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Guo R, Xie X, Ren Q, Liew PX. New insights on extramedullary granulopoiesis and neutrophil heterogeneity in the spleen and its importance in disease. J Leukoc Biol 2025; 117:qiae220. [PMID: 39514106 DOI: 10.1093/jleuko/qiae220] [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: 09/03/2024] [Indexed: 11/16/2024] Open
Abstract
Neutrophils are traditionally viewed as uncomplicated exterminators that arrive quickly at sites of infection, kill pathogens, and then expire. However, recent studies employing modern transcriptomics coupled with novel imaging modalities have discovered that neutrophils exhibit significant heterogeneity within organs and have complex functional roles ranging from tissue homeostasis to cancer and chronic pathologies. This has revised the view that neutrophils are simplistic butchers, and there has been a resurgent interest in neutrophils. The spleen was described as a granulopoietic organ more than 4 decades ago, and studies indicate that neutrophils are briefly retained in the spleen before returning to circulation after proliferation. Transcriptomic studies have discovered that splenic neutrophils are heterogeneous and distinct compared with those in blood. This suggests that a unique hematopoietic niche exists in the splenic microenvironment, i.e., capable of programming neutrophils in the spleen. During severe systemic inflammation with an increased need of neutrophils, the spleen can adapt by producing neutrophils through emergency granulopoiesis. In this review, we describe the structure and microanatomy of the spleen and examine how cells within the splenic microenvironment help to regulate splenic granulopoiesis. A focus is placed on exploring the increase in splenic granulopoiesis to meet host needs during infection and inflammation. Emerging technologies such as single-cell RNA sequencing, which provide valuable insight into splenic neutrophil development and heterogeneity, are also discussed. Finally, we examine how tumors subvert this natural pathway in the spleen to generate granulocytic suppressor cells to promote tumor growth.
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Affiliation(s)
- Rongxia Guo
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, Hubei 430071, China
| | - Xuemei Xie
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA 02115, United States
| | - Qian Ren
- State Key Laboratory of Experimental Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Heping District, Tianjin 300020, China
- Tianjin Institutes of Health Science, Chinese Academy of Medical Sciences, 288 Nanjing Road, Heping District, Tianjin 300020, China
| | - Pei Xiong Liew
- Immunology Center of Georgia, Augusta University, 1410 Laney Walker Blvd, Augusta, GA 30912, United States
- Department of Cellular Biology and Anatomy, Augusta University, 1434 Laney Walker Blvd, Augusta, GA 30912, United States
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Lopes MM, Clouard C, Vincent A, Thomas F, Hérault F, Louveau I, Resmond R, Jammes H, Merlot E. Immune transcriptomic profile in adult female pigs: dominance status has more influence than environmental enrichment. BMC Genomics 2024; 25:1211. [PMID: 39695383 DOI: 10.1186/s12864-024-11116-1] [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: 03/05/2024] [Accepted: 12/03/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Assessing farm animals' welfare is crucial, yet practical physiological tools are still lacking. In this study, we tested whether the peripheral blood mononuclear cell (PBMC) transcriptome shows variations in association with sows' welfare. To do this, we compared animals whose welfare states were assumed to differ due to their lives in more or less enriched environments and to their different dominance statuses. Sows were housed in a conventional (C, n = 36) or enriched (E, n = 35) environments from gestation day 0 (G0) until three weeks before farrowing (G105), after which they were transferred to individual farrowing crates. From G99 to G103, behavioral analyses were conducted, and sows' dominance status was evaluated. A subset of 28 multiparous sows (C, n = 14 and E, n = 14) was selected for the collection of saliva on G35 and G98 and hair on G98 for cortisol measurement, and of blood samples for PBMC transcriptome analysis on G98 and on lactation day 12 (L12). RESULTS Both environmental enrichment (EE) and dominance status influenced cortisol and variables related to social and exploratory behavior, indicating an influence on sows' welfare. In the transcriptomic analysis, among the 12,260 genes submitted to differential analysis on G98, EE impacted 31 genes, while dominance status impacted 449 genes. Compared with subordinate sows (SUB), dominant (DOM) sows exhibited an upregulation of genes related to inflammatory process and plasma cell function, and downregulation of genes related to B-cell activation. In groups of sows, dominance status is partly related to sows' parity; therefore, we compared the effect of dominance with that of parity. Some common genes emerged when comparing high-parity (HP) vs. low-parity (LP) sows (542 differentially expressed genes (DEGs), including 180 in common with dominance-related genes), indicating that some effects of dominance on the transcriptome during gestation were in fact more due to age or reproductive cycles than to dominance itself. EE and dominance effects appeared relatively short-term, as DEG numbers decreased on L12 (four DEGs for E vs. C, 25 for DOM vs. SUB). CONCLUSIONS Dominance status exerted a more pronounced influence on sows' PBMC transcriptome than did environmental enrichment. In particular, dominance status modulated genes associated with B cells and plasma cell functions. Some of the genes identified in this study could be tested in the future as potential molecular markers of well-being.
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Affiliation(s)
- Mariana Mescouto Lopes
- PEGASE, INRAE, Institut Agro, Saint-Gilles, 35590, France.
- PEGASE, INRAE, Institut Agro, 16 Le Clos, Saint-Gilles, 35590, France.
| | | | - Annie Vincent
- PEGASE, INRAE, Institut Agro, Saint-Gilles, 35590, France
| | | | | | | | - Rémi Resmond
- IGEPP, INRAE, Institut Agro, Université de Rennes 1, Le Rheu, 35653, France
| | - Hélène Jammes
- Université Paris-Saclay, AP-HP, UVSQ, INRAE, BREED, Jouy-en-Josas, 78350, France
- Ecole Nationale Vétérinaire d'Alfort, BREED, Maisons-Alfort, 94700, France
| | - Elodie Merlot
- PEGASE, INRAE, Institut Agro, Saint-Gilles, 35590, France
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Lim JH, Kim Y, Kim MY, Kim EN, Kim TW, Choi BS, Kim WU, Kim HW, Park JY, Park CW. Placental growth factor deficiency initiates obesity- and aging-associated metabolic syndrome. Metabolism 2024; 161:156002. [PMID: 39173826 DOI: 10.1016/j.metabol.2024.156002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/18/2024] [Accepted: 08/19/2024] [Indexed: 08/24/2024]
Abstract
Obesity often leads to inadequate angiogenesis in expanding adipose tissue, resulting in inflammation and insulin resistance. We explored the role of placental growth factor (PlGF) in metabolic syndrome (MS) using mice models of type 2 diabetes, high-fat diet, or aging. Reduced serum PlGF levels were associated with decreased insulin sensitivity and development of MS features. PlGF was localized within endothelial cells and pericytes of adipose tissue. In vitro, low PlGF levels in hypoxic conditions worsened oxidative stress, apoptosis, and reduced autophagy. This was associated with a reduction in expression of vascular endothelial growth factor (VEGF)-A/VEGF-R1/-R2, which was influenced by a decrease and increase in PlGF/pAMPK/PI3K-pAkt/PLCγ1-iCa++/eNOS and PTEN/GSK3β axes, respectively. PlGF-knockout mice exhibited MS traits through alterations in the same signaling pathways, and these changes were mitigated by recombinant PlGF and metformin. These enhanced angiogenesis and lipid metabolism, underscoring PlGF's role in age-related MS and its potential as a therapeutic target.
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Affiliation(s)
- Ji Hee Lim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yaeni Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Min Young Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Nim Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Tae Woo Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bum Soon Choi
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Wan-Uk Kim
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hye Won Kim
- Department of Rehabilitation Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea
| | - Ji Yong Park
- Department of Psychology, Korea University, Seoul, Republic of Korea
| | - Cheol Whee Park
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Dauter UM, Gliga AR, Albin M, Broberg K. Longitudinal changes in cardiovascular disease-related proteins in welders. Int Arch Occup Environ Health 2024; 97:803-812. [PMID: 38958674 PMCID: PMC11416389 DOI: 10.1007/s00420-024-02086-8] [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: 01/26/2024] [Accepted: 06/26/2024] [Indexed: 07/04/2024]
Abstract
OBJECTIVE Occupational exposure to welding fumes is linked to a higher risk of cardiovascular disease; however, the threshold exposure level is unknown. Here, we aimed to identify changes in proteins associated with cardiovascular disease in relation to exposure to welding fumes. METHODS Data were obtained from two timepoints six years apart for 338 non-smoking men (171 welders, 167 controls); of these, 174 (78 welders, 96 controls) had measurements available at both timepoints. Exposure was measured as personal respirable dust (adjusted for personal protective equipment), welding years, and cumulative exposure. Proximity extension assays were used to measure a panel of 92 proteins involved in cardiovascular processes in serum samples. Linear mixed models were used for longitudinal analysis. The biological functions and diseases related to the identified proteins were explored using the Ingenuity Pathway Analysis software. RESULTS At both timepoints, the median respirable dust exposure was 0.7 mg/m3 for the welders. Seven proteins were differentially abundant between the welders and controls and increased incrementally with respirable dust: FGF23, CEACAM8, CD40L, PGF, CXCL1, CD84, and HO1. CD84 was significant after adjusting for multiple comparisons. These proteins have been linked to disorders of blood pressure, damage related to clogged blood vessels, and chronic inflammatory disorders. CONCLUSION Exposure to mild steel welding fumes below current occupational exposure limits for respirable particles and welding fumes in Europe and the US (1-5 mg/m3) was associated with changes in the abundance of proteins related to cardiovascular disease. Further research should evaluate the utility of these proteins as prospective biomarkers of occupational cardiovascular disease.
