<0.001; moderate certainty). In further analyses, VEGF concentrations were significantly higher in SSc patients with diffused disease than those with localized disease (SMD=0.30, 95% CI 0.01 to 0.59, p=0.046; very low certainty), in patients with late vs. active video capillaroscopy pattern (SMD=0.35, 95% CI 0.09 to 0.61, p=0.008; very low certainty), and in patients with pulmonary hypertension than those without (SMD=0.93, 95% CI 0.34 to 1.53, p=0.002; very low certainty). By contrast, no significant differences were observed between SSc patients with and without digital ulcers, interstitial lung disease, and telangiectasias, whereas limited evidence was available for alveolitis. Meta-regression and subgroup analysis of studies investigating VEGF in SSc patients and controls showed no significant associations between the effects size and various patient and study characteristics, including SSc duration and use of corticosteroids, immunosuppressors and vasodilators. By contrast, significant associations were observed with the geographical location where the study was conducted. Discussion The results of this systematic review and meta-analysis suggest that VEGF can be useful in the assessment and management of SSc and in the identification of novel therapeutic strategies in this patient group. Systematic Review Registration https://www.crd.york.ac.uk/prospero, identifier CRD42024552925.
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Affiliation(s)
- Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Arduino A. Mangoni
- Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
- Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Bedford Park, SA, Australia
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Wazan LE, Widhibrata A, Liu GS. Soluble FLT-1 in angiogenesis: pathophysiological roles and therapeutic implications. Angiogenesis 2024; 27:641-661. [PMID: 39207600 DOI: 10.1007/s10456-024-09942-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
Fine-tuning angiogenesis, the development of new blood vessels, is essential for maintaining a healthy circulatory and lymphatic system. The small glycoprotein vascular endothelial growth factors (VEGF) are the key mediators in this process, binding to their corresponding membrane-bound VEGF receptors (VEGFRs) to activate angiogenesis signaling pathways. These pathways are crucial throughout human life as they are involved in lymphatic and vascular endothelial cell permeability, migration, proliferation, and survival. Neovascularization, the formation of abnormal blood vessels, occurs when there is a dysregulation of angiogenesis and can result in debilitating disease. Hence, VEGFRs have been widely studied to understand their role in disease-causing angiogenesis. VEGFR1, also known as Fms-like tyrosine kinase-1 (FLT-1), is also found in a soluble form, soluble FLT-1 or sFLT-1, which is known to act as a VEGF neutralizer. It is incorporated into anti-VEGF therapy, designed to treat diseases caused by neovascularization. Here we review the journey of sFLT-1 discovery and delve into the alternative splicing mechanism that creates the soluble receptor, its prevalence in disease states, and its use in current and future potential therapies.
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Affiliation(s)
- Layal Ei Wazan
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Level 7, 32 Gisborne Street, East Melbourne, VIC, 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia
| | - Ariel Widhibrata
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Level 7, 32 Gisborne Street, East Melbourne, VIC, 3002, Australia
| | - Guei-Sheung Liu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Level 7, 32 Gisborne Street, East Melbourne, VIC, 3002, Australia.
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia.
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
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Dumitru CS, Raica M. A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition. Int J Mol Sci 2024; 25:8855. [PMID: 39201541 PMCID: PMC11354464 DOI: 10.3390/ijms25168855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/10/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Angiogenesis, primarily mediated by vascular endothelial growth factor (VEGF), is a fundamental step in the progression and metastasis of head and neck squamous cell carcinoma (HNSCC). Traditional anti-angiogenic therapies that target the VEGF pathway have shown promise but are often associated with significant side effects and variable efficacy due to the complexity of the angiogenic signaling pathway. This review highlights the potential of a specific VEGF splice form, VEGF165b, as an innovative therapeutic target for HNSCC. VEGF165b, unlike standard VEGF, is a natural inhibitor that binds to VEGF receptors without triggering pro-angiogenic signaling. Its distinct molecular structure and behavior suggest ways to modulate angiogenesis. This concept is particularly relevant when studying HNSCC, as introducing VEGF165b's anti-angiogenic properties offers a novel approach to understanding and potentially influencing the disease's dynamics. The review synthesizes experimental evidence suggesting the efficacy of VEGF165b in inhibiting tumor-induced angiogenesis and provides insight into a novel therapeutic strategy that could better manage HNSCC by selectively targeting aberrant vascular growth. This approach not only provides a potential pathway for more targeted and effective treatment options but also opens the door to a new paradigm in anti-angiogenic therapy with the possibility of reduced systemic toxicity. Our investigation is reshaping the future of HNSCC treatment by setting the stage for future research on VEGF splice variants as a tool for personalized medicine.
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Affiliation(s)
- Cristina Stefania Dumitru
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
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Xue J, Deng J, Qin H, Yan S, Zhao Z, Qin L, Liu J, Wang H. The interaction of platelet-related factors with tumor cells promotes tumor metastasis. J Transl Med 2024; 22:371. [PMID: 38637802 PMCID: PMC11025228 DOI: 10.1186/s12967-024-05126-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 03/22/2024] [Indexed: 04/20/2024] Open
Abstract
Platelets not only participate in thrombosis and hemostasis but also interact with tumor cells and protect them from mechanical damage caused by hemodynamic shear stress and natural killer cell lysis, thereby promoting their colonization and metastasis to distant organs. Platelets can affect the tumor microenvironment via interactions between platelet-related factors and tumor cells. Metastasis is a key event in cancer-related death and is associated with platelet-related factors in lung, breast, and colorectal cancers. Although the factors that promote platelet expression vary slightly in terms of their type and mode of action, they all contribute to the overall process. Recognizing the correlation and mechanisms between these factors is crucial for studying the colonization of distant target organs and developing targeted therapies for these three types of tumors. This paper reviews studies on major platelet-related factors closely associated with metastasis in lung, breast, and colorectal cancers.
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Affiliation(s)
- Jie Xue
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, China
- Department of Blood Transfusion, The Central Hospital of Qingdao Jiaozhou, 99 Yunxi River South Road, Qingdao, 266300, Shandong, China
| | - Jianzhao Deng
- Clinical Laboratory, The Central Hospital of Qingdao Jiaozhou, 99 Yunxi River South Road, Qingdao, 266300, Shandong, China
| | - Hongwei Qin
- Department of Blood Transfusion, The Central Hospital of Qingdao Jiaozhou, 99 Yunxi River South Road, Qingdao, 266300, Shandong, China
| | - Songxia Yan
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, China
| | - Zhen Zhao
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, China
| | - Lifeng Qin
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, China
| | - Jiao Liu
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, China
| | - Haiyan Wang
- Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Shinan District, Qingdao, 266000, Shandong, China.
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Gudenschwager-Basso EK, Frydman G, Weerakoon S, Andargachew H, Piltaver CM, Huckle WR. Morphological evaluation of the feline placenta correlates with gene expression of vascular growth factors and receptors†. Biol Reprod 2024; 110:569-582. [PMID: 38092011 DOI: 10.1093/biolre/ioad167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 09/06/2023] [Accepted: 11/30/2023] [Indexed: 03/16/2024] Open
Abstract
Placental angiogenesis is critical for normal development. Angiogenic factors and their receptors are key regulators of this process. Dysregulated placental vascular development is associated with pregnancy complications. Despite their importance, vascular growth factor expression has not been thoroughly correlated with placental morphologic development across gestation in cats. We postulate that changes in placental vessel morphology can be appreciated as consequences of dynamic expression of angiogenic signaling agents. Here, we characterized changes in placental morphology alongside expression analysis of angiogenic factor splice variants and receptors throughout pregnancy in domestic shorthair cats. We observed increased vascular and lamellar density in the lamellar zone during mid-pregnancy. Immunohistochemical analysis localized the vascular endothelial growth factor A (VEGF-A) receptor KDR to endothelial cells of the maternal and fetal microvasculatures. PlGF and its principal receptor Flt-1 were localized to the trophoblasts and fetal vasculature. VEGF-A was found in trophoblast cells and associated with endothelial cells. We detected expression of two Plgf splice variants and four Vegf-a variants. Quantitative real-time polymerase chain reaction analysis showed upregulation of mRNAs encoding pan Vegf-a and all Vegf-a splice forms at gestational days 30-35. Vegf-A showed a marked relative increase in expression during mid-pregnancy, consistent with the pro-angiogenic changes seen in the lamellar zone at days 30-35. Flt-1 was upregulated during late pregnancy. Plgf variants showed stable expression during the first two-thirds of pregnancy, followed by a marked increase toward term. These findings revealed specific spatiotemporal expression patterns of VEGF-A family members consistent with pivotal roles during normal placental development.
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Affiliation(s)
- Erwin K Gudenschwager-Basso
- Department of Biomedical Sciences & Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Galit Frydman
- Department of Biomedical Sciences & Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Shaneke Weerakoon
- Department of Biomedical Sciences & Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
- Virginia Tech Carilion School of Medicine, Virginia Tech, Blacksburg, VA, USA
| | - Hariyat Andargachew
- Department of Biomedical Sciences & Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Cassandra M Piltaver
- Department of Biomedical Sciences & Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - William R Huckle
- Department of Biomedical Sciences & Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA
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Ahmed I, John P, Bhatti A. Association analysis of Vascular Endothelial Growth Factor-A (VEGF-A) polymorphism in rheumatoid arthritis using computational approaches. Sci Rep 2023; 13:21957. [PMID: 38081836 PMCID: PMC10713577 DOI: 10.1038/s41598-023-47780-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023] Open
Abstract
Rheumatoid arthritis (RA), is marked by joint inflammation leading to pannus formation which results in cartilage destruction promoting bone erosion. The pathological hallmark of RA includes synovial hyperplasia and synovial angiogenesis. Active tissue neovascularization is observed in RA. Vascular endothelial Growth factor A (VEGFA), an endothelial cell-specific proangiogenic molecule is triggered by hypoxic cells and its levels are upregulated in RA. The aim of this study was to investigate functional and pathogenic VEGFA variants and to identify the impact of point mutation in VEGFA's interaction with VEGFR2 and how these polymorphisms affect the susceptibility and severity of RA. We investigated impact of these point mutations on the stability of VEGFA using various computational tools. These mutations were further identified by conservational profile as they are highly involved as structural and functional mutations. Furthermore, these selected variants were modelled and docked against targeted domain regions IGD2 and IGD3 of VEGFR2. Further molecular dynamic simulations were performed using Gromacs. Out of 168 nsSNPS, 19 were highlighted as highly pathogenic using insilico prediction tools. InterPro and ConSurf revealed domains and conserved variants respectively. After stability analysis, we concluded that almost all the mutations were responsible for decreasing the protein stability. HOPE predicted that all the selected damaging nsSNPs were present in the domain which is essential for the functioning of VEGFA protein. Constructed Ramachandran plot and ERRAT validated the quality of all the models. Based on the interactions predicted by STRING database, we performed Protein-Protein docking between VEGFA and VEGFR2. We found few conserved interactions and new polar contacts among wild-type and mutants with VEGFR2. From the simulations, we concluded that mutant R108Q was the most stabilizing mutant among all others whereas R82Q, C86Y, and R108W complexed with VEGFR2 were comparatively less stabilizing as compared to the wild type. This study provides insight into pathogenic nsSNPs that can affect VEGFA protein structure and function. These high-risk variants must be taken into consideration for genetic screening of patients suffering from RA.