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Affiliation(s)
- Ulrike Maria Dauter
- Institute of Environmental Medicine, Karolinska Institute, Nobels Väg 13, 171 77, Stockholm, Sweden
| | - Anda Roxana Gliga
- Institute of Environmental Medicine, Karolinska Institute, Nobels Väg 13, 171 77, Stockholm, Sweden
| | - Maria Albin
- Institute of Environmental Medicine, Karolinska Institute, Nobels Väg 13, 171 77, Stockholm, Sweden
- Centre for Occupational and Environmental Medicine, Region Stockholm, Sweden
| | - Karin Broberg
- Institute of Environmental Medicine, Karolinska Institute, Nobels Väg 13, 171 77, Stockholm, Sweden.
- Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
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Tarallo V, Magliacane Trotta S, Panico S, D'Orsi L, Mercadante G, Cicatiello V, De Falco S. PlGF and VEGF-A/PlGF Heterodimer are Crucial for Recruitment and Activation of Immune Cells During Choroid Neovascularization. Invest Ophthalmol Vis Sci 2024; 65:12. [PMID: 38967942 PMCID: PMC11232896 DOI: 10.1167/iovs.65.8.12] [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: 03/25/2024] [Accepted: 06/06/2024] [Indexed: 07/06/2024] Open
Abstract
Purpose Recruitment and activation of inflammatory cells, such as retinal microglia/macrophages, in the subretinal space contribute significantly to the pathogenesis of age-related macular degeneration (AMD). This study aims to explore the functional role of vascular endothelial growth factor (VEGF-A), placental growth factor (PlGF) and VEGF-A/PlGF heterodimer in immune homeostasis and activation during pathological laser-induced choroidal neovascularization (CNV). Methods To investigate these roles, we utilized the PlGF-DE knockin (KI) mouse model, which is the full functional knockout (KO) of PlGF. In this model, mice express a variant of PlGF, named PlGF-DE, that is unable to bind and activate VEGFR-1 but can still form heterodimer with VEGF-A. Results Our findings demonstrate that, although there is no difference in healthy conditions, PlGF-DE-KI mice exhibit decreased microglia reactivity and reduced recruitment of both microglia and monocyte-macrophages, compared to wild-type mice during laser-induced CNV. This impairment is associated with a reduction in VEGF receptor 1 (VEGFR-1) phosphorylation in the retinae of PlGF-DE-KI mice compared to C57Bl6/J mice. Corroborating these data, intravitreal delivery of PlGF or VEGF-A/PlGF heterodimer in PlGF-DE-KI mice rescued the immune cell response at the early phase of CNV compared to VEGF-A delivery. Conclusions In summary, our study suggests that targeting PlGF and the VEGF-A/PlGF heterodimer, thereby preventing VEGFR-1 activation, could represent a potential therapeutic approach for the management of inflammatory processes in diseases such as AMD.
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Affiliation(s)
- Valeria Tarallo
- Angiogenesis Lab, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ - CNR, Naples, Italy
| | - Sara Magliacane Trotta
- Angiogenesis Lab, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ - CNR, Naples, Italy
| | - Sonia Panico
- Angiogenesis Lab, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ - CNR, Naples, Italy
| | - Luca D'Orsi
- Angiogenesis Lab, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ - CNR, Naples, Italy
- BIOVIIIx srl, Via Alessandro Manzoni 1, Napoli, Italy
| | - Grazia Mercadante
- Angiogenesis Lab, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ - CNR, Naples, Italy
| | - Valeria Cicatiello
- Angiogenesis Lab, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ - CNR, Naples, Italy
| | - Sandro De Falco
- Angiogenesis Lab, Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ - CNR, Naples, Italy
- BIOVIIIx srl, Via Alessandro Manzoni 1, Napoli, Italy
- AnBition srl, Via Alessandro Manzoni 1, Napoli, Italy
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Balaji S, Rao A, Saraswathi KK, Sethu Nagarajan R, Santhi R, Kim U, Muthukkaruppan V, Vanniarajan A. Focused cancer pathway analysis revealed unique therapeutic targets in retinoblastoma. Med Oncol 2024; 41:168. [PMID: 38834895 DOI: 10.1007/s12032-024-02391-9] [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: 03/12/2024] [Accepted: 04/24/2024] [Indexed: 06/06/2024]
Abstract
Retinoblastoma (RB) is a pediatric cancer of the eye that occurs in 1/15000 live births worldwide. Albeit RB is initiated by the inactivation of RB1 gene, the disease progression relies largely on transcriptional alterations. Therefore, evaluating gene expression is vital to unveil the therapeutic targets in RB management. In this study, we employed an RT2 Profiler™ PCR array for a focused analysis of 84 cancer-specific genes in RB. An interaction network was built with gene expression data to identify the dysregulated pathways in RB. The key transcript alterations identified in 13 tumors by RT2 Profiler™ PCR array was further validated in 15 tumors by independent RT-qPCR. Out of 84 cancer-specific genes, 68 were dysregulated in RB tumors. Among the 68 genes, 23 were chosen for further analysis based on statistical significance and abundance across multiple tumors. Pathway analysis of altered genes showed the frequent perturbations of cell cycle, angiogenesis and apoptotic pathways in RB. Notably, upregulation of MCM2, MKI67, PGF, WEE1, CDC20 and downregulation of COX5A were found in all the tumors. Western blot confirmed the dysregulation of identified targets at protein levels as well. These alterations were more prominent in invasive RB, correlating with the disease pathogenesis. Our molecular analysis thus identified the potential therapeutic targets for improving retinoblastoma treatment. We also suggest that PCR array can be used as a tool for rapid and cost-effective gene expression analysis.
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Affiliation(s)
- Sekaran Balaji
- Department of Molecular Genetics, Aravind Medical Research Foundation, 1, Anna Nagar, Madurai, Tamil Nadu, 625 020, India
| | - Anindita Rao
- Department of Molecular Genetics, Aravind Medical Research Foundation, 1, Anna Nagar, Madurai, Tamil Nadu, 625 020, India
| | - Karuvel Kannan Saraswathi
- Department of Molecular Genetics, Aravind Medical Research Foundation, 1, Anna Nagar, Madurai, Tamil Nadu, 625 020, India
- Department of Molecular Biology, Aravind Medical Research Foundation - Affiliated to Alagappa University, Karaikudi, Tamil Nadu, 630003, India
| | - Rathinavel Sethu Nagarajan
- Department of Molecular Genetics, Aravind Medical Research Foundation, 1, Anna Nagar, Madurai, Tamil Nadu, 625 020, India
- Department of Molecular Biology, Aravind Medical Research Foundation - Affiliated to Alagappa University, Karaikudi, Tamil Nadu, 630003, India
| | - Radhakrishnan Santhi
- Department of Pathology, Aravind Eye Hospital, Madurai, Tamil Nadu, 625 020, India
| | - Usha Kim
- Department of Orbit, Oculoplasty and Ocular Oncology, Aravind Eye Hospital, Madurai, Tamil Nadu, 625 020, India
| | - Veerappan Muthukkaruppan
- Department of Immunology and Stem Cell Biology, Aravind Medical Research Foundation, Madurai, Tamil Nadu, 625 020, India
| | - Ayyasamy Vanniarajan
- Department of Molecular Genetics, Aravind Medical Research Foundation, 1, Anna Nagar, Madurai, Tamil Nadu, 625 020, India.
- Department of Molecular Biology, Aravind Medical Research Foundation - Affiliated to Alagappa University, Karaikudi, Tamil Nadu, 630003, India.