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Affiliation(s)
- Iraj Ahmed
- Atta-Ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Peter John
- Faculty of Applied Biosciences, ASAB, NUST, Islamabad, Pakistan.
| | - Attya Bhatti
- Faculty of Applied Biosciences, ASAB, NUST, Islamabad, Pakistan
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Dimtsas GS, Tsiogka A, Moschos MM. VEGF levels in the aqueous humor of patients with primary open angle glaucoma: A systematic review and a meta-analysis. Eur J Ophthalmol 2023; 33:2228-2235. [PMID: 37038334 DOI: 10.1177/11206721231168146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
PURPOSE To compare the VEGF levels in the aqueous humor of patients with Primary Open Angle Glaucoma (POAG) and non-glaucomatous eyes and reveal any potential statistically significant correlations. METHODS We searched PubMed, from inception to December 31, 2021. Key search terms included VEGF and Glaucoma. All relevant studies that evaluated the VEGF levels in patients with POAG and in the control group were included in this systematic review. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines were followed. Data were extracted independently by 2 authors. Heterogeneity was statistically quantified by Q, H, and I2 statistics, and a meta-analysis was performed using the random-effects model. RESULTS Seven cross-sectional studies were included in the meta-analysis. 144 eyes were enrolled in the POAG group and 162 eyes in the control group. The random effect model showed no statistically significant difference between the two groups (SMD =0.284, 95% CI = -0.173 to 0.741; P = 0.223), but we noticed a trend towards elevated VEGF levels in the aqueous humor of POAG patients. Significant heterogeneity was detected (I2 = 74.1%, P = 0.001). CONCLUSIONS This systematic review and meta-analysis indicates a trend towards elevated VEGF-A levels in the aqueous humor of patients with POAG and suggests a potential neuroprotective role of VEGF in patients with POAG. Future studies are required to evaluate the exact role of VEGF in POAG.
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Affiliation(s)
- Georgios S Dimtsas
- 1st Department of Ophthalmology, National and Kapodistrian University of Athens, "G. Gennimatas" General Hospital, Athens, Greece
| | - Anastasia Tsiogka
- 1st Department of Ophthalmology, National and Kapodistrian University of Athens, "G. Gennimatas" General Hospital, Athens, Greece
| | - Marilita M Moschos
- 1st Department of Ophthalmology, National and Kapodistrian University of Athens, "G. Gennimatas" General Hospital, Athens, Greece
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Li M, Wang YN, Wang L, Meah WY, Shi DC, Heng KK, Wang L, Khor CC, Bei JX, Cheng CY, Aung T, Liao YH, Chen QK, Gu JR, Kong YZ, Lee J, Chong SA, Subramaniam M, Foo JN, Cai FT, Jiang GR, Xu G, Wan JX, Chen MH, Yin PR, Dong XQ, Feng SZ, Tang XQ, Zhong Z, Tan EK, Chen N, Zhang H, Liu ZH, Tai ES, Liu JJ, Yu XQ. Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy. J Am Soc Nephrol 2023; 34:1900-1913. [PMID: 37787447 PMCID: PMC10631603 DOI: 10.1681/asn.0000000000000222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 08/17/2023] [Indexed: 10/04/2023] Open
Abstract
SIGNIFICANCE STATEMENT Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.
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Affiliation(s)
- Ming Li
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Yan-Na Wang
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ling Wang
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Wee-Yang Meah
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Dian-Chun Shi
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Khai-Koon Heng
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Li Wang
- Department of Nephrology, Sichuan Provincial People's Hospital, Chengdu, China
| | - Chiea-Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- Singapore Eye Research Institute, Singapore, Singapore
| | - Jin-Xin Bei
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ching-Yu Cheng
- Singapore Eye Research Institute, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tin Aung
- Singapore Eye Research Institute, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yun-Hua Liao
- Department of Nephrology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Qin-Kai Chen
- Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jie-Ruo Gu
- Department of Rheumatology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yao-Zhong Kong
- Department of Nephrology, The First People's Hospital of Foshan, Foshan, China
| | - Jimmy Lee
- Institute of Mental Health, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | | | | | - Jia-Nee Foo
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Feng-Tao Cai
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Geng-Ru Jiang
- Department of Nephrology, XinHua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Gang Xu
- Department of Nephrology, Tongji Hospital, Tongji Medical College of Huazhong University of science & Technology, Wuhan, China
| | - Jian-Xin Wan
- Department of Nephrology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Meng-Hua Chen
- Department of Nephrology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Pei-Ran Yin
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Xiu-Qing Dong
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Shao-Zhen Feng
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Xue-Qing Tang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Zhong Zhong
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
| | - Eng-King Tan
- Duke-NUS Medical School, Singapore, Singapore
- National Neuroscience Institute, Singapore, Singapore
- Department of Neurology, Singapore General Hospital, Singapore, Singapore
| | - Nan Chen
- Department of Nephrology, RuiJin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Beijing, China
| | - Zhi-Hong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - E. Shyong Tai
- Duke-NUS Medical School, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore
| | - Jian-Jun Liu
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore
| | - Xue-Qing Yu
- Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China
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10
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Pérez-Gutiérrez L, Ferrara N. Biology and therapeutic targeting of vascular endothelial growth factor A. Nat Rev Mol Cell Biol 2023; 24:816-834. [PMID: 37491579 DOI: 10.1038/s41580-023-00631-w] [Citation(s) in RCA: 149] [Impact Index Per Article: 74.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2023] [Indexed: 07/27/2023]
Abstract
The formation of new blood vessels, called angiogenesis, is an essential pathophysiological process in which several families of regulators have been implicated. Among these, vascular endothelial growth factor A (VEGFA; also known as VEGF) and its two tyrosine kinase receptors, VEGFR1 and VEGFR2, represent a key signalling pathway mediating physiological angiogenesis and are also major therapeutic targets. VEGFA is a member of the gene family that includes VEGFB, VEGFC, VEGFD and placental growth factor (PLGF). Three decades after its initial isolation and cloning, VEGFA is arguably the most extensively investigated signalling system in angiogenesis. Although many mediators of angiogenesis have been identified, including members of the FGF family, angiopoietins, TGFβ and sphingosine 1-phosphate, all current FDA-approved anti-angiogenic drugs target the VEGF pathway. Anti-VEGF agents are widely used in oncology and, in combination with chemotherapy or immunotherapy, are now the standard of care in multiple malignancies. Anti-VEGF drugs have also revolutionized the treatment of neovascular eye disorders such as age-related macular degeneration and ischaemic retinal disorders. In this Review, we emphasize the molecular, structural and cellular basis of VEGFA action as well as recent findings illustrating unexpected interactions with other pathways and provocative reports on the role of VEGFA in regenerative medicine. We also discuss clinical and translational aspects of VEGFA. Given the crucial role that VEGFA plays in regulating angiogenesis in health and disease, this molecule is largely the focus of this Review.
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Affiliation(s)
- Lorena Pérez-Gutiérrez
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Napoleone Ferrara
- Department of Pathology, University of California San Diego, La Jolla, CA, USA.
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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11
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Ramezani A, Zareinejad M, Mahmoudi Maymand E, Kaviani E, Ghaderi A. Production of a biosimilar version of aflibercept to improve VEGF blocker cytotoxicity on endothelial cells. Growth Factors 2023:1-12. [PMID: 37377438 DOI: 10.1080/08977194.2023.2227271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 05/08/2023] [Indexed: 06/29/2023]
Abstract
This project aimed to produce a biosimilar version of aflibercept (AFL) and evaluate the effect of the co-treatment of AFL with other vascular endothelial growth factor (VEGF) blocker drugs. For this purpose, the optimized gene was inserted into the pCHO1.0 plasmid and transfected into the CHO-S cell line. The final concentration of biosimilar-AFL for the selected clone was 782 mg/L. Results revealed that the inhibition potential of the biosimilar-AFL on HUVEC cells was significant at 10 and 100 nM concentrations and in a dose-dependent manner. Furthermore, co-treatment of biosimilar-AFL with Everolimus (EVR), Lenvatinib (LEN), and Sorafenib (SOR) could reduce HUVEC cell viability/proliferation, more than when used alone. When LEN and SOR were co-treated with biosimilar-AFL, their cytotoxicity increased 10-fold. The most and least efficient combination was seen when biosimilar-AFL combined with LEN and EVR, respectively. Finally, biosimilar-AFL may improve the efficiency of LEN, EVR, and SOR in reducing the VEGF effect on endothelial cells.
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Affiliation(s)
- Amin Ramezani
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- School of Medicine, Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadrasul Zareinejad
- School of Medicine, Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elham Mahmoudi Maymand
- School of Medicine, Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elina Kaviani
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- School of Medicine, Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- School of Medicine, Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
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12
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Mohan M, Mannan A, Singh TG. Therapeutic implication of Sonic Hedgehog as a potential modulator in ischemic injury. Pharmacol Rep 2023:10.1007/s43440-023-00505-0. [PMID: 37347388 DOI: 10.1007/s43440-023-00505-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/23/2023]
Abstract
Sonic Hedgehog (SHh) is a homology protein that is involved in the modeling and development of embryonic tissues. As SHh plays both protective and harmful roles in ischemia, any disruption in the transduction and regulation of the SHh signaling pathway causes ischemia to worsen. The SHh signal activation occurs when SHh binds to the receptor complex of Ptc-mediated Smoothened (Smo) (Ptc-smo), which initiates the downstream signaling cascade. This article will shed light on how pharmacological modifications to the SHh signaling pathway transduction mechanism alter ischemic conditions via canonical and non-canonical pathways by activating certain downstream signaling cascades with respect to protein kinase pathways, angiogenic cytokines, inflammatory mediators, oxidative parameters, and apoptotic pathways. The canonical pathway includes direct activation of interleukins (ILs), angiogenic cytokines like hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and hypoxia-inducible factor alpha (HIF-), which modulate ischemia. The non-canonical pathway includes indirect activation of certain pathways like mTOR, PI3K/Akt, MAPK, RhoA/ROCK, Wnt/-catenin, NOTCH, Forkhead box protein (FOXF), Toll-like receptors (TLR), oxidative parameters such as GSH, SOD, and CAT, and some apoptotic parameters such as Bcl2. This review provides comprehensive insights that contribute to our knowledge of how SHh impacts the progression and outcomes of ischemic injuries.
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Affiliation(s)
- Maneesh Mohan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
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13
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A review of vascular endothelial growth factor and its potential to improve functional outcomes following spinal cord injury. Spinal Cord 2023; 61:231-237. [PMID: 36879041 DOI: 10.1038/s41393-023-00884-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/16/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023]
Abstract
Spinal cord injuries (SCI) are traumatic events with limited treatment options. Following injury, the lesion site experiences a drastic change to both its structure and vasculature which reduces its ability for tissue regeneration. Despite the lack of clinical options, researchers are investigating therapies to induce neuronal regeneration. Cell-based therapies have long been assessed in the context of SCI to promote neuronal protection and repair. Vascular endothelial growth factor (VEGF) not only demonstrates this ability, but also demonstrates angiogenic potential to promote blood vessel formation. While there have been numerous animal studies investigating VEGF, further research is still warranted to pinpoint its role following SCI. This review aims to discuss the literature surrounding the role of VEGF following SCI and its potential in promoting functional recovery.
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14
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Abstract
Dysregulated RNA splicing is a molecular feature that characterizes almost all tumour types. Cancer-associated splicing alterations arise from both recurrent mutations and altered expression of trans-acting factors governing splicing catalysis and regulation. Cancer-associated splicing dysregulation can promote tumorigenesis via diverse mechanisms, contributing to increased cell proliferation, decreased apoptosis, enhanced migration and metastatic potential, resistance to chemotherapy and evasion of immune surveillance. Recent studies have identified specific cancer-associated isoforms that play critical roles in cancer cell transformation and growth and demonstrated the therapeutic benefits of correcting or otherwise antagonizing such cancer-associated mRNA isoforms. Clinical-grade small molecules that modulate or inhibit RNA splicing have similarly been developed as promising anticancer therapeutics. Here, we review splicing alterations characteristic of cancer cell transcriptomes, dysregulated splicing's contributions to tumour initiation and progression, and existing and emerging approaches for targeting splicing for cancer therapy. Finally, we discuss the outstanding questions and challenges that must be addressed to translate these findings into the clinic.
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Affiliation(s)
- Robert K Bradley
- Computational Biology Program, Public Health Sciences Division and Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
| | - Olga Anczuków
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
- Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA.
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15
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Basu D, Pal R, Sarkar M, Barma S, Halder S, Roy H, Nandi S, Samadder A. To Investigate Growth Factor Receptor Targets and Generate Cancer Targeting Inhibitors. Curr Top Med Chem 2023; 23:2877-2972. [PMID: 38164722 DOI: 10.2174/0115680266261150231110053650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 01/03/2024]
Abstract
Receptor tyrosine kinase (RTK) regulates multiple pathways, including Mitogenactivated protein kinases (MAPKs), PI3/AKT, JAK/STAT pathway, etc. which has a significant role in the progression and metastasis of tumor. As RTK activation regulates numerous essential bodily processes, including cell proliferation and division, RTK dysregulation has been identified in many types of cancers. Targeting RTK is a significant challenge in cancer due to the abnormal upregulation and downregulation of RTK receptors subfamily EGFR, FGFR, PDGFR, VEGFR, and HGFR in the progression of cancer, which is governed by multiple RTK receptor signalling pathways and impacts treatment response and disease progression. In this review, an extensive focus has been carried out on the normal and abnormal signalling pathways of EGFR, FGFR, PDGFR, VEGFR, and HGFR and their association with cancer initiation and progression. These are explored as potential therapeutic cancer targets and therefore, the inhibitors were evaluated alone and merged with additional therapies in clinical trials aimed at combating global cancer.
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Affiliation(s)
- Debroop Basu
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Riya Pal
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, IndiaIndia
| | - Maitrayee Sarkar
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Soubhik Barma
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sumit Halder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Harekrishna Roy
- Nirmala College of Pharmacy, Vijayawada, Guntur, Andhra Pradesh, India
| | - Sisir Nandi
- Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur, 244713, India
| | - Asmita Samadder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
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16
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Kishi H, Komatsu W, Uchiyama K, Takayama H, Udagawa T, Ohhira S, Kobashi G. Vascular endothelial growth factor isoforms are expressed in the uterus during estrous cycle of golden hamsters (Mesocricetus auratus). Anim Sci J 2023; 94:e13804. [PMID: 36617429 DOI: 10.1111/asj.13804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 11/07/2022] [Accepted: 12/09/2022] [Indexed: 01/10/2023]
Abstract
We investigated VEGF expression in the uterus during the estrous cycle in the golden hamster (Mesocricetus auratus). Reverse transcription polymerase chain reaction of genes expressed in the uterus revealed the presence of at least three different VEGF isoforms (hamster VEGF188, VEGF164, and VEGF120). They were highly homologous to the respective mouse and human isoforms. Furthermore, VEGF164 and VEGF120 were predominantly expressed in the hamster uterus during the estrous cycle. In situ hybridization revealed that VEGF is expressed only in the luminal and glandular epithelium of the endometrium but not in the stromal cells or myometrium. The positive reaction of luminal and glandular epithelial cells on day 4 of the estrous cycle (day 1 = day of ovulation) was a little stronger than that of other days of the cycle. These findings suggest that VEGF molecules are secreted by endometrial epithelial cells and play an important role in the maintenance of blood vessels in the endometrial stroma. These results also suggest that uterine changes, such as edema, observed from day 4 to day 1 of the estrous cycle, are expected to occur primarily through the action of VEGF secreted by the uterine endometrial epithelium in preparation for subsequent embryo implantation.
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Affiliation(s)
- Hisashi Kishi
- Department of Public Health, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Wataru Komatsu
- Department of Public Health, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Koji Uchiyama
- Department of Public Health, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Hidehito Takayama
- Department of Public Health, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Tomomi Udagawa
- Department of Public Health, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Shuji Ohhira
- Department of Public Health, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Gen Kobashi
- Department of Public Health, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
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17
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A phase II study to explore biomarkers for the use of mFOLFOX6/XELOX plus bevacizumab as a first-line chemotherapy in patients with metastatic colorectal cancer (WJOG7612GTR). ESMO Open 2022; 7:100592. [PMID: 36502778 PMCID: PMC9808456 DOI: 10.1016/j.esmoop.2022.100592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/07/2022] [Accepted: 08/23/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The purpose of this prospective study was to assess the ability of plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) to predict bevacizumab (BV) efficacy and to explore other circulating biomarkers in metastatic colorectal cancer (mCRC) patients treated with modified FOLFOX6/XELOX plus BV (mFOLFOX6/XELOX + BV). PATIENTS AND METHODS Pre-treatment plasma samples were collected from 100 mCRC patients receiving first-line chemotherapy with mFOLFOX6/XELOX + BV. The plasma levels of 11 angiogenesis-associated molecules, including pVEGF-Asi and 22 cancer-associated gene mutations in circulating tumor DNA, were analyzed. For the primary endpoint, we assumed that the hazard ratio (HR) for progression-free survival (PFS) calculated using a Cox proportional hazards model was <1.15, comparing patients with a high versus those with a low pVEGF-Asi level divided according to the median pVEGF-Asi value. RESULTS The median value of pVEGF-Asi was 37 (range 6.5-262) pg/ml. The HR for PFS between the high and low pVEGF-Asi patient groups was 1.3 [95% confidence interval (CI) 0.8-2.1; log rank, P = 0.25], which was larger than the predefined threshold of 1.15. The multivariate analysis demonstrated that PFS was significantly associated with plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus <190.0 ng/ml; HR 2.1; 95% CI 1.3-3.5), RAS (mutant versus wild; HR 2.5; 95% CI 1.5-4.3), and FBXW7 (mutant versus wild; HR 2.8; 95% CI 1.2-6.8), whereas overall survival was significantly associated with pICAM-1 (HR 2.0; 95% CI 1.1-3.7) and RAS (HR 2.6; 95% CI 1.5-4.6). CONCLUSIONS The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further.
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18
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SenthilKumar G, Gutierrez-Huerta CA, Freed JK, Beyer AM, Fancher IS, LeBlanc AJ. New developments in translational microcirculatory research. Am J Physiol Heart Circ Physiol 2022; 323:H1167-H1175. [PMID: 36306213 PMCID: PMC9678417 DOI: 10.1152/ajpheart.00566.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 01/28/2023]
Abstract
Microvascular disease plays a critical role in systemic end-organ dysfunction, and treatment of microvascular pathologies may greatly reduce cardiovascular morbidity and mortality. The Call for Papers collection: New Developments in Translational Microcirculatory Research highlights key advances in our understanding of the role of microvessels in the development of chronic diseases as well as therapeutic strategies to enhance microvascular function. This Mini Review provides a concise summary of these advances and draws from other relevant research to provide the most up-to-date information on the influence of cutaneous, cerebrovascular, coronary, and peripheral microcirculation on the pathophysiology of obesity, hypertension, cardiovascular aging, peripheral artery disease, and cognitive impairment. In addition to these disease- and location-dependent research articles, this Call for Papers includes state-of-the-art reviews on coronary endothelial function and assessment of microvascular health in different organ systems, with an additional focus on establishing rigor and new advances in clinical trial design. These articles, combined with original research evaluating cellular, exosomal, pharmaceutical, exercise, heat, and dietary interventional therapies, establish the groundwork for translating microcirculatory research from bench to bedside. Although numerous studies in this collection are focused on human microcirculation, most used robust preclinical models to probe mechanisms of pathophysiology and interventional benefits. Future work focused on translating these findings to humans are necessary for finding clinical strategies to prevent and treat microvascular dysfunction.
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Affiliation(s)
- Gopika SenthilKumar
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Cristhian A Gutierrez-Huerta
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Julie K Freed
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Andreas M Beyer
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ibra S Fancher
- Department of Kinesiology and Applied Physiology, College of Health Sciences, University of Delaware, Newark, Delaware
| | - Amanda Jo LeBlanc
- Department of Cardiovascular and Thoracic Surgery, School of Medicine, University of Louisville, Louisville, Kentucky
- Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky
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19
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Ali M, Kwak SH, Lee BT, Choi HJ. Controlled release of vascular endothelial growth factor (VEGF) in alginate and hyaluronic acid (ALG–HA) bead system to promote wound healing in punch-induced wound rat model. JOURNAL OF BIOMATERIALS SCIENCE, POLYMER EDITION 2022; 34:612-631. [PMID: 36218190 DOI: 10.1080/09205063.2022.2135264] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
For wound healing, angiogenesis is one of the main therapeutic factors for recovering the injured tissue. To address this issue, a combination of two different polymers, alginate (ALG) and hyaluronic acid (HA) in an 80:20 ratio composition is used to optimize the bead system along with the 5 IU heparin (Hep) by crosslinking into calcium chloride (CaCl2). Encapsulation of Vascular endothelial growth factor (VEGF) in the bead system shows delayed cumulative release in phosphate buffer saline (PBS). For in vitro studies, calf pulmonary artery endothelial (CPAE) cells showed biocompatibility. ALG-HA/VEGF150 improves endothelial Vascular cell adhesion protein 1 (VCAM1) and endothelial nitric oxide synthase (eNOS) expression markers in CPAE cells. In vivo evaluation of the bead system shows around 68% of wound closure 2 weeks post-implantation in 8 mm punch wound models. The treatment group shows decreased epithelial gap between the ends of the wound and neo-epidermal regeneration. ALG-HA/VEGF150 induced significant vascularization, collagen type-1 (Col-1) and fibronectin (FN) development in the in vivo models after 2 weeks of the implantation. Hence, ALG-HA/VEGF150 beads can be used to promote wound healing.
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Affiliation(s)
- Maqsood Ali
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Si Hyun Kwak
- Department of Plastic and Reconstructive surgery, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Byong-Taek Lee
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea
- Institute of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea
| | - Hwan Jun Choi
- Department of Plastic and Reconstructive surgery, College of Medicine, Soonchunhyang University, Cheonan, South Korea
- Institute of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea
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20
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Supradit K, Boonsri B, Duangdara J, Thitiphatphuvanon T, Suriyonplengsaeng C, Kangsamaksin T, Janvilisri T, Tohtong R, Yacqub-Usman K, Grabowska AM, Bates DO, Wongprasert K. Inhibition of serine/arginine-rich protein kinase-1 (SRPK1) prevents cholangiocarcinoma cells induced angiogenesis. Toxicol In Vitro 2022; 82:105385. [PMID: 35568131 DOI: 10.1016/j.tiv.2022.105385] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 03/31/2022] [Accepted: 05/09/2022] [Indexed: 11/22/2022]
Abstract
The serine/arginine-rich protein kinase-1 (SRPK1) is an enzyme that has an essential role in regulating numerous aspects of mRNA splicing. SRPK1 has been reported to be overexpressed in multiple cancers, suggesting it as a promising therapeutic target in oncology. No previous studies reported the role of SRPK1 in cholangiocarcinoma (CCA) cells. This study aimed to examine the expression of SRPK1 and the effects of SRPK1 inhibition on the viability and angiogenesis activity of CCA cells using a selective SRPK1 inhibitor, SPHINX31. Here, we demonstrate that SPHINX31 (0.3-10 μM) had no inhibitory effects on CCA cells' viability and proliferation. However, SPHINX31 decreased the mRNA expression of pro-angiogenic VEGF-A165a isoform. In addition, SPHINX31 attenuated SRSF1 phosphorylation and nuclear localization, and increased the ratio of VEGF-A165b/total VEGF-A proteins. Moreover, when HUVECs were grown in conditioned medium from SPHINX31-treated CCA cells, migration slowed, and tube formation decreased. The present study demonstrates that targeting SRPK1 in CCA cells effectively attenuates angiogenesis by suppressing pro-angiogenic VEGF-A isoform splicing. These findings suggest a potential therapeutic treatment using SRPK1 inhibitors for the inhibition of angiogenesis in cholangiocarcinoma.