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Sun Z, Yun Z, Lin J, Sun X, Wang Q, Duan J, Li C, Zhang X, Xu S, Wang Z, Xiong X, Yao K. Comprehensive mendelian randomization analysis of plasma proteomics to identify new therapeutic targets for the treatment of coronary heart disease and myocardial infarction. J Transl Med 2024; 22:404. [PMID: 38689297 PMCID: PMC11061979 DOI: 10.1186/s12967-024-05178-8] [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: 02/25/2024] [Accepted: 04/05/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Ischemic heart disease is one of the leading causes of mortality worldwide, and thus calls for development of more effective therapeutic strategies. This study aimed to identify potential therapeutic targets for coronary heart disease (CHD) and myocardial infarction (MI) by investigating the causal relationship between plasma proteins and these conditions. METHODS A two-sample Mendelian randomization (MR) study was performed to evaluate more than 1600 plasma proteins for their causal associations with CHD and MI. The MR findings were further confirmed through Bayesian colocalization, Summary-data-based Mendelian Randomization (SMR), and Transcriptome-Wide Association Studies (TWAS) analyses. Further analyses, including enrichment analysis, single-cell analysis, MR analysis of cardiovascular risk factors, phenome-wide Mendelian Randomization (Phe-MR), and protein-protein interaction (PPI) network construction were conducted to verify the roles of selected causal proteins. RESULTS Thirteen proteins were causally associated with CHD, seven of which were also causal for MI. Among them, FES and PCSK9 were causal proteins for both diseases as determined by several analytical methods. PCSK9 was a risk factor of CHD (OR = 1.25, 95% CI: 1.13-1.38, P = 7.47E-06) and MI (OR = 1.36, 95% CI: 1.21-1.54, P = 2.30E-07), whereas FES was protective against CHD (OR = 0.68, 95% CI: 0.59-0.79, P = 6.40E-07) and MI (OR = 0.65, 95% CI: 0.54-0.77, P = 5.38E-07). Further validation through enrichment and single-cell analysis confirmed the causal effects of these proteins. Moreover, MR analysis of cardiovascular risk factors, Phe-MR, and PPI network provided insights into the potential drug development based on the proteins. CONCLUSIONS This study investigated the causal pathways associated with CHD and MI, highlighting the protective and risk roles of FES and PCSK9, respectively. FES. Specifically, the results showed that these proteins are promising therapeutic targets for future drug development.
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Affiliation(s)
- Ziyi Sun
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 10053, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, 10029, China
| | - Zhangjun Yun
- Graduate School, Beijing University of Chinese Medicine, Beijing, 10029, China
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 10070, China
| | - Jianguo Lin
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 10053, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, 10070, China
| | - Xiaoning Sun
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 10053, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, 10070, China
| | - Qingqing Wang
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 10053, China
| | - Jinlong Duan
- Department of Andrology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 10053, China
| | - Cheng Li
- Eye Hospital, China Academy of Chinese Medical Sciences, Beijing, 10040, China
| | - Xiaoxiao Zhang
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 10053, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, 10070, China
| | - Siyu Xu
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 10053, China
- Graduate School, Beijing University of Chinese Medicine, Beijing, 10029, China
| | - Zeqi Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 10070, China
| | - Xingjiang Xiong
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 10053, China.
| | - Kuiwu Yao
- Department of Cardiovascular, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 10053, China.
- Eye Hospital, China Academy of Chinese Medical Sciences, Beijing, 10040, China.
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Khorami-Sarvestani S, Vanaki N, Shojaeian S, Zarnani K, Stensballe A, Jeddi-Tehrani M, Zarnani AH. Placenta: an old organ with new functions. Front Immunol 2024; 15:1385762. [PMID: 38707901 PMCID: PMC11066266 DOI: 10.3389/fimmu.2024.1385762] [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: 02/13/2024] [Accepted: 04/08/2024] [Indexed: 05/07/2024] Open
Abstract
The transition from oviparity to viviparity and the establishment of feto-maternal communications introduced the placenta as the major anatomical site to provide nutrients, gases, and hormones to the developing fetus. The placenta has endocrine functions, orchestrates maternal adaptations to pregnancy at different periods of pregnancy, and acts as a selective barrier to minimize exposure of developing fetus to xenobiotics, pathogens, and parasites. Despite the fact that this ancient organ is central for establishment of a normal pregnancy in eutherians, the placenta remains one of the least studied organs. The first step of pregnancy, embryo implantation, is finely regulated by the trophoectoderm, the precursor of all trophoblast cells. There is a bidirectional communication between placenta and endometrium leading to decidualization, a critical step for maintenance of pregnancy. There are three-direction interactions between the placenta, maternal immune cells, and the endometrium for adaptation of endometrial immune system to the allogeneic fetus. While 65% of all systemically expressed human proteins have been found in the placenta tissues, it expresses numerous placenta-specific proteins, whose expression are dramatically changed in gestational diseases and could serve as biomarkers for early detection of gestational diseases. Surprisingly, placentation and carcinogenesis exhibit numerous shared features in metabolism and cell behavior, proteins and molecular signatures, signaling pathways, and tissue microenvironment, which proposes the concept of "cancer as ectopic trophoblastic cells". By extensive researches in this novel field, a handful of cancer biomarkers has been discovered. This review paper, which has been inspired in part by our extensive experiences during the past couple of years, highlights new aspects of placental functions with emphasis on its immunomodulatory role in establishment of a successful pregnancy and on a potential link between placentation and carcinogenesis.
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Affiliation(s)
- Sara Khorami-Sarvestani
- Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Negar Vanaki
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sorour Shojaeian
- Department of Biochemistry, School of Medical Sciences, Alborz University of Medical Sciences, Karaj, Iran
| | - Kayhan Zarnani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Allan Stensballe
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
- Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - Mahmood Jeddi-Tehrani
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Amir-Hassan Zarnani
- Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Lee YE, Lee SH, Kim WU. Cytokines, Vascular Endothelial Growth Factors, and PlGF in Autoimmunity: Insights From Rheumatoid Arthritis to Multiple Sclerosis. Immune Netw 2024; 24:e10. [PMID: 38455464 PMCID: PMC10917575 DOI: 10.4110/in.2024.24.e10] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
In this review, we will explore the intricate roles of cytokines and vascular endothelial growth factors in autoimmune diseases (ADs), with a particular focus on rheumatoid arthritis (RA) and multiple sclerosis (MS). AD is characterized by self-destructive immune responses due to auto-reactive T lymphocytes and Abs. Among various types of ADs, RA and MS possess inflammation as a central role but in different sites of the patients. Other common aspects among these two ADs are their chronicity and relapsing-remitting symptoms requiring continuous management. First factor inducing these ADs are cytokines, such as IL-6, TNF-α, and IL-17, which play significant roles in the pathogenesis by contributing to inflammation, immune cell activation, and tissue damage. Secondly, vascular endothelial growth factors, including VEGF and angiopoietins, are crucial in promoting angiogenesis and inflammation in these two ADs. Finally, placental growth factor (PlGF), an emerging factor with bi-directional roles in angiogenesis and T cell differentiation, as we introduce as an "angio-lymphokine" is another key factor in ADs. Thus, while angiogenesis recruits more inflammatory cells into the peripheral sites, cytokines secreted by effector cells play critical roles in the pathogenesis of ADs. Various therapeutic interventions targeting these soluble molecules have shown promise in managing autoimmune pathogenic conditions. However, delicate interplay between cytokines, angiogenic factors, and PlGF has more to be studied when considering their complementary role in actual pathogenic conditions. Understanding the complex interactions among these factors provides valuable insights for the development of innovative therapies for RA and MS, offering hope for improved patient outcomes.
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Affiliation(s)
- Young eun Lee
- Graduate School of Medical Science and Engineering (GSMSE), Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Seung-Hyo Lee
- Graduate School of Medical Science and Engineering (GSMSE), Biomedical Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
| | - Wan-Uk Kim
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul 06591, Korea
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10
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Jumaniyazova E, Lokhonina A, Dzhalilova D, Kosyreva A, Fatkhudinov T. Role of Microenvironmental Components in Head and Neck Squamous Cell Carcinoma. J Pers Med 2023; 13:1616. [PMID: 38003931 PMCID: PMC10672525 DOI: 10.3390/jpm13111616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/04/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Head and neck squamous cell cancer (HNSCC) is one of the ten most common malignant neoplasms, characterized by an aggressive course, high recurrence rate, poor response to treatment, and low survival rate. This creates the need for a deeper understanding of the mechanisms of the pathogenesis of this cancer. The tumor microenvironment (TME) of HNSCC consists of stromal and immune cells, blood and lymphatic vessels, and extracellular matrix. It is known that HNSCC is characterized by complex relationships between cancer cells and TME components. TME components and their dynamic interactions with cancer cells enhance tumor adaptation to the environment, which provides the highly aggressive potential of HNSCC and resistance to antitumor therapy. Basic research aimed at studying the role of TME components in HNSCC carcinogenesis may serve as a key to the discovery of both new biomarkers-predictors of prognosis and targets for new antitumor drugs. This review article focuses on the role and interaction with cancer of TME components such as newly formed vessels, cancer-associated fibroblasts, and extracellular matrix.