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Affiliation(s)
- Kittiya Supradit
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Boonyakorn Boonsri
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Songkhla, Thailand
| | - Jinchutha Duangdara
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | | | | | - Thaned Kangsamaksin
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kiren Yacqub-Usman
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, Biodiscovery Institute, School of Medicine, University of Nottingham, United Kingdom
| | - Anna M Grabowska
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - David O Bates
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kanokpan Wongprasert
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand.
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21
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Characterization of the Expression of Angiogenic Factors in Cutaneous Squamous Cell Carcinoma of Domestic Cats. Vet Sci 2022; 9:vetsci9070375. [PMID: 35878392 PMCID: PMC9351683 DOI: 10.3390/vetsci9070375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 11/16/2022] Open
Abstract
Cutaneous squamous cell carcinoma (CSCC) is a common malignant skin cancer with a significant impact on health, and it is important to determine the degree of reliance of CSCC on angiogenesis for growth and metastasis. Major regulators of angiogenesis are the vascular endothelial growth factor (VEGF) family and their associated receptors. Alternative pre-mRNA splicing produces multiple isoforms of VEGF-A and PLGF with distinct biological properties. Several studies highlight the function of VEGF-A in CSCC, but there are no studies of the different isoforms of VEGF-A and PLGF for this neoplasm. We characterized the expression of three isoforms of VEGF-A, two isoforms of PLGF, and their receptors in cat CSCC biopsies compared to normal haired skin (NHS). Although our results revealed no significant changes in transcript levels of panVEGF-A or their isoforms, the mRNA levels of PLGF I and the receptors Flt-1 and KDR were downregulated in CSCC compared to NHS. Differences were observed in ligand:receptor mRNA expression ratio, with the expression of VEGF-A relative to its receptor KDR higher in CSCC, which is consistent with our hypothesis and prior human SCC studies. Immunolocalization in tissue showed increased expression of all measured factors and receptors in tumor cells compared to NHS and surrounding vasculature. We conclude that the factors measured may play a pivotal role in CSCC growth, although further studies are needed to clarify the role of angiogenic factors in feline CSCC.
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Malhi NK, Allen CL, Stewart E, Horton KL, Riu F, Batson J, Amoaku W, Morris JC, Arkill KP, Bates DO. Serine-arginine-rich protein kinase-1 inhibition for the treatment of diabetic retinopathy. Am J Physiol Heart Circ Physiol 2022; 322:H1014-H1027. [PMID: 35302878 PMCID: PMC9109797 DOI: 10.1152/ajpheart.00001.2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Angiogenic VEGF isoforms are upregulated in diabetic retinopathy (DR), driving pathological growth and fluid leakage. Serine-arginine-rich protein kinase-1 (SRPK1) regulates VEGF splicing, and its inhibition blocks angiogenesis. We tested the hypothesis that SRPK1 is activated in diabetes, and an SRPK1 inhibitor (SPHINX31) switches VEGF splicing in DR and prevents increased vascular permeability into the retina. SRPK1 was activated by high glucose (HG), in a PKC-dependent manner, and was blocked by SPHINX31. HG induced release of SRSF1 from the nuclear speckles, which was also SRPK1 dependent, and increased retinal pigment epithelial (RPE) monolayer admittance, which was reversed by SRPK1 inhibition (P < 0.05). Diabetes increased retinal permeability and thickness after 14 days which was blocked by treatment with SPHINX31 eye drops (P < 0.0001). These results show that SRPK1 inhibition, administered as an eye drop, protected the retinal barrier from hyperglycemia-associated loss of integrity in RPE cells in vitro and in diabetic rats in vivo. A clinical trial of another SRPK1 inhibitor has now been initiated in patients with diabetic macular edema.NEW & NOTEWORTHY VEGF-A165b splicing is induced by hyperglycemia through PKC-mediated activation of SRPK1 in RPE cells, increasing their permeability and angiogenic capability. SRPK1 inhibitors can be given as eye drops to reduce retinal permeability and edema in diabetic retinopathy.
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Affiliation(s)
- Naseeb K Malhi
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Claire L Allen
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | | | - Katherine L Horton
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Federica Riu
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | | | - Winfried Amoaku
- Division of Clinical Neuroscience, Department of Ophthalmology, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Jonathan C Morris
- School of Chemistry, University of New South Wales, Sydney, New South Wales, Australia
| | - Kenton P Arkill
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - David O Bates
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.,Exonate Limited, Duxford, United Kingdom.,COMPARE, University of Birmingham and University of Nottingham Midlands, Nottingham, United Kingdom
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Study of the Association between VEGF Polymorphisms and the Risk of Coronary Artery Disease in Koreans. J Pers Med 2022; 12:jpm12050761. [PMID: 35629182 PMCID: PMC9144104 DOI: 10.3390/jpm12050761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 02/05/2023] Open
Abstract
Coronary artery disease (CAD), a leading cause of death worldwide, has a complex etiology comprising both traditional risk factors (type 2 diabetes, dyslipidemia, arterial hypertension, and cigarette smoking) and genetic factors. Vascular endothelial growth factor (VEGF) notably contributes to angiogenesis and endothelial homeostasis. However, little is known about the relationship between CAD and VEGF polymorphisms in Koreans. The aim of this study is to investigate the associations of 2 VEGF promoter region polymorphisms (−1154G>A [rs1570360], −1498T>C [rs833061]) and 4 VEGF 3′-UTR polymorphisms (+936C>T [rs3025039], +1451C>T [rs3025040], +1612G>A [rs10434], and +1725G>A [rs3025053]) with CAD susceptibility in Koreans. We studied 885 subjects: 463 CAD patients and 422 controls. Genotyping was conducted with polymerase chain reaction-restriction fragment length polymorphism analysis and TaqMan allelic discrimination assays, and the genotype frequencies were calculated. We then performed haplotype and genotype combination analyses and measured the associations between VEGF polymorphisms and clinical variables in both the CAD patients and control subjects. We detected statistically significant associations between CAD and certain VEGF allele combinations. In the haplotypes of 5 single-nucleotide polymorphisms, the VEGF allele combination −1154A/+936T was associated with a decreased prevalence of CAD (A-T-T-G-G of VEGF −1154G>A/−1498T>C/+936C>T/+1612G>A/+1725G>A, AOR = 0.077, p = 0.021). In contrast, the VEGF allele combinations −1498T/+1725A and −1498T/+1612A/+1725A were associated with an increased prevalence of CAD (G-T-C-C-A of VEGF −1154G>A/−1498T>C/+936C>T/+1451C>T/+1725G>A, AOR = 1.602, p = 0.047; T-C-C-A-A of VEGF −1498T>C/+936C>T/+1451C>T/+1612G>A/+1725G>A, AOR = 1.582, p = 0.045). Gene−environment combinatorial analysis showed that the combination of the VEGF +1725AA genotype and several clinical factors (e.g., body mass index, hemoglobin A1c, and low-density lipoprotein cholesterol) increased the risk of CAD. Therefore, we suggest that VEGF polymorphisms and clinical factors may impact CAD prevalence.
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Saker Z, Rizk M, Bahmad HF, Nabha SM. Targeting Angiogenic Factors for the Treatment of Medulloblastoma. Curr Treat Options Oncol 2022; 23:864-886. [PMID: 35412196 DOI: 10.1007/s11864-022-00981-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2022] [Indexed: 11/24/2022]
Abstract
OPINION STATEMENT Medulloblastoma (MB) is the most frequent pediatric brain tumor. Despite conventional therapy, MB patients have high mortality and morbidity rates mainly due to the incomplete understanding of the molecular and cellular processes involved in development of this cancer. Similar to other solid tumors, MB demonstrated high endothelial cell proliferation and angiogenic activity, wherein new blood vessels arise from the pre-existing vasculature, a process named angiogenesis. MB angiogenesis is considered a hallmark for MB development, progression, and metastasis emphasizing its potential target for antitumor therapy. However, angiogenesis is tightly regulated by a set of angiogenic factors making it a complex process to be targeted. Although agents targeting these factors and their receptors are early in development, the potential for their targeting may translate into improvement in the clinical care for MB patients. In this review, we focus on the most potent angiogenic factors and their corresponding receptors, highlighting their basic properties and expression in MB. We describe their contribution to MB tumorigenesis and angiogenesis and the potential therapeutic targeting of these factors.
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Affiliation(s)
- Zahraa Saker
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Mahdi Rizk
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Hisham F Bahmad
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, 4300 Alton Rd, Miami Beach, FL, 33140, USA.
| | - Sanaa M Nabha
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.
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Al Kawas H, Saaid I, Jank P, Westhoff CC, Denkert C, Pross T, Weiler KBS, Karsten MM. How VEGF-A and its splice variants affect breast cancer development - clinical implications. Cell Oncol (Dordr) 2022; 45:227-239. [PMID: 35303290 PMCID: PMC9050780 DOI: 10.1007/s13402-022-00665-w] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2022] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Altered expression levels and structural variations in the vascular endothelial growth factor (VEGF) have been found to play important roles in cancer development and to be associated with the overall survival and therapy response of cancer patients. Particularly VEGF-A and its splice variants have been found to affect physiological and pathological angiogenic processes, including tumor angiogenesis, correlating with tumor progression, mostly caused by overexpression. This review focuses on the expression and impact of VEGF-A splice variants under physiologic conditions and in tumors and, in particular, the distribution and role of isoform VEGF165b in breast cancer. CONCLUSIONS AND PERSPECTIVES Many publications already highlighted the importance of VEGF-A and its splice variants in tumor therapy, especially in breast cancer, which are summarized in this review. Furthermore, we were able to demonstrate that cytoplasmatic VEGFA/165b expression is higher in invasive breast cancer tumor cells than in normal tissues or stroma. These examples show that the detection of VEGF splice variants can be performed also on the protein level in formalin fixed tissues. Although no quantitative conclusions can be drawn, these results may be the starting point for further studies at a quantitative level, which can be a major step towards the design of targeted antibody-based (breast) cancer therapies.