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Affiliation(s)
- Enar Jumaniyazova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia; (A.L.); (A.K.); (T.F.)
| | - Anastasiya Lokhonina
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia; (A.L.); (A.K.); (T.F.)
- Avtsyn Research Institute of Human Morphology of FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997 Moscow, Russia
| | - Dzhuliia Dzhalilova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia; (A.L.); (A.K.); (T.F.)
- Avtsyn Research Institute of Human Morphology of FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Anna Kosyreva
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia; (A.L.); (A.K.); (T.F.)
- Avtsyn Research Institute of Human Morphology of FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Timur Fatkhudinov
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia; (A.L.); (A.K.); (T.F.)
- Avtsyn Research Institute of Human Morphology of FSBSI Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
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11
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Zuo B, Zhu S, Zhong G, Bu H, Chen H. Causal association between placental growth factor and coronary heart disease: a Mendelian randomization study. Aging (Albany NY) 2023; 15:10117-10132. [PMID: 37787982 PMCID: PMC10599727 DOI: 10.18632/aging.205061] [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: 02/20/2023] [Accepted: 08/28/2023] [Indexed: 10/04/2023]
Abstract
OBJECTIVE Placental growth factor (PlGF), an important polypeptide hormone, plays an important regulatory role in various physiological processes. Observational studies have shown that PlGF is associated with the risk of coronary heart disease (CHD). However, the causal association between PlGF and CHD is unclear at present. This study aimed to investigate the causal association between genetically predicted PlGF levels and CHD. METHODS Single nucleotide polymorphisms (SNPs) associated with PlGF were selected as instrumental variables (IVs) to evaluate the causal association between genetically predicted circulating PlGF levels and CHD risk by two-sample Mendelian randomization (MR). RESULTS Inverse variance weighted (IVW) analysis showed that there was a suggestive causal association between genetically predicted PlGF level and the risk of CHD (OR = 0.79, 95% CI: 0.66-0.95, P = 0.011) overall. In addition, PlGF levels had a significant negative causal association with the risk of myocardial infarction (OR = 0.83, 95% CI: 0.72-0.95, P = 0.007). A negative correlation trend was found between PlGF level and the risk of angina pectoris (OR = 0.89, 95% CI: 0.79-1.01, P = 0.067). In addition, PlGF levels had a significant negative association with the risk of unstable angina pectoris (OR = 0.78, 95% CI: 0.64-0.94, P = 0.008). PlGF levels were negatively correlated with CHD events with suggestive significance (OR = 0.89, 95% CI: 0.80-0.99, P = 0.046). CONCLUSION Genetically predicted circulating PlGF levels are causally associated with the risk of CHD, especially acute coronary syndrome, and PlGF is a potential therapeutic target for CHD.
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Affiliation(s)
- Bo Zuo
- Department of Cardiology, Cardiovascular Centre, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Sha Zhu
- Department of Neurology, Peking University International Hospital, Beijing 102206, China
| | - Guoting Zhong
- Department of Neurology, Peking University International Hospital, Beijing 102206, China
| | - Haoyang Bu
- Department of Neurology, The First Hospital of Handan, Handan, China
| | - Hui Chen
- Department of Cardiology, Cardiovascular Centre, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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12
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Joshi NP, Madiwale SD, Sundrani DP, Joshi SR. Fatty acids, inflammation and angiogenesis in women with gestational diabetes mellitus. Biochimie 2023; 212:31-40. [PMID: 37059350 DOI: 10.1016/j.biochi.2023.04.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 03/01/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023]
Abstract
Gestational diabetes mellitus (GDM) is a metabolic disorder in pregnancy whose prevalence is on the rise. Reports suggest a likely association between inflammation and maternal GDM. A balance between pro and anti-inflammatory cytokines is necessary for the regulation of maternal inflammation system throughout pregnancy. Along with various inflammatory markers, fatty acids also act as pro-inflammatory molecules. However, studies reporting the role of inflammatory markers in GDM are contradictory, suggesting the need of more studies to better understand the role of inflammation in pregnancies complicated by GDM. Inflammatory response can be regulated by angiopoietins suggesting a link between inflammation and angiogenesis. Placental angiogenesis is a normal physiological process which is tightly regulated during pregnancy. Various pro and anti-angiogenic factors influence the regulation of the feto-placental vascular development. Studies evaluating the levels of angiogenic markers in women with GDM are limited and the findings are inconsistent. This review summarizes the available literature on fatty acids, inflammatory markers and angiogenesis in women with GDM. We also discuss the possible link between them and their influence on placental development in GDM.
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Affiliation(s)
- Nikita P Joshi
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India
| | - Shweta D Madiwale
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India
| | - Deepali P Sundrani
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India
| | - Sadhana R Joshi
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India.
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13
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Jordao H, Herink K, Ka E, McVicker L, Kearns C, McMenamin ÚC. Pre-eclampsia during pregnancy and risk of endometrial cancer: a systematic review and meta-analysis. BMC Womens Health 2023; 23:259. [PMID: 37173714 PMCID: PMC10182685 DOI: 10.1186/s12905-023-02408-x] [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: 01/16/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Pre-eclampsia may be associated with the development of endometrial cancer; however, previous findings have been conflicting. OBJECTIVES To investigate if pre-eclampsia is associated with an increased risk of endometrial cancer. METHOD Two independent reviewers screened titles and abstracts of studies identified in MEDLINE, Embase, and Web of Science databases from inception until March 2022. Studies were included if they investigated pre-eclampsia and subsequent risk of endometrial cancer (or precursor lesions). Random-effects meta-analysis was used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between pre-eclampsia during pregnancy and endometrial cancer risk. MAIN RESULTS There were seven articles identified which investigated endometrial cancer, of which one also investigated endometrial cancer precursors. Overall, the studies include 11,724 endometrial cancer cases. No association was observed between pre-eclampsia and risk of endometrial cancer with moderate heterogeneity observed (pooled HR 1.07, 95% CI 0.79-1.46, I2 = 34.1%). In sensitivity analysis investigating risk of endometrial neoplasia (atypical hyperplasia, carcinoma in situ, or cancer), there was some evidence that pre-eclampsia was associated with an increased risk (HR 1.34, 95% CI 1.15-1.57, I2 = 29.6%). CONCLUSIONS Pre-eclampsia was not associated with an increased risk of endometrial cancer. Additional large studies with information on pre-eclampsia sub-type aiming to investigate endometrial cancer precursor conditions are merited.
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Affiliation(s)
- H Jordao
- Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences-B Building, Royal Victoria Hospital site, Grosvenor Rd, Belfast, Northern Ireland, BT12 6BJ, UK.
| | - K Herink
- Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences-B Building, Royal Victoria Hospital site, Grosvenor Rd, Belfast, Northern Ireland, BT12 6BJ, UK
| | - Eastwood Ka
- Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences-B Building, Royal Victoria Hospital site, Grosvenor Rd, Belfast, Northern Ireland, BT12 6BJ, UK
- Department of St. Michael's Hospital, Bristol, UK
| | - L McVicker
- Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences-B Building, Royal Victoria Hospital site, Grosvenor Rd, Belfast, Northern Ireland, BT12 6BJ, UK
| | - C Kearns
- Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences-B Building, Royal Victoria Hospital site, Grosvenor Rd, Belfast, Northern Ireland, BT12 6BJ, UK
| | - Ú C McMenamin
- Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences-B Building, Royal Victoria Hospital site, Grosvenor Rd, Belfast, Northern Ireland, BT12 6BJ, UK
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14
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Chen L, Yu YN, Liu J, Chen YY, Wang B, Qi YF, Guan S, Liu X, Li B, Zhang YY, Hu Y, Wang Z. Modular networks and genomic variation during progression from stable angina pectoris through ischemic cardiomyopathy to chronic heart failure. Mol Med 2022; 28:140. [DOI: 10.1186/s10020-022-00569-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 11/04/2022] [Indexed: 11/28/2022] Open
Abstract
Abstract
Background
Analyzing disease–disease relationships plays an important role for understanding etiology, disease classification, and drug repositioning. However, as cardiovascular diseases with causative links, the molecular relationship among stable angina pectoris (SAP), ischemic cardiomyopathy (ICM) and chronic heart failure (CHF) is not clear.
Methods
In this study, by integrating the multi-database data, we constructed paired disease progression modules (PDPMs) to identified relationship among SAP, ICM and CHF based on module reconstruction pairs (MRPs) of K-value calculation (a Euclidean distance optimization by integrating module topology parameters and their weights) methods. Finally, enrichment analysis, literature validation and structural variation (SV) were performed to verify the relationship between the three diseases in PDPMs.
Results
Total 16 PDPMs were found with K > 0.3777 among SAP, ICM and CHF, in which 6 pairs in SAP–ICM, 5 pairs for both ICM–CHF and SAP–CHF. SAP–ICM was the most closely related by having the smallest average K-value (K = 0.3899) while the maximum is SAP–CHF (K = 0.4006). According to the function of the validation gene, inflammatory response were through each stage of SAP–ICM–CHF, while SAP–ICM was uniquely involved in fibrosis, and genes were related in affecting the upstream of PI3K–Akt signaling pathway. 4 of the 11 genes (FLT1, KDR, ANGPT2 and PGF) in SAP–ICM–CHF related to angiogenesis in HIF-1 signaling pathway. Furthermore, we identified 62.96% SVs were protein deletion in SAP–ICM–CHF, and 53.85% SVs were defined as protein replication in SAP–ICM, while ICM–CHF genes were mainly affected by protein deletion.
Conclusion
The PDPMs analysis approach combined with genomic structural variation provides a new avenue for determining target associations contributing to disease progression and reveals that inflammation and angiogenesis may be important links among SAP, ICM and CHF progression.
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15
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The Anti-Vascular Endothelial Growth Factor Receptor 1 (VEGFR-1) D16F7 Monoclonal Antibody Inhibits Melanoma Adhesion to Soluble VEGFR-1 and Tissue Invasion in Response to Placenta Growth Factor. Cancers (Basel) 2022; 14:cancers14225578. [PMID: 36428669 PMCID: PMC9688925 DOI: 10.3390/cancers14225578] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/02/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
Placenta growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family involved in tumor-associated angiogenesis and melanoma invasion of the extra-cellular matrix (ECM) through activation of membrane VEGF receptor 1 (VEGFR-1). A soluble VEGFR-1 (sVEGFR-1) form is released in the ECM, where it sequesters proangiogenic factors and stimulates endothelial or tumor cell adhesion and chemotaxis through interaction with α5β1 integrin. The anti-VEGFR-1 monoclonal antibody (D16F7 mAb) inhibits VEGF-A or PlGF-mediated signal transduction without affecting ligand interaction, thus preserving sVEGFR-1 decoy function. The aim of this study was to investigate whether D16F7 mAb hampers melanoma spread by in vitro analysis of cell adhesion to sVEGFR-1, ECM invasion, transmigration through an endothelial cell monolayer and in vivo evaluation of tumor infiltrative potential in a syngeneic murine model. Results indicate that D16F7 mAb significantly inhibits melanoma adhesion to sVEGFR-1 and ECM invasion, as well as transmigration in response to PlGF. Moreover, treatment of melanoma-bearing mice with the anti-VEGFR-1 mAb not only inhibits tumor growth but also induces a significant reduction in bone infiltration associated with a decrease in PlGF-positive melanoma cells. Furthermore, D16F7 mAb reduces PlGF production by melanoma cells. Therefore, blockade of PLGF/VEGFR-1 signaling represents a suitable strategy to counteract the metastatic potential of melanoma.
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16
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Tseng HY, Chen YW, Lee BS, Chang PC, Wang YP, Lin CP, Cheng SJ, Kuo MYP, Hou HH. The neutrophil elastase-upregulated placenta growth factor promotes the pathogenesis and progression of periodontal disease. J Periodontol 2022; 93:1401-1410. [PMID: 34967007 DOI: 10.1002/jper.21-0587] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 12/10/2021] [Accepted: 12/20/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND Periodontal disease is a chronic inflammatory disease. Given its high prevalence, especially in aging population, the detailed mechanisms about pathogenesis of periodontal disease are important issues for study. Neutrophil firstly infiltrates to periodontal disease-associated pathogen loci and amplifies the inflammatory response for host defense. However, excessive neutrophil-secreted neutrophil elastase (NE) damages the affected gingival. In lung and esophageal epithelium, NE had been proved to upregulate several growth factors including placenta growth factor (PGF). PGF is an angiogenic factor with proinflammatory properties, which mediates the progression of inflammatory disease. Therefore, we hypothesize excessive NE upregulates PGF and participates in the pathogenesis and progression of periodontal disease. METHODS In gingival epithelial cells (GEC), growth factors array demonstrated NE-increased growth factors and further be corroborated by Western blot assay and ELISA. The GEC inflammation was evaluated by ELISA. In mice, the immunohistochemistry results demonstrated ligature implantation-induced neutrophil infiltration and growth factor upregulation. By multiplex assay, the ligature-induced proinflammatory cytokines level in gingival crevicular fluid (GCF) were evaluated. Finally, alveolar bone absorption was analyzed by micro-CT images and H & E staining. RESULTS NE upregulated PGF expression and secretion in GEC. PGF promoted GEC to secret IL-1β, IL-6, and TNF-α in GCF In periodontal disease animal model, ligature implantation triggered NE infiltration and PGF expression. Blockade of PGF attenuated the ligature implantation-induced IL-1β, IL-6, TNF-α and MIP-2 secretion and ameliorated the alveolar bone loss in mice. CONCLUSION In conclusion, the NE-induced PGF triggers gingival epithelium inflammation and promotes the pathogenesis and progression of periodontal disease.
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Affiliation(s)
- Hsiu-Yang Tseng
- Department of Mechanical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan
| | - Yi-Wen Chen
- Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.,Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - Bor-Shiunn Lee
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Po-Chun Chang
- Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.,Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Ping Wang
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.,Department of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chun-Pin Lin
- Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.,Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.,Department of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Jung Cheng
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mark Yen-Ping Kuo
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.,Department of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsin-Han Hou
- Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Oral Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
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17
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Azzarito G, Visentin M, Leeners B, Dubey RK. Transcriptomic and Functional Evidence for Differential Effects of MCF-7 Breast Cancer Cell-Secretome on Vascular and Lymphatic Endothelial Cell Growth. Int J Mol Sci 2022; 23:ijms23137192. [PMID: 35806196 PMCID: PMC9266834 DOI: 10.3390/ijms23137192] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/16/2022] [Accepted: 06/24/2022] [Indexed: 01/14/2023] Open
Abstract
Vascular and lymphatic vessels drive breast cancer (BC) growth and metastasis. We assessed the cell growth (proliferation, migration, and capillary formation), gene-, and protein-expression profiles of Vascular Endothelial Cells (VECs) and Lymphatic Endothelial Cells (LECs) exposed to a conditioned medium (CM) from estrogen receptor-positive BC cells (MCF-7) in the presence or absence of Estradiol. We demonstrated that MCF-7-CM stimulated growth and capillary formation in VECs but inhibited LEC growth. Consistently, MCF-7-CM induced ERK1/2 and Akt phosphorylation in VECs and inhibited them in LECs. Gene expression analysis revealed that the LECs were overall (≈10-fold) more sensitive to MCF-7-CM exposure than VECs. Growth/angiogenesis and cell cycle pathways were upregulated in VECs but downregulated in LECs. An angiogenesis proteome array confirmed the upregulation of 23 pro-angiogenesis proteins in VECs. In LECs, the expression of genes related to ATP synthesis and the ATP content were reduced by MCF-7-CM, whereas MTHFD2 gene, involved in folate metabolism and immune evasion, was upregulated. The contrasting effect of MCF-7-CM on the growth of VECs and LECs was reversed by inhibiting the TGF-β signaling pathway. The effect of MCF-7-CM on VEC growth was also reversed by inhibiting the VEGF signaling pathway. In conclusion, BC secretome may facilitate cancer cell survival and tumor growth by simultaneously promoting vascular angiogenesis and inhibiting lymphatic growth. The differential effects of BC secretome on LECs and VECs may be of pathophysiological relevance in BC.
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Affiliation(s)
- Giovanna Azzarito
- Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland; (G.A.); (B.L.)
| | - Michele Visentin
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Brigitte Leeners
- Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland; (G.A.); (B.L.)
| | - Raghvendra K. Dubey
- Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland; (G.A.); (B.L.)
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Correspondence:
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18
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Kopec M, Abramczyk H. The role of pro- and antiangiogenic factors in angiogenesis process by Raman spectroscopy. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2022; 268:120667. [PMID: 34865975 DOI: 10.1016/j.saa.2021.120667] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 06/13/2023]
Abstract
Raman spectroscopy and Raman imaging are powerful techniques to monitor biochemical composition around blood vessel. The aim of this study was to understand the role of pro- and antiangiogenic factors in angiogenesis process. Raman imaging and Raman single spectrum measurements allow the diagnosis of cancer biochemical changes in blood vessel based on several biomarkers simultaneously. We have demonstrated that Raman imaging combined with statistical methods are useful to monitoring pro- and antiangiogenic factors responsible for angiogenesis process. In this work Raman markers of proangiogenic and antiangiogenic factors were identified based on their vibrational signatures. Obtained results can help understand how growing tumor create its vascular system.