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Affiliation(s)
- Hivin Al Kawas
- Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Inas Saaid
- Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Paul Jank
- Institute of Pathology, Philipps-Universität Marburg, 35043, Marburg, Germany
| | | | - Carsten Denkert
- Institute of Pathology, Philipps-Universität Marburg, 35043, Marburg, Germany
| | - Therese Pross
- Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | | | - Maria Margarete Karsten
- Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
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A review on inflammation and angiogenesis as key mechanisms involved in the pathogenesis of bovine cystic ovarian disease. Theriogenology 2022; 186:70-85. [DOI: 10.1016/j.theriogenology.2022.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/01/2022] [Accepted: 04/05/2022] [Indexed: 11/23/2022]
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Thirunavukkarasu M, Pradeep SR, Ukani G, Abunnaja S, Youssef M, Accorsi D, Swaminathan S, Lim ST, Parker V, Campbell J, Rishi MT, Palesty JA, Maulik N. Gene therapy with Pellino-1 improves perfusion and decreases tissue loss in Flk-1 heterozygous mice but fails in MAPKAP Kinase-2 knockout murine hind limb ischemia model. Microvasc Res 2022; 141:104311. [PMID: 34999110 PMCID: PMC9250804 DOI: 10.1016/j.mvr.2022.104311] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/30/2021] [Accepted: 01/02/2022] [Indexed: 10/19/2022]
Abstract
OBJECTIVES In the United States, over 8.5 million people suffer from peripheral arterial disease (PAD). Previously we reported that Pellino-1(Peli1) gene therapy reduces ischemic damage in the myocardium and skin flaps in Flk-1 [Fetal Liver kinase receptor-1 (Flk-1)/ Vascular endothelial growth factor receptor-2/VEGFR2] heterozygous (Flk-1+/-) mice. The present study compares the angiogenic response and perfusion efficiency following hind limb ischemia (HLI) in, Flk-1+/- and, MAPKAPKINASE2 (MK2-/-) knockout (KO) mice to their control wild type (WT). We also demonstrated the use of Peli1 gene therapy to improve loss of function following HLI. STUDY DESIGN AND METHODS Femoral artery ligation (HLI) was performed in both Flk-1+/-and MK2-/-mice along with their corresponding WT. Another set of Flk-1+/- and MK2-/- were injected with either Adeno-LacZ (Ad.LacZ) or Adeno-Peli1 (Ad.Peli1) after HLI. Hind limb perfusion was assessed by laser doppler imaging at specific time points. A standardized scoring scale is used to quantify the extent of ischemia. Histology analysis performed includes capillary density, fibrosis, pro-angiogenic and anti-apoptotic proteins. RESULTS Flk-1+/- and MK2-/- had a slower recovery of perfusion efficiency in the ischemic limbs than controls. Both Flk-1+/-and MK2-/-KO mice showed decreased capillary density and capillary myocyte ratios with increased fibrosis than their corresponding wild types. Ad.Peli1 injected ischemic Flk-1+/- limb showed improved perfusion, increased capillary density, and pro-angiogenic molecules with reduced fibrosis compared to Ad.LacZ group. No significant improvement in perfusion was observed in MK2-/- ischemic limb after Ad. Peli1 injection. CONCLUSION Deletion of Flk-1 and MK2 impairs neovascularization and perfusion following HLI. Treatment with Ad. Peli1 results in increased angiogenesis and improved perfusion in Flk-1+/- mice but fails to rectify perfusion in MK2 KO mice. Overall, Peli1 gene therapy is a promising candidate for the treatment of PAD.
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Affiliation(s)
- Mahesh Thirunavukkarasu
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA
| | - Seetur R Pradeep
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA
| | - Gopi Ukani
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA; Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury 06706, CT, USA
| | - Salim Abunnaja
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA; Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury 06706, CT, USA
| | - Mark Youssef
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA; Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury 06706, CT, USA
| | - Diego Accorsi
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA; Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury 06706, CT, USA
| | - Santosh Swaminathan
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA; Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury 06706, CT, USA
| | - Sue Ting Lim
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA; Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury 06706, CT, USA
| | - Virginia Parker
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA; Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury 06706, CT, USA
| | - Jacob Campbell
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA
| | - Muhammad Tipu Rishi
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA; Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury 06706, CT, USA
| | - J Alexander Palesty
- Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury 06706, CT, USA
| | - Nilanjana Maulik
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, University of Connecticut Health, Farmington 06030, CT, USA.
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Pan XW, Xu D, Chen WJ, Chen JX, Chen WJ, Ye JQ, Gan SS, Zhou W, Song X, Shi L, Cui XG. USP39 promotes malignant proliferation and angiogenesis of renal cell carcinoma by inhibiting VEGF-A 165b alternative splicing via regulating SRSF1 and SRPK1. Cancer Cell Int 2021; 21:486. [PMID: 34544400 PMCID: PMC8454004 DOI: 10.1186/s12935-021-02161-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/18/2021] [Indexed: 01/01/2023] Open
Abstract
Background The benefit of targeted therapy for renal cell carcinoma (RCC) is largely crippled by drug resistance. Rapid disease progression and poor prognosis occur in patients with drug resistance. New treatments demand prompt exploration for clinical therapies. Ubiquitin-specific peptidase 39 (USP39) serves as the pro-tumor factor in several previous studies of other malignant tumors. To investigate the function and mechanism of USP39 in promoting malignant proliferation and angiogenesis of RCC. Methods We applied ONCOMINE database to analyze the correlation between USP39 expression level and the clinical characteristics of RCC. USP39 knockdown or overexpression plasmids were transfected into 786-O and ACHN cells. The HUVEC received cell supernatants of 786-O and ACHN cells with knockdown or overexpression USP39.The effect of USP39 on RCC was evaluated by MTT assay, cell cycle analysis, colony formation assay and tubule formation assay. The interaction between USP39 and VEGF-A alternative splicing was assessed by affinity purification and mass spectrometry, co-immunoprecipitation and Western blot assays. Results The mRNA expression level of USP39 in RCC was significantly higher than that in normal renal tissue (P < 0.001), and negatively correlated with the survival rate of RCC patients (P < 0.01). Silencing of USP39 in 786-O and ACHN cells inhibited cell proliferation and colony formation, and induced S phase arrest. USP39 overexpression significantly increased the number of tubules (P < 0.05) and branches (P < 0.01) formed by HUVEC cells, and USP39 knockdown produced an opposite effect (P < 0.05). The USP39 (101–565) fragment directly mediated its binding to SRSF1 and SRPK1, and promoted the phosphorylation of SRSF1 to regulate VEGF-A alternative splicing. USP39 knockdown upregulated the expression of VEGF-A165b, and USP39 overexpression downregulated the expression of VEGF-A165b significantly (both P < 0.05). Conclusion USP39 acted as a pro-tumor factor by motivating the malignant biological processes of RCC, probably through inhibiting VEGF-A165b alternative splicing and regulating SRSF1 and SRPK1. USP39 may prove to be a potential therapeutic target for RCC. Graphic abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02161-x.
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Affiliation(s)
- Xiu-Wu Pan
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China.,Depanrtment of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China
| | - Da Xu
- Depanrtment of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China
| | - Wen-Jin Chen
- Depanrtment of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China
| | - Jia-Xin Chen
- Depanrtment of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China
| | - Wei-Jie Chen
- Depanrtment of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China
| | - Jian-Qing Ye
- Depanrtment of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China
| | - Si-Shun Gan
- Depanrtment of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China
| | - Wang Zhou
- Depanrtment of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China.
| | - Xu Song
- Department of Urology, Shanghai Seventh People's Hospital, Shandong, 200137, China.
| | - Lei Shi
- Department of Urology, Yantai Yuhuangding Hospital of Qingdao University Medical College, Shandong, 264000, China.
| | - Xin-Gang Cui
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China.
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A Multifunctional Nanoplatform Made of Gold Nanoparticles and Peptides Mimicking the Vascular Endothelial Growth Factor. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11146333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In this work, nanobiohybrids of plasmonic gold nanoparticles (AuNP, anti-angiogenic) and a peptide mimicking the vascular endothelial growth factor (VEGF, pro-angiogenic) were assembled and scrutinized in terms of physicochemical characterization, including optical properties, surface charge, surface chemical structure and morphology of the bioengineered metal nanoparticles, for their potential application as multifunctional theranostic (i.e., therapy + sensing) nanoplatform (AuNP/VEGF). Specifically, a peptide sequence encompassing the VEGF cellular receptor domain 73–101 (VEGF73–101) and its single point cysteine mutated were immobilized onto AuNP by physi- and chemi-sorption, respectively. The new hybrid systems were characterized by means of a multitechnique approach, including dynamic light scattering (DLS) analyses, zeta potential (ZP), spectroscopic (UV-Vis, FT-IR, XPS), spectrometric (TOF-SIMS) and microscopic (AFM, SEM) techniques. Proof-of-work cellular experiments in human umbilical vein endothelial cells (HUVEC) upon the treatment with AuNP/VEGF samples, demonstrated no toxicity up to 24 h (MTT assay) as well an effective internalization (laser confocal microscopy, LSM).
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Snake venom vascular endothelial growth factors (svVEGFs): Unravelling their molecular structure, functions, and research potential. Cytokine Growth Factor Rev 2021; 60:133-143. [PMID: 34090786 DOI: 10.1016/j.cytogfr.2021.05.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/18/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023]
Abstract
Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, a physiological process characterized by the formation of new vessels from a preexisting endothelium. VEGF has also been implicated in pathologic states, such as neoplasias, intraocular neovascular disorders, among other conditions. VEGFs are distributed in seven different families: VEGF-A, B, C, D, and PIGF (placental growth factor), which are identified in mammals; VEGF-E, which are encountered in viruses; and VEGF-F or svVEGF (snake venom VEGF) described in snake venoms. This is the pioneer review of svVEGF family, exploring its distribution among the snake venoms, molecular structure, main functions, and potential applications.
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Heparin-binding VEGFR1 variants as long-acting VEGF inhibitors for treatment of intraocular neovascular disorders. Proc Natl Acad Sci U S A 2021; 118:1921252118. [PMID: 34006633 PMCID: PMC8166142 DOI: 10.1073/pnas.1921252118] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Neovascularization is a key feature of ischemic retinal diseases and the wet form of age-related macular degeneration (AMD), all leading causes of severe vision loss. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders. Millions of patients have been treated with these drugs worldwide. However, in real-life clinical settings, many patients do not experience the same degree of benefit observed in clinical trials, in part because they receive fewer anti-VEGF injections. Therefore, there is an urgent need to discover and identify novel long-acting VEGF inhibitors. We hypothesized that binding to heparan-sulfate proteoglycans (HSPG) in the vitreous, and possibly other ocular structures, may be a strategy to promote intraocular retention, ultimately leading to a reduced burden of intravitreal injections. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics and ability to bind to vitreous matrix. Our data indicate that some of our variants have longer duration and greater efficacy in animal models of intraocular neovascularization than current standard of care. Our study represents a systematic attempt to exploit the functional diversity associated with heparin affinity of a VEGF receptor.