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Affiliation(s)
- M Kopec
- Lodz University of Technology, Institute of Applied Radiation Chemistry, Laboratory of Laser Molecular Spectroscopy, Wroblewskiego 15, 93-590 Lodz, Poland.
| | - H Abramczyk
- Lodz University of Technology, Institute of Applied Radiation Chemistry, Laboratory of Laser Molecular Spectroscopy, Wroblewskiego 15, 93-590 Lodz, Poland
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19
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Stalin J, Imhof BA, Coquoz O, Jeitziner R, Hammel P, McKee TA, Jemelin S, Poittevin M, Pocard M, Matthes T, Kaci R, Delorenzi M, Rüegg C, Miljkovic-Licina M. Targeting OLFML3 in Colorectal Cancer Suppresses Tumor Growth and Angiogenesis, and Increases the Efficacy of Anti-PD1 Based Immunotherapy. Cancers (Basel) 2021; 13:cancers13184625. [PMID: 34572851 PMCID: PMC8464773 DOI: 10.3390/cancers13184625] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 12/24/2022] Open
Abstract
The role of the proangiogenic factor olfactomedin-like 3 (OLFML3) in cancer is unclear. To characterize OLFML3 expression in human cancer and its role during tumor development, we undertook tissue expression studies, gene expression analyses of patient tumor samples, in vivo studies in mouse cancer models, and in vitro coculture experiments. OLFML3 was expressed at high levels, mainly in blood vessels, in multiple human cancers. We focused on colorectal cancer (CRC), as elevated expression of OLFML3 mRNA correlated with shorter relapse-free survival, higher tumor grade, and angiogenic microsatellite stable consensus molecular subtype 4 (CMS4). Treatment of multiple in vivo tumor models with OLFML3-blocking antibodies and deletion of the Olfml3 gene from mice decreased lymphangiogenesis, pericyte coverage, and tumor growth. Antibody-mediated blockade of OLFML3 and deletion of host Olfml3 decreased the recruitment of tumor-promoting tumor-associated macrophages and increased infiltration of the tumor microenvironment by NKT cells. Importantly, targeting OLFML3 increased the antitumor efficacy of anti-PD-1 checkpoint inhibitor therapy. Taken together, the results demonstrate that OLFML3 is a promising candidate therapeutic target for CRC.
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Affiliation(s)
- Jimmy Stalin
- Department of Pathology and Immunology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland; (B.A.I.); (P.H.); (S.J.); (M.P.); (M.M.-L.)
- Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700 Fribourg, Switzerland; (O.C.); (C.R.)
- Correspondence: ; Tel.: +41-26-300-8658
| | - Beat A. Imhof
- Department of Pathology and Immunology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland; (B.A.I.); (P.H.); (S.J.); (M.P.); (M.M.-L.)
- Medicity Research Laboratory, University of Turku, Tykistökatu 6A, 20520 Turku, Finland
| | - Oriana Coquoz
- Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700 Fribourg, Switzerland; (O.C.); (C.R.)
| | - Rachel Jeitziner
- Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland; (R.J.); (M.D.)
| | - Philippe Hammel
- Department of Pathology and Immunology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland; (B.A.I.); (P.H.); (S.J.); (M.P.); (M.M.-L.)
| | - Thomas A. McKee
- Division of Clinical Pathology, Geneva University Hospital, Rue Michel Servet 1, CH-1211 Geneva, Switzerland;
| | - Stephane Jemelin
- Department of Pathology and Immunology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland; (B.A.I.); (P.H.); (S.J.); (M.P.); (M.M.-L.)
| | - Marine Poittevin
- Department of Pathology and Immunology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland; (B.A.I.); (P.H.); (S.J.); (M.P.); (M.M.-L.)
| | - Marc Pocard
- CAP Paris-Tech, Université de Paris Diderot, INSERM U1275, 49 Boulevard de la Chapelle, CEDEX 10, F-75475 Paris, France; (M.P.); (R.K.)
- Department of Oncologic and Digestive Surgery, AP-HP, Hôpital Lariboisière, 2 Rue Ambroise Paré, CEDEX 10, F-75475 Paris, France
| | - Thomas Matthes
- Department of Oncology, Hematology Service, Geneva University Hospital, Rue Michel Servet 1, CH-1211 Geneva, Switzerland;
- Department of Diagnostics, Clinical Pathology Service, Geneva University Hospital, Rue Michel Servet 1, CH-1211 Geneva, Switzerland
- Translational Research Centre in Oncohaematology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland
| | - Rachid Kaci
- CAP Paris-Tech, Université de Paris Diderot, INSERM U1275, 49 Boulevard de la Chapelle, CEDEX 10, F-75475 Paris, France; (M.P.); (R.K.)
- Department of Anatomopathology, AP-HP, Hôpital Lariboisière, 2 Rue Ambroise Paré, CEDEX 10, F-75475 Paris, France
| | - Mauro Delorenzi
- Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland; (R.J.); (M.D.)
- Department of Oncology, University Lausanne, CH-1011 Lausanne, Switzerland
| | - Curzio Rüegg
- Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, CH-1700 Fribourg, Switzerland; (O.C.); (C.R.)
| | - Marijana Miljkovic-Licina
- Department of Pathology and Immunology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland; (B.A.I.); (P.H.); (S.J.); (M.P.); (M.M.-L.)
- Department of Oncology, Hematology Service, Geneva University Hospital, Rue Michel Servet 1, CH-1211 Geneva, Switzerland;
- Department of Diagnostics, Clinical Pathology Service, Geneva University Hospital, Rue Michel Servet 1, CH-1211 Geneva, Switzerland
- Translational Research Centre in Oncohaematology, University of Geneva Medical School, Rue Michel Servet 1, CH-1211 Geneva, Switzerland
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20
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Uemura A, Fruttiger M, D'Amore PA, De Falco S, Joussen AM, Sennlaub F, Brunck LR, Johnson KT, Lambrou GN, Rittenhouse KD, Langmann T. VEGFR1 signaling in retinal angiogenesis and microinflammation. Prog Retin Eye Res 2021; 84:100954. [PMID: 33640465 PMCID: PMC8385046 DOI: 10.1016/j.preteyeres.2021.100954] [Citation(s) in RCA: 176] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 02/12/2021] [Accepted: 02/19/2021] [Indexed: 12/13/2022]
Abstract
Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, -C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.
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Affiliation(s)
- Akiyoshi Uemura
- Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
| | - Marcus Fruttiger
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
| | - Patricia A D'Amore
- Schepens Eye Research Institute of Massachusetts Eye and Ear, 20 Staniford Street, Boston, MA, 02114, USA.
| | - Sandro De Falco
- Angiogenesis Laboratory, Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", Via Pietro Castellino 111, 80131 Naples, Italy; ANBITION S.r.l., Via Manzoni 1, 80123, Naples, Italy.
| | - Antonia M Joussen
- Department of Ophthalmology, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, and Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Florian Sennlaub
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France.
| | - Lynne R Brunck
- Bayer Consumer Care AG, Pharmaceuticals, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland.
| | - Kristian T Johnson
- Bayer Consumer Care AG, Pharmaceuticals, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland.
| | - George N Lambrou
- Bayer Consumer Care AG, Pharmaceuticals, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland.
| | - Kay D Rittenhouse
- Bayer Consumer Care AG, Pharmaceuticals, Peter-Merian-Strasse 84, CH-4052 Basel, Switzerland.
| | - Thomas Langmann
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany.
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21
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Shantha Kumara HMC, Miyagaki H, Herath SA, Pettke E, Yan X, Cekic V, Whelan RL. Plasma MMP-2 and MMP-7 levels are elevated first month after surgery and may promote growth of residual metastases. World J Gastrointest Oncol 2021; 13:879-892. [PMID: 34457193 PMCID: PMC8371512 DOI: 10.4251/wjgo.v13.i8.879] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/16/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND MMP-2 also known as gelatinase A and MMP-7 (matrilysin) are members of the zinc-dependent family of MMPs (Matrix metalloproteinase). MMP-2 and MMP-7 are remodeling enzymes that digest extracellular matrix; MMP-2 is extensively expressed during development and is upregulated at sites of tissue damage, inflammation, and in stromal cells of metastatic tumors. MMP-7 is expressed in the epithelial cells and in a variety of cancers including colon tumors. Plasma MMP-2 and MMP-7 levels were assessed before and after minimally invasive colorectal resection for cancer pathology.
AIM To determine plasma MMP-2 and MMP-7 levels before and after minimally invasive colorectal resection for cancer pathology.
METHODS Patients enrolled in a plasma bank for whom plasma was available were eligible. Plasma obtained from preoperative (Preop) and postoperative blood samples was used. Only colorectal cancer (CRC) patients who underwent elective minimally invasive cancer resection with preop, post-operative day (POD) 1, 3 and at least 1 late postop sample (POD 7-34) were included. Late samples were bundled into 7 d blocks (POD 7-13, 14-20, etc.) and treated as single time points. Plasma MMP-2 and MMP-7 levels were determined via enzyme-linked immunosorbent assay in duplicate.
RESULTS Total 88 minimally invasive CRC resection CRC patients were studied (right colectomy, 37%; sigmoid, 24%; and LAR/AR 18%). Cancer stages were: 1, 31%; 2, 30%; 3, 34%; and 4, 5%. Mean Preop MMP-2 plasma level (ng/mL) was 179.3 ± 40.9 (n = 88). Elevated mean levels were noted on POD1 (214.3 ± 51.2, n = 87, P < 0.001), POD3 (258.0 ± 63.9, n = 80, P < 0.001), POD7-13 (229.9 ± 62.3, n = 65, P < 0.001), POD 14-20 (234.9 ± 47.5, n = 25, P < 0.001), POD 21-27 (237.0 ± 63.5, n = 17, P < 0.001,) and POD 28-34 (255.4 ± 59.7, n = 15, P < 0.001). Mean Preop MMP-7 level was 3.9 ± 1.9 (n = 88). No significant differences were noted on POD 1 or 3, however, significantly elevated levels were noted on POD 7-13 (5.7 ± 2.5, n = 65, P < 0.001), POD 14-20 (5.9 ± 2.5, n = 25, P < 0.001), POD 21-27 (6.1 ± 3.6, n = 17, P = 0.002) and on POD 28-34 (6.8 ± 3.3, n = 15 P < 0.001,) vs preop levels.
CONCLUSION MMP-2 levels are elevated for 5 wk and MMP-7 levels elevated for weeks 2-6. The etiology of these changes in unclear, trauma and wound healing likely play a role. These changes may promote residual tumor growth and metastasis.
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Affiliation(s)
- HMC Shantha Kumara
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
| | - Hiromichi Miyagaki
- Department of Gastroenterological Surgery, Osaka University, Suita 565-0862, Osaka, Japan
| | - Sajith A Herath
- Analytic Department, Novartis, Morris Plains, NJ 07905, United States
| | - Erica Pettke
- Department of Surgery, Swedish Medical Center, Seattle, WA 98122, United States
| | - Xiaohong Yan
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
| | - Vesna Cekic
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
| | - Richard L Whelan
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, United States
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22
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Chen Y, Nilsson AH, Goncalves I, Edsfeldt A, Engström G, Melander O, Orho-Melander M, Rauch U, Tengryd C, Venuraju SM, Lahiri A, Liang C, Nilsson J. Evidence for a protective role of placental growth factor in cardiovascular disease. Sci Transl Med 2021; 12:12/572/eabc8587. [PMID: 33268513 DOI: 10.1126/scitranslmed.abc8587] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022]
Abstract
Placental growth factor (PlGF) is a mitogen for endothelial cells, but it can also act as a proinflammatory cytokine. Because it promotes early stages of plaque formation in experimental models of atherosclerosis and was implicated in epidemiological associations with risk of cardiovascular disease (CVD), PlGF has been attributed a pro-atherogenic role. Here, we investigated whether PlGF has a protective role in CVD and whether elevated PlGF reflects activation of repair processes in response to vascular stress. In a population cohort of 4742 individuals with 20 years of follow-up, high baseline plasma PlGF was associated with increased risk of cardiovascular death, myocardial infarction, and stroke, but these associations were lost or weakened when adjusting for cardiovascular risk factors known to cause vascular stress. Exposure of cultured endothelial cells to high glucose, oxidized low-density lipoprotein (LDL) or an inducer of apoptosis enhanced the release of PlGF. Smooth muscle cells and endothelial cells treated with PlGF small interference RNA demonstrated that autocrine PlGF stimulation plays an important role in vascular repair responses. High expression of PlGF in human carotid plaques removed at surgery was associated with a more stable plaque phenotype and a lower risk of future cardiovascular events. When adjusting associations of PlGF with cardiovascular risk in the population cohort for plasma soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2, a biomarker of cellular stress, a high PlGF/TRAIL receptor-2 ratio was associated with a lower risk. Our findings provide evidence for a protective role of PlGF in CVD.
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Affiliation(s)
- Yihong Chen
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.,Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, 200003 Shanghai, China
| | | | - Isabel Goncalves
- Department of Clinical Sciences Malmö, Lund University, 21428 Malmö, Sweden.,Department of Cardiology, Skåne University Hospital, 20502 Malmö, Sweden
| | - Andreas Edsfeldt
- Department of Clinical Sciences Malmö, Lund University, 21428 Malmö, Sweden.,Wallenberg Center for Molecular Medicine, Lund University, Sweden-Klinikgatan 32, 22184 Lund, Sweden
| | - Gunnar Engström
- Department of Clinical Sciences Malmö, Lund University, 21428 Malmö, Sweden
| | - Olle Melander
- Department of Clinical Sciences Malmö, Lund University, 21428 Malmö, Sweden.,Department of Emergency and Internal Medicine, Skåne University Hospital, 20502 Malmö, Sweden
| | | | - Uwe Rauch
- Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
| | | | | | | | - Chun Liang
- Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, 200003 Shanghai, China
| | - Jan Nilsson
- Department of Clinical Sciences Malmö, Lund University, 21428 Malmö, Sweden. .,Department of Emergency and Internal Medicine, Skåne University Hospital, 20502 Malmö, Sweden
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23
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Camargo S, Gofrit ON, Assis A, Mitrani E. Paracrine Signaling from a Three-Dimensional Model of Bladder Carcinoma and from Normal Bladder Switch the Phenotype of Stromal Fibroblasts. Cancers (Basel) 2021; 13:2972. [PMID: 34198488 PMCID: PMC8231763 DOI: 10.3390/cancers13122972] [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: 05/05/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/21/2022] Open
Abstract
We present a three-dimensional model based on acellular scaffolds to recreate bladder carcinoma in vitro that closely describes the in vivo behavior of carcinoma cells. The integrity of the basement membrane and protein composition of the bladder scaffolds were examined by Laminin immunostaining and LC-MS/MS. Human primary bladder carcinoma cells were then grown on standard monolayer cultures and also seeded on the bladder scaffolds. Apparently, carcinoma cells adhered to the scaffold basement membrane and created a contiguous one-layer epithelium (engineered micro-carcinomas (EMCs)). Surprisingly, the gene expression pattern displayed by EMCs was similar to the profile expressed by the carcinoma cells cultured on plastic. However, the pattern of secreted growth factors was significantly different, as VEGF, FGF, and PIGF were secreted at higher levels by EMCs. We found that only the combination of factors secreted by EMCs, but not the carcinoma cells grown on plastic dishes, was able to induce either the pro-inflammatory phenotype or the myofibroblast phenotype depending on the concentration of the secreted factors. We found that the pro-inflammatory phenotype could be reversed. We propose a unique platform that allows one to decipher the paracrine signaling of bladder carcinoma and how this molecular signaling can switch the phenotypes of fibroblasts.
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Affiliation(s)
- Sandra Camargo
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel; (S.C.); (A.A.)
| | - Ofer N. Gofrit
- Department of Urology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel;
| | - Assaf Assis
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel; (S.C.); (A.A.)
| | - Eduardo Mitrani
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel; (S.C.); (A.A.)