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Atta-Allah SR, AboulMagd AM, Farag PS. Design, microwave assisted synthesis, and molecular modeling study of some new 1,3,4-thiadiazole derivatives as potent anticancer agents and potential VEGFR-2 inhibitors. Bioorg Chem 2021; 112:104923. [PMID: 33932767 DOI: 10.1016/j.bioorg.2021.104923] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/02/2021] [Accepted: 04/14/2021] [Indexed: 11/19/2022]
Abstract
A green and efficient method was developed for the synthesis of 1,3,4-thiadiazole based compounds under microwave (MW) activation. The nucleophile N-(5-amino-1,3,4-thiadiazol-2-yl)thiophene-2-carboxamide (3) was synthesized and reacted with different carbon electrophilic reagents to afford thiadiazolo-pyrimidine or imidazolo-thiadiazoline derivatives (4-6 and 8), respectively. Furthermore, a one-pot reaction of 3 with p-chlorobenzaldehyde and different carbon electrophile/ or nucleophiles under microwave irradiation yields the cyclic thiadiazolo-pyrimidine derivatives 10-15. Additionally, nucleophilic substitution of aromatic amines and/or potassium salts of some heterocyclic compounds with chloroacetamido-thiadiazole 6 yields derivatives 16-20. All the new derivatives were synthesized by both conventional and MW irradiation methods. All the new 1,3,4-thiadiazole derivatives were evaluated against four cancer cell lines, HepG-2, MCF-7, HCT-116, and PC-3. The anti-proliferative activity of most of the synthesized compounds exhibited excellent broad-spectrum cytotoxic activity against the cancer cell lines with IC50 values ranging from 3.97 to 9.62 μM. Moreover, the enzymatic assessment of five derivatives (2,4b, 6, 8, 9a) against VEGFR-2 tyrosine kinase showed significant inhibitory activities with IC50 of 11.5, 8.2, 10.3, 10.5 and 9.4 nM respectively. Further studies revealed the ability of compound 9a to have a strong DNA-binding affinity of 36.06 μM via DNA/methyl green assay. Moreover, molecular docking study was carried out to reveal the binding interactions of compounds in the binding site of VEGFR-2 enzyme explaining the significant inhibitory activity of these derivatives. Finally, ADME/Tox studies was performed to predict the pharmacokinetics of the synthesized compounds.
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Affiliation(s)
- Saad R Atta-Allah
- Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, 11566 Cairo, Egypt.
| | - Asmaa M AboulMagd
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University (NUB), Beni-Suef, Egypt.
| | - Paula S Farag
- Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, 11566 Cairo, Egypt
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Wiszniak S, Schwarz Q. Exploring the Intracrine Functions of VEGF-A. Biomolecules 2021; 11:biom11010128. [PMID: 33478167 PMCID: PMC7835749 DOI: 10.3390/biom11010128] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/13/2021] [Accepted: 01/15/2021] [Indexed: 12/16/2022] Open
Abstract
Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and VEGFR2 are expressed in many non-vascular cell-types, as well as various cancers. In addition to secreted VEGF binding to its receptors in the extracellular space at the cell membrane (i.e., in a paracrine or autocrine mode), intracellularly localised VEGF is emerging as an important signalling molecule regulating cell growth, survival, and metabolism. This intracellular mode of signalling has been termed “intracrine”, and refers to the direct action of a signalling molecule within the cell without being secreted. In this review, we describe examples of intracrine VEGF signalling in regulating cell growth, differentiation and survival, both in normal cell homeostasis and development, as well as in cancer. We further discuss emerging evidence for the molecular mechanisms underpinning VEGF intracrine function, as well as the implications this intracellular mode of VEGF signalling may have for use and design of anti-VEGF cancer therapeutics.
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Ung C, Lains I, Miller JW, Kim IK. Current Management of Age-Related Macular Degeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1256:295-314. [PMID: 33848007 DOI: 10.1007/978-3-030-66014-7_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Age-related macular degeneration (AMD) remains a leading cause of blindness worldwide. The assessment and management of patients with this condition has evolved in the last decades. In this chapter, current standards for diagnosis, follow-up, and treatment of patients with AMD are reviewed and summarized. Namely, we highlight how current assessment has moved from conventional ophthalmoscopy and fluorescein angiography testing to a multimodal approach, and its important advantages. Alternatives to visual acuity for functional assessment of patients with AMD are also presented. Regarding strategies for follow-up and treatment, we provide specific information for the different stages (i.e., early, intermediate, and late) and forms (for example, choroidal neovascularization and geographic atrophy) of AMD. Specifically, we discuss the relevance and options for self-monitoring and non-pharmacological interventions. Additionally, a summary of the important trials (both on exudative and non-exudative AMD) that have helped inform clinical practice is provided, including data on antiangiogenic agents currently available, and outcomes of the different regimens that have been studied. The influence of advances in imaging on treatment strategies is also discussed.In summary, this chapter is a resource for all clinicians engaged in providing state of the art care for patients with AMD, and can help improve diagnosis, management, and outcomes of individuals with this blinding condition.
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Affiliation(s)
- Cindy Ung
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Ines Lains
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Joan W Miller
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Ivana K Kim
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
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Vasculogenesis from Human Dental Pulp Stem Cells Grown in Matrigel with Fully Defined Serum-Free Culture Media. Biomedicines 2020; 8:biomedicines8110483. [PMID: 33182239 PMCID: PMC7695282 DOI: 10.3390/biomedicines8110483] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/04/2020] [Accepted: 11/05/2020] [Indexed: 12/24/2022] Open
Abstract
The generation of vasculature is one of the most important challenges in tissue engineering and regeneration. Human dental pulp stem cells (hDPSCs) are some of the most promising stem cell types to induce vasculogenesis and angiogenesis as they not only secrete vascular endothelial growth factor (VEGF) but can also differentiate in vitro into both endotheliocytes and pericytes in serum-free culture media. Moreover, hDPSCs can generate complete blood vessels containing both endothelial and mural layers in vivo, upon transplantation into the adult brain. However, many of the serum free media employed for the growth of hDPSCs contain supplements of an undisclosed composition. This generates uncertainty as to which of its precise components are necessary and which are dispensable for the vascular differentiation of hDPSCs, and also hinders the transfer of basic research findings to clinical cell therapy. In this work, we designed and tested new endothelial differentiation media with a fully defined composition using standard basal culture media supplemented with a mixture of B27, heparin and growth factors, including VEGF-A165 at different concentrations. We also optimized an in vitro Matrigel assay to characterize both the ability of hDPSCs to differentiate to vascular cells and their capacity to generate vascular tubules in 3D cultures. The description of a fully defined serum-free culture medium for the induction of vasculogenesis using human adult stem cells highlights its potential as a relevant innovation for tissue engineering applications. In conclusion, we achieved efficient vasculogenesis starting from hDPSCs using serum-free culture media with a fully defined composition, which is applicable for human cell therapy purposes.
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Riccardi C, Napolitano E, Platella C, Musumeci D, Melone MAB, Montesarchio D. Anti-VEGF DNA-based aptamers in cancer therapeutics and diagnostics. Med Res Rev 2020; 41:464-506. [PMID: 33038031 DOI: 10.1002/med.21737] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 09/12/2020] [Accepted: 09/23/2020] [Indexed: 12/13/2022]
Abstract
The vascular endothelial growth factor (VEGF) family and its receptors play fundamental roles not only in physiological but also in pathological angiogenesis, characteristic of cancer progression. Aiming at finding putative treatments for several malignancies, various small molecules, antibodies, or protein-based drugs have been evaluated in vitro and in vivo as VEGF inhibitors, providing efficient agents approved for clinical use. Due to the high clinical importance of VEGF, also a great number of anti-VEGF nucleic acid-based aptamers-that is, oligonucleotides able to bind with high affinity and specificity a selected biological target-have been developed as promising agents in anticancer strategies. Notable research efforts have been made in optimization processes of the identified aptamers, searching for increased target affinity and/or bioactivity by exploring structural analogues of the lead compounds. This review is focused on recent studies devoted to the development of DNA-based aptamers designed to target VEGF. Their therapeutic potential as well as their significance in the construction of highly selective biosensors is here discussed.
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Affiliation(s)
- Claudia Riccardi
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy.,Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and Inter-University Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Ettore Napolitano
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
| | - Chiara Platella
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
| | - Domenica Musumeci
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy.,Institute of Biostructures and Bioimages, Naples, Italy
| | - Mariarosa A B Melone
- Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and Inter-University Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Daniela Montesarchio
- Department of Chemical Sciences, University of Naples Federico II, Naples, Italy
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Rezaei ZS, Shahangian SS, Hasannia S, Sajedi RH. Development of a phage display-mediated immunoassay for the detection of vascular endothelial growth factor. Anal Bioanal Chem 2020; 412:7639-7648. [PMID: 32876721 DOI: 10.1007/s00216-020-02901-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 08/15/2020] [Accepted: 08/19/2020] [Indexed: 01/08/2023]
Abstract
Because of the critical role of vascular endothelial growth factor (VEGF) in angiogenesis and its significantly increased serum levels in early stages of cancer, VEGF is considered an important prognostic biomarker in different cancers. Herein, the amplification power of PCR combined with phage displaying anti-VEGF VHH, a sensitive real-time immunoassay, was precisely designed based on phage display-mediated immuno-PCR (PD-IPCR) for the detection of VEGF. This system benefits from strong and specific binding of antigen and antibody in a sandwich immunosorbent assay platform using avastin (anti-VEGF monoclonal antibody) as the capture antibody. The anti-VEGF phage particles were used as both anti-VEGF agent and DNA template in the PD-IPCR. Anti-VEGF phage ELISA showed a linear range of 3-250 ng/ml and a limit of detection (LOD) of 1.1 ng/ml. Using the PD-IPCR method, the linear range of VEGF detection was found to be 0.06-700 ng/ml, with a detection limit of 3 pg/ml. The recovery rate in serum ranged from 83% to 99%, with a relative standard deviation of 1.2-4.9%. These values indicate that the method has good sensitivity for use in clinical analysis. The proposed method was successfully applied to the clinical determination of VEGF in human serum samples, and the results showed excellent correlation with conventional ELISA (R2 = 0.995). The novel immunoassay provides a specific and sensitive immunoassay protocol for VEGF detection at very low levels. Graphical abstract.
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Affiliation(s)
- Zahra S Rezaei
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Jalal Ale Ahmad Highway, Tehran, 14115-154, Iran
| | - S Shirin Shahangian
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Guilan, 4199613776, Iran
| | - Sadegh Hasannia
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Jalal Ale Ahmad Highway, Tehran, 14115-154, Iran
| | - Reza H Sajedi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Jalal Ale Ahmad Highway, Tehran, 14115-154, Iran.
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Kaumaya PTP. B-cell epitope peptide cancer vaccines: a new paradigm for combination immunotherapies with novel checkpoint peptide vaccine. Future Oncol 2020; 16:1767-1791. [PMID: 32564612 PMCID: PMC7426751 DOI: 10.2217/fon-2020-0224] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 05/26/2020] [Indexed: 12/22/2022] Open
Abstract
In light of the numerous US FDA-approved humanized monoclonal antibodies (mAbs) for cancer immunotherapy, it is surprising that the advancement of B-cell epitope vaccines designed to elicit a natural humoral polyclonal antibody response has not gained traction in the immune-oncology landscape. Passive immunotherapy with humanized mAbs (Trastuzumab [Herceptin®]; Pertuzumab [Perjeta®]) has provided clinical benefit to breast cancer patients, albeit with significant shortcomings including toxicity problems and resistance, high costs, sophisticated therapeutic regimen and long half-life. The role of B-cell humoral immunity in cancer is under appreciated and underdeveloped. We have advanced the idea of active immunotherapy with chimeric B-cell epitope peptides incorporating a 'promiscuous' T-cell epitope that elicits a polyclonal antibody response, which provides safe, cost-effective therapeutic advantage over mAbs. We have created a portfolio of validated B-cell peptide epitopes against multiple receptor tyrosine kinases (HER-1, HER-3, IGF-1R and VEGF). We have successfully translated two HER-2 combination B-cell peptide vaccines in Phase I and II clinical trials. We have recently developed an effective novel PD-1 vaccine. In this article, I will review our approaches and strategies that focus on B-cell epitope cancer vaccines.
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Affiliation(s)
- Pravin TP Kaumaya
- Department of Obstetrics & Gynecology, College of Medicine, Wexner Medical Center, The James Cancer Hospital & Solove Research Institute, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
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Zhao J, Chang L, Gu X, Liu J, Sun B, Wei X. Systematic profiling of alternative splicing signature reveals prognostic predictor for prostate cancer. Cancer Sci 2020; 111:3020-3031. [PMID: 32530556 PMCID: PMC7419053 DOI: 10.1111/cas.14525] [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] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/21/2020] [Accepted: 06/02/2020] [Indexed: 01/14/2023] Open
Abstract
Alternative splicing (AS) provides the primary mechanism for producing protein diversity. There is growing evidence that AS is involved in the development and progression of cancers. The rapid accumulation of high‐throughput sequencing technologies and clinical data sets offers an opportunity to systematically profile the relationship between mRNA variants and clinical outcomes. However, there is a lack of systematic analysis of AS in prostate cancer: Download RNA‐seq data and clinical information from The Cancer Genome Atlas (TCGA) data portal. Evaluate RNA splicing patterns by SpliceSeq and calculate splicing percentage (PSI) values. Different expressions were identified as differently expressed AS events (DEAs) based on PSI values. Bioinformatics methods were used for further analysis of DEAs and their splicing networks. Kaplan‐Meier, Cox proportional regression, and unsupervised cluster analysis were used to assess the correlation between DEAs and clinical characteristics. In total, 43 834 AS events were identified, of which 1628 AS events were differentially expressed. The parental genes of these DEAs played a significant role in the regulation of prostate cancer‐related processes. In total, 226 DEAs events were found to be associated with disease‐free survival. Four clusters of molecules with different survival modes were revealed by unsupervised cluster analysis of DEAs. AS events may be important determinants of prognosis and bio‐modulation in prostate cancer. In this study, we established strong prognostic predictors, discovered a splicing network that may be a potential mechanism, and provided further validated therapeutic targets.
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Affiliation(s)
- Jiyu Zhao
- Department of Urology, ChuiYangLiu Hospital affiliated to Tsinghua University, Beijing, China
| | - Luchen Chang
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xianen Gu
- Department of Urology, ChuiYangLiu Hospital affiliated to Tsinghua University, Beijing, China
| | - Jia Liu
- Department of Urology, ChuiYangLiu Hospital affiliated to Tsinghua University, Beijing, China
| | - Bei Sun
- Department of Outpatient Office, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xi Wei
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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Vanderstraeten J, Baselet B, Buset J, Ben Said N, de Ville de Goyet C, Many MC, Gérard AC, Derradji H. Modulation of VEGF Expression and Oxidative Stress Response by Iodine Deficiency in Irradiated Cancerous and Non-Cancerous Breast Cells. Int J Mol Sci 2020; 21:ijms21113963. [PMID: 32486504 PMCID: PMC7312479 DOI: 10.3390/ijms21113963] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/23/2020] [Accepted: 05/28/2020] [Indexed: 12/21/2022] Open
Abstract
Breast cancer remains a major concern and its physiopathology is influenced by iodine deficiency (ID) and radiation exposure. Since radiation and ID can separately induce oxidative stress (OS) and microvascular responses in breast, their combination could additively increase these responses. Therefore, ID was induced in MCF7 and MCF12A breast cell lines by medium change. Cells were then X-irradiated with doses of 0.05, 0.1, or 3 Gy. In MCF12A cells, both ID and radiation (0.1 and 3 Gy) increased OS and vascular endothelial growth factor (VEGF) expression, with an additive effect when the highest dose was combined with ID. However, in MCF7 cells no additive effect was observed. VEGF mRNA up-regulation was reactive oxygen species (ROS)-dependent, involving radiation-induced mitochondrial ROS. Results on total VEGF mRNA hold true for the pro-angiogenic isoform VEGF165 mRNA, but the treatments did not modulate the anti-angiogenic isoform VEGF165b. Radiation-induced antioxidant response was differentially regulated upon ID in both cell lines. Thus, radiation response is modulated according to iodine status and cell type and can lead to additive effects on ROS and VEGF. As these are often involved in cancer initiation and progression, we believe that iodine status should be taken into account in radiation prevention policies.
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Affiliation(s)
- Jessica Vanderstraeten
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), 1200 Brussels, Belgium; (N.B.S.); (C.d.V.d.G.); (M.-C.M.)
- Correspondence:
| | - Bjorn Baselet
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), 2400 Mol, Belgium; (B.B.); (J.B.); (H.D.)
| | - Jasmine Buset
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), 2400 Mol, Belgium; (B.B.); (J.B.); (H.D.)
| | - Naziha Ben Said
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), 1200 Brussels, Belgium; (N.B.S.); (C.d.V.d.G.); (M.-C.M.)
| | - Christine de Ville de Goyet
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), 1200 Brussels, Belgium; (N.B.S.); (C.d.V.d.G.); (M.-C.M.)
| | - Marie-Christine Many
- Pole of Morphology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), 1200 Brussels, Belgium; (N.B.S.); (C.d.V.d.G.); (M.-C.M.)
| | - Anne-Catherine Gérard
- Service d’Endocrino-Diabétologie, Centre Hospitalier Régional (CHR) Mons-Hainaut, 7000 Mons, Belgium;
| | - Hanane Derradji
- Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), 2400 Mol, Belgium; (B.B.); (J.B.); (H.D.)
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Madu CO, Wang S, Madu CO, Lu Y. Angiogenesis in Breast Cancer Progression, Diagnosis, and Treatment. J Cancer 2020; 11:4474-4494. [PMID: 32489466 PMCID: PMC7255381 DOI: 10.7150/jca.44313] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 04/04/2020] [Indexed: 02/07/2023] Open
Abstract
Angiogenesis is a significant event in a wide range of healthy and diseased conditions. This process frequently involves vasodilation and an increase in vascular permeability. Numerous players referred to as angiogenic factors, work in tandem to facilitate the outgrowth of endothelial cells (EC) and the consequent vascularity. Conversely, angiogenic factors could also feature in pathological conditions. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. An increased level of angiogenesis is associated with decreased survival in breast cancer patients. Therefore, a good understanding of the angiogenic mechanism holds a promise of providing effective treatments for breast cancer progression, thereby enhancing patients' survival. Disrupting the initiation and progression of this process by targeting angiogenic factors such as vascular endothelial growth factor (Vegf)-one of the most potent member of the VEGF family- or by targeting transcription factors, such as Hypoxia-Inducible Factors (HIFs) that act as angiogenic regulators, have been considered potential treatment options for several types of cancers. The objective of this review is to highlight the mechanism of angiogenesis in diseases, specifically its role in the progression of malignancy in breast cancer, as well as to highlight the undergoing research in the development of angiogenesis-targeting therapies.
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Affiliation(s)
- Chikezie O. Madu
- Departments of Biological Sciences, University of Memphis, Memphis, TN 38152. USA
| | - Stephanie Wang
- Departments of Biology and Advanced Placement Biology, White Station High School, Memphis, TN 38117. USA
| | - Chinua O. Madu
- Departments of Biology and Advanced Placement Biology, White Station High School, Memphis, TN 38117. USA
| | - Yi Lu
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN 38163. USA
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Does Diabetes Induce the Vascular Endothelial Growth Factor (VEGF) Expression in Periodontal Tissues? A Systematic Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17082765. [PMID: 32316357 PMCID: PMC7215273 DOI: 10.3390/ijerph17082765] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/11/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022]
Abstract
Aim: Diabetes and periodontal disease are both chronic pathological conditions linked by several underlying biological mechanisms, in which the inflammatory response plays a critical role, and their association has been largely recognized. Recently, attention has been given to diabetes as an important mediator of vascular endothelial growth factor (VEGF) overexpression in periodontal tissues, by virtue of its ability to affect microvasculature. This review aims to summarize the findings from studies that explored VEGF expression in diabetic patients with periodontitis, compared to periodontally healthy subjects. Materials and Methods: A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was carried out to identify all studies reporting findings about VEGF expression in periodontal tissues of diabetic patients up to May 2018. The inclusion criteria were studies on VEGF expression in periodontally diseased tissues of diabetic patients compared with nondiabetic subjects, with any method of analysis, and published in the English language. Results: Eight articles met the inclusion criteria. Immunohistochemistry was used in six of the studies, reverse transcriptase polymerase chain reaction (real-time RT-PCR) aiming to quantify mRNA VEGF expression was used in one study, and ELISA analysis was used for one study. Compared with nondiabetic patients, a higher VEGF expression in gingival tissue and gingival crevicular fluid (GCF) samples in diabetic patients with periodontitis was reported. Conclusions: Overall, novel evidence for the VEGF expression within the periodontal tissue of diabetic patients paves the way for further studies on the role of this protein in neovascularization physiology and pathophysiology in microvasculature of the periodontium.
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de la Torre P, Pérez-Lorenzo MJ, Alcázar-Garrido Á, Flores AI. Cell-Based Nanoparticles Delivery Systems for Targeted Cancer Therapy: Lessons from Anti-Angiogenesis Treatments. Molecules 2020; 25:715. [PMID: 32046010 PMCID: PMC7038177 DOI: 10.3390/molecules25030715] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/03/2020] [Accepted: 02/05/2020] [Indexed: 02/05/2023] Open
Abstract
The main strategy of cancer treatment has focused on attacking the tumor cells. Some cancers initially responsive to chemotherapy become treatment-resistant. Another strategy is to block the formation of tumor vessels. However, tumors also become resistant to anti-angiogenic treatments, mostly due to other cells and factors present in the tumor microenvironment, and hypoxia in the central part of the tumor. The need for new cancer therapies is significant. The use of nanoparticle-based therapy will improve therapeutic efficacy and targeting, while reducing toxicity. However, due to inefficient accumulation in tumor sites, clearance by reticuloendothelial organs and toxicity, internalization or conjugation of drug-loaded nanoparticles (NPs) into mesenchymal stem cells (MSCs) can increase efficacy by actively delivering them into the tumor microenvironment. Nanoengineering MSCs with drug-loaded NPs can increase the drug payload delivered to tumor sites due to the migratory and homing abilities of MSCs. However, MSCs have some disadvantages, and exosomes and membranes from different cell types can be used to transport drug-loaded NPs actively to tumors. This review gives an overview of different cancer approaches, with a focus on hypoxia and the emergence of NPs as drug-delivery systems and MSCs as cellular vehicles for targeted delivery due to their tumor-homing potential.
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Affiliation(s)
| | | | | | - Ana I. Flores
- Grupo de Medicina Regenerativa, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas 12), Avda. de Cordoba s/n, 28041 Madrid, Spain; (P.d.l.T.); (M.J.P.-L.)
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Chen WZ, Jiang JX, Yu XY, Xia WJ, Yu PX, Wang K, Zhao ZY, Chen ZG. Endothelial cells in colorectal cancer. World J Gastrointest Oncol 2019; 11:946-956. [PMID: 31798776 PMCID: PMC6883186 DOI: 10.4251/wjgo.v11.i11.946] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 08/18/2019] [Accepted: 09/26/2019] [Indexed: 02/05/2023] Open
Abstract
The dependence of tumor growth on neovascularization has become an important aspect of cancer biology. Tumor angiogenesis is one of the key mechanisms of tumorigenesis, growth and metastasis. The key events involved in this process are endothelial cell proliferation, migration, and vascular formation. Recent studies have revealed the importance of tumor-associated endothelial cells (TECs) in the development and progression of colorectal cancer (CRC), including epithelial proliferation, stem cell maintenance, angiogenesis, and immune remodeling. Decades of research have identified that the molecular basis of tumor angiogenesis includes vascular endothelial growth factors (VEGFs) and their receptor family, which are the main targets of antiangiogenesis therapy. VEGFs and their receptors play key roles in the pathology of angiogenesis, and their overexpression indicates poor prognosis in CRC. This article reviews the characteristics of the tumor vasculature and the role of TECs in different stages of CRC and immune remodeling. We also discuss the biological effects of VEGFs and their receptor family as angiogenesis regulators and emphasize the clinical implications of TECs in clinical treatment.