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24
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Serrand C, Mura T, Fabbro-Peray P, Seni G, Mousty È, Boudemaghe T, Gris JC. Assessment of All-Cause Cancer Incidence Among Individuals With Preeclampsia or Eclampsia During First Pregnancy. JAMA Netw Open 2021; 4:e2114486. [PMID: 34160606 PMCID: PMC8223101 DOI: 10.1001/jamanetworkopen.2021.14486] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
IMPORTANCE Preeclampsia or eclampsia (preeclampsia/eclampsia) during pregnancy induces major physiological changes and may be associated with specific cancer occurrences in later life. The current data regarding the association between preeclampsia/eclampsia and cancer are heterogeneous, and cancer risk after preeclampsia/eclampsia could be different depending on the organ. These uncertainties warrant reexamination of the association between preeclampsia/eclampsia and the risk of cancer overall and by specific cancer type. OBJECTIVE To evaluate the risk of cancer, overall and by type, after preeclampsia/eclampsia during a first pregnancy. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study used data from the French hospital discharge database to identify all female individuals who had a pregnancy-associated hospitalization between January 1, 2010, and December 31, 2019. To allow a minimum of 2 years for the detection of medical history, individuals with a first detected pregnancy before January 1, 2012, were excluded, as were those with a cancer-associated hospitalization before or during their first detected pregnancy. Exposures, comorbidities, and occurrences of cancer were evaluated using data from the medico-administrative registers of hospitalizations in private and public French hospitals. Cox proportional hazards models were used to analyze cancer risk according to the occurrence of preeclampsia/eclampsia during first pregnancy. EXPOSURES Preeclampsia/eclampsia-associated hospitalization during the first detected pregnancy. MAIN OUTCOMES AND MEASURES The primary outcome was the incidence of cancer, including myelodysplastic or myeloproliferative diseases, after a first pregnancy with and without preeclampsia/eclampsia. RESULTS After exclusions, a total of 4 322 970 female individuals (mean [SD] age at first detected pregnancy, 29.6 [6.2] years) with and without preeclampsia/eclampsia during their first pregnancy were included. Of those, 45 523 individuals (1.1%) were diagnosed with preeclampsia/eclampsia during their first detected pregnancy. The maximum follow-up was 8 years, during which 29 173 individuals (0.7%) were diagnosed with cancer. No significant difference in overall cancer incidence was found between those with and without preeclampsia/eclampsia during their first pregnancy (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.84-1.05). Preeclampsia/eclampsia was associated with an increase in the risk of myelodysplastic syndromes or myeloproliferative diseases (AHR, 2.43; 95% CI, 1.46-4.06) and kidney cancer (AHR, 2.19; 95% CI, 1.09-4.42) and a decrease in the risk of breast cancer (AHR, 0.79; 95% CI, 0.62-0.99) and cervical cancer (AHR, 0.75; 95% CI, 0.58-0.96). CONCLUSIONS AND RELEVANCE In this study, a history of preeclampsia/eclampsia during first pregnancy was associated with an increase in the incidence of myelodysplastic or myeloproliferative diseases and kidney cancer and a decrease in the incidence of cervical and breast cancers. These associations might reflect an underlying common factor among preeclampsia/eclampsia and these pathologies and/or an association between preeclampsia/eclampsia and the development of these cancers.
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Affiliation(s)
- Chris Serrand
- Department of Biostatistics, Clinical Epidemiology, Public Health, and Innovation in Methodology, Centre Hospitalier Universitaire de Nîmes, Groupe Hospitalo–Universitaire Caremeau, Nîmes, France
- Faculty of Medicine, University of Montpellier, Montpellier, France
| | - Thibault Mura
- Department of Biostatistics, Clinical Epidemiology, Public Health, and Innovation in Methodology, Centre Hospitalier Universitaire de Nîmes, Groupe Hospitalo–Universitaire Caremeau, Nîmes, France
- Faculty of Medicine, University of Montpellier, Montpellier, France
| | - Pascale Fabbro-Peray
- Department of Biostatistics, Clinical Epidemiology, Public Health, and Innovation in Methodology, Centre Hospitalier Universitaire de Nîmes, Groupe Hospitalo–Universitaire Caremeau, Nîmes, France
- Faculty of Medicine, University of Montpellier, Montpellier, France
- Institut National de la Santé et de la Recherche Médicale UA11, Institut Desbrest d’Épidémiologie et de Santé Publique, University of Montpellier, Montpellier, France
| | - Gilles Seni
- Department of Medical Information, Methods and Research, Centre Hospitalier Universitaire de Nîmes, University of Montpellier, Nîmes, France
| | - Ève Mousty
- Department of Gynecology and Obstetrics, Centre Hospitalier Universitaire de Nîmes, University of Montpellier, Nîmes, France
| | - Thierry Boudemaghe
- Institut National de la Santé et de la Recherche Médicale UA11, Institut Desbrest d’Épidémiologie et de Santé Publique, University of Montpellier, Montpellier, France
- Department of Medical Information, Methods and Research, Centre Hospitalier Universitaire de Nîmes, University of Montpellier, Nîmes, France
| | - Jean-Christophe Gris
- Institut National de la Santé et de la Recherche Médicale UA11, Institut Desbrest d’Épidémiologie et de Santé Publique, University of Montpellier, Montpellier, France
- Department of Gynecology and Obstetrics, Centre Hospitalier Universitaire de Nîmes, University of Montpellier, Nîmes, France
- Department of Hematology, Centre Hospitalier Universitaire de Nîmes, University of Montpellier, Nîmes, France
- Faculty of Pharmaceutical and Biological Sciences, University of Montpellier, Montpellier, France
- I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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25
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Bejleri J, Jirström E, Donovan P, Williams DJ, Pfeiffer S. Diagnostic and Prognostic Circulating MicroRNA in Acute Stroke: A Systematic and Bioinformatic Analysis of Current Evidence. J Stroke 2021; 23:162-182. [PMID: 34102753 PMCID: PMC8189849 DOI: 10.5853/jos.2020.05085] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 03/19/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND PURPOSE Stroke is the second leading cause of death and disability worldwide and its diagnosis, and assessment of prognosis, remains challenging. There is a need for improved diagnostic and prognostic biomarkers. MicroRNAs (miRNAs) play important roles in the post-transcriptional regulation of gene expression and their secretion and remarkable stability in biofluids highlights their potential as sensitive biomarkers in the diagnosis and prognosis of acute stroke. METHODS We carried out a systematic review to assess current evidence supporting the potential of miRNAs to act as unique diagnostic and prognostic biomarkers in blood samples collected from patients suffering acute stroke within 24 hours of symptoms onset. RESULTS We identified 22 studies eligible for inclusion with 33 dysregulated miRNAs having diagnostic potential in the acute phase of the disease. We identified miR-16, miR-126, and miR-335 as having the highest sensitivity as diagnostic and prognostic biomarkers in acute ischaemic stroke and present original bioinformatic and pathway enrichment analysis of putative miRNA-target interactions. CONCLUSIONS miRNAs represent unique biomarkers which have a promising future in stroke diagnosis and prognosis. However, there is a need for more standardized and consistent methodology for the accurate interpretation and translation of miRNAs as novel specific and sensitive biomarkers into clinical practice.
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Affiliation(s)
- Jorin Bejleri
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Geriatric & Stroke Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Elisabeth Jirström
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.,Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Paul Donovan
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.,Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - David J Williams
- Department of Geriatric & Stroke Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Shona Pfeiffer
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.,Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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26
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Chakraborty G, Patail NK, Hirani R, Nandakumar S, Mazzu YZ, Yoshikawa Y, Atiq M, Jehane LE, Stopsack KH, Lee GSM, Abida W, Morris MJ, Mucci LA, Danila D, Kantoff PW. Attenuation of SRC Kinase Activity Augments PARP Inhibitor-mediated Synthetic Lethality in BRCA2-altered Prostate Tumors. Clin Cancer Res 2021; 27:1792-1806. [PMID: 33334906 PMCID: PMC7956224 DOI: 10.1158/1078-0432.ccr-20-2483] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/04/2020] [Accepted: 12/14/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Alterations in DNA damage repair (DDR) pathway genes occur in 20%-25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although PARP inhibitors (PARPis) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable. EXPERIMENTAL DESIGN We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2 null with BRCA2 wild-type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPis and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids. RESULTS We observed significant enrichment of the SRC signaling pathway in BRCA2-altered mCRPC. BRCA2-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (e.g., dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPis and SRC inhibitors was antiproliferative and had a synergistic effect in BRCA2-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in BRCA2-null prostate cancer cells. Moreover, SRC knockdown increased PARPi sensitivity in BRCA2-null prostate cancer cells. CONCLUSIONS This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPis and SRC inhibitors may be a promising therapeutic strategy for patients with BRCA2-null mCRPC.
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Affiliation(s)
- Goutam Chakraborty
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nabeela Khan Patail
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Rahim Hirani
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Subhiksha Nandakumar
- Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ying Z. Mazzu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yuki Yoshikawa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mohammad Atiq
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lina E. Jehane
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Konrad H. Stopsack
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Wassim Abida
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael J. Morris
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lorelei A. Mucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Daniel Danila
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Philip W. Kantoff
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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27
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Yang SH, Wang XL, Cai J, Wang SH. Diagnostic Value of Circulating PIGF in Combination with Flt-1 in Early Cervical Cancer. Curr Med Sci 2020; 40:973-978. [PMID: 33123910 DOI: 10.1007/s11596-020-2269-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/21/2020] [Indexed: 12/29/2022]
Abstract
The utility of placental growth factor (PlGF) and its receptor VEGFR-1 (Flt-1) as biomarkers for cervical cancer has not been clarified yet. To address this issue, we investigated the levels of soluble PlGF (sPlGF) and soluble Flt-1 (sFlt-1) in the serum from patients with early cervical cancer, cervical intraepithelial neoplasia