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Affiliation(s)
- Wu-Zhen Chen
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Jing-Xin Jiang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Xiu-Yan Yu
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Wen-Jie Xia
- Department of Breast Surgery, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Peng-Xin Yu
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Ke Wang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Zhi-Yong Zhao
- Department of Administrative Office, the First People’s Hospital of Jiande, Hangzhou 310000, Zhejiang Province, China
| | - Zhi-Gang Chen
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
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Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer. Pharmaceutics 2019; 11:pharmaceutics11100542. [PMID: 31635263 PMCID: PMC6835230 DOI: 10.3390/pharmaceutics11100542] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/12/2019] [Accepted: 10/15/2019] [Indexed: 01/06/2023] Open
Abstract
Elastin-like polypeptides (ELP) are versatile protein biopolymers used in drug delivery due to their modular nature, allowing fusion of therapeutics and targeting agents. We previously developed an ELP fusion with vascular endothelial growth factor (VEGF) and demonstrated its therapeutic efficacy in translational swine models of renovascular disease and chronic kidney disease. The goal of the current work was to refine renal targeting and reduce off-target tissue deposition of ELP–VEGF. The ELP–VEGF fusion protein was modified by adding a kidney-targeting peptide (KTP) to the N-terminus. All control proteins (ELP, KTP–ELP, ELP–VEGF, and KTP–ELP–VEGF) were also produced to thoroughly assess the effects of each domain on in vitro cell binding and activity and in vivo pharmacokinetics and biodistribution. KTP–ELP–VEGF was equipotent to ELP–VEGF and free VEGF in vitro in the stimulation of primary glomerular microvascular endothelial cell proliferation, tube formation, and extracellular matrix invasion. The contribution of each region of the KTP–ELP–VEGF protein to the cell binding specificity was assayed in primary human renal endothelial cells, tubular epithelial cells, and podocytes, demonstrating that the VEGF domain induced binding to endothelial cells and the KTP domain increased binding to all renal cell types. The pharmacokinetics and biodistribution of KTP–ELP–VEGF and all control proteins were determined in SKH-1 Elite hairless mice. The addition of KTP to ELP slowed its in vivo clearance and increased its renal deposition. Furthermore, addition of KTP redirected ELP–VEGF, which was found at high levels in the liver, to the kidney. Intrarenal histology showed similar distribution of all proteins, with high levels in blood vessels and tubules. The VEGF-containing proteins also accumulated in punctate foci in the glomeruli. These studies provide a thorough characterization of the effects of a kidney-targeting peptide and an active cytokine on the biodistribution of these novel biologics. Furthermore, they demonstrate that renal specificity of a proven therapeutic can be improved using a targeting peptide.
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Contribution of the VEGF system to the follicular persistence associated with bovine cystic ovaries. Theriogenology 2019; 138:52-65. [DOI: 10.1016/j.theriogenology.2019.07.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/05/2019] [Accepted: 07/02/2019] [Indexed: 01/09/2023]
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Jászai J, Schmidt MHH. Trends and Challenges in Tumor Anti-Angiogenic Therapies. Cells 2019; 8:cells8091102. [PMID: 31540455 PMCID: PMC6770676 DOI: 10.3390/cells8091102] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/09/2019] [Accepted: 09/14/2019] [Indexed: 01/18/2023] Open
Abstract
Excessive abnormal angiogenesis plays a pivotal role in tumor progression and is a hallmark of solid tumors. This process is driven by an imbalance between pro- and anti-angiogenic factors dominated by the tissue hypoxia-triggered overproduction of vascular endothelial growth factor (VEGF). VEGF-mediated signaling has quickly become one of the most promising anti-angiogenic therapeutic targets in oncology. Nevertheless, the clinical efficacy of this approach is severely limited in certain tumor types or shows only transient efficacy in patients. Acquired or intrinsic therapy resistance associated with anti-VEGF monotherapeutic approaches indicates the necessity of a paradigm change when targeting neoangiogenesis in solid tumors. In this context, the elaboration of the conceptual framework of “vessel normalization” might be a promising approach to increase the efficacy of anti-angiogenic therapies and the survival rates of patients. Indeed, the promotion of vessel maturation instead of regressing tumors by vaso-obliteration could result in reduced tumor hypoxia and improved drug delivery. The implementation of such anti-angiogenic strategies, however, faces several pitfalls due to the potential involvement of multiple pro-angiogenic factors and modulatory effects of the innate and adaptive immune system. Thus, effective treatments bypassing relapses associated with anti-VEGF monotherapies or breaking the intrinsic therapy resistance of solid tumors might use combination therapies or agents with a multimodal mode of action. This review enumerates some of the current approaches and possible future directions of treating solid tumors by targeting neovascularization.
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Affiliation(s)
- József Jászai
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, 01307 Dresden, Germany.
| | - Mirko H H Schmidt
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, 01307 Dresden, Germany.
- German Cancer Consortium (DKTK), Partner Site Dresden, 01307 Dresden, Germany.
- German Cancer Research Center (DKFZ), 61920 Heidelberg, Germany.
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Laddha AP, Kulkarni YA. VEGF and FGF-2: Promising targets for the treatment of respiratory disorders. Respir Med 2019; 156:33-46. [PMID: 31421589 DOI: 10.1016/j.rmed.2019.08.003] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 08/05/2019] [Accepted: 08/07/2019] [Indexed: 12/19/2022]
Abstract
The endothelial cells play a crucial role in the progression of angiogenesis, which causes cell re-modulation, proliferation, adhesion, migration, invasion and survival. Angiogenic factors like cytokines, cell adhesion molecules, growth factors, vasoactive peptides, proteolytic enzymes (metalloproteinases) and plasminogen activators bind to their receptors on endothelial cells and activate the signal transduction pathways like epidermal growth factor receptor (EGFR phosphatidylinositol 3-kinase and (PI3K)/AKT/mammalian target of rapamycin (mTOR) which initiate the process of angiogenesis. Cytokines that stimulate angiogenesis include direct and indirect proangiogenic markers. The direct proangiogenic group of markers consists of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) and hepatocyte growth factor (HGF) whereas the indirect proangiogenic markers include transforming growth factor-beta (TGF-β), interleukin 6 (IL-6), interleukin 8 (IL-8) and platelet-derived growth factor (PDGF). VEGF and FGF-2 are the strongest activators of angiogenesis which stimulate migration and proliferation of endothelial cells in existing vessels to generate and stabilize new blood vessels. VEGF is released in hypoxic conditions as an effect of the hypoxia-inducible factor (HIF-1α) and causes re-modulation and inflammation of bronchi cell. Cell re-modulation and inflammation leads to the development of various lung disorders like pulmonary hypertension, chronic obstructive pulmonary disease, asthma, fibrosis and lung cancer. This indicates that there is a firm link between overexpression of VEGF and FGF-2 with lung disorders. Various natural and synthetic drugs are available for reducing the overexpression of VEGF and FGF-2 which can be helpful in treating lung disorders. Researchers are still searching for new angiogenic inhibitors which can be helpful in the treatment of lung disorders. The present review emphasizes on molecular mechanisms and new drug discovery focused on VEGF and FGF-2 inhibitors and their role as anti-angiogenetic agents in lung disorders.
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Affiliation(s)
- Ankit P Laddha
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, 400 056, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, 400 056, India.
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Formisano L, Jansen VM, Marciano R, Bianco R. From Biology to Therapy: Improvements of Therapeutic Options in Lung Cancer. Anticancer Agents Med Chem 2019; 18:1235-1240. [PMID: 28901258 DOI: 10.2174/1871520617666170912123416] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 07/12/2017] [Accepted: 08/25/2017] [Indexed: 12/14/2022]
Abstract
Lung cancer is the leading cause of cancer-related mortality around the world, despite effective chemotherapeutic agents, the prognosis has remained poor for a long time. The discovery of molecular changes that drive lung cancer has led to a dramatic shift in the therapeutic landscape of this disease. In "in vitro" and "in vivo" models of NSCLC (Non-Small Cell Lung Cancer), angiogenesis blockade has demonstrated an excellent anti-tumor activity, thus, a number of anti-angiogenic drugs have been approved by regulatory authorities for use in clinical practice. Much more interesting is the discovery of EGFR (Epithelial Growth Factor Receptor) mutations that predict sensitivity to the anti-EGFR Tyrosine Kinase Inhibitors (TKIs), a class of drugs that has shown to significantly improve survival when compared with standard chemotherapy in the first-line treatment of metastatic NSCLC. Nevertheless, after an initial response, resistance often occurs and prognosis becomes dismal. Biomolecular studies on cell line models have led to the discovery of mutations (e.g., T790M) that confer resistance to anti-EGFR inhibitors. Fortunately, drugs that are able to circumvent this mechanism of resistance have been developed and have been recently approved for clinical use. The discovery of robust intratumor lymphocyte infiltration in NSCLC has paved the way to several strategies able to restore the immune response. Thus, agents interfering with PD-1/PD-L1 (Programmed Death) pathways make up a significant portion of the armamentarium of cancer therapies for NSCLC. In all the above-mentioned situations, the basis of the success in treating NSCLC has started from understanding of the mutational landscape of the tumor.
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Affiliation(s)
- Luigi Formisano
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Italy
| | - Valerie M Jansen
- Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Roberta Marciano
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Italy
| | - Roberto Bianco
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Italy
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Metal Nanoparticles Released from Dental Implant Surfaces: Potential Contribution to Chronic Inflammation and Peri-Implant Bone Loss. MATERIALS 2019; 12:ma12122036. [PMID: 31242601 PMCID: PMC6630980 DOI: 10.3390/ma12122036] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 06/18/2019] [Accepted: 06/20/2019] [Indexed: 02/06/2023]
Abstract
Peri-implantitis is an inflammatory disease affecting tissues surrounding dental implants. Although it represents a common complication of dental implant treatments, the underlying mechanisms have not yet been fully described. The aim of this study is to identify the role of titanium nanoparticles released form the implants on the chronic inflammation and bone lysis in the surrounding tissue. We analyzed the in vitro effect of titanium (Ti) particle exposure on mesenchymal stem cells (MSCs) and fibroblasts (FU), evaluating cell proliferation by MTT test and the generation of reactive oxygen species (ROS). Subsequently, in vivo analysis of peri-implant Ti particle distribution, histological, and molecular analyses were performed. Ti particles led to a time-dependent decrease in cell viability and increase in ROS production in both MSCs and FU. Tissue analyses revealed presence of oxidative stress, high extracellular and intracellular Ti levels and imbalanced bone turnover. High expression of ZFP467 and the presence of adipose-like tissue suggested dysregulation of the MSC population; alterations in vessel morphology were identified. The results suggest that Ti particles may induce the production of high ROS levels, recruiting abnormal quantity of neutrophils able to produce high level of metalloproteinase. This induces the degradation of collagen fibers. These events may influence MSC commitment, with an imbalance of bone regeneration.
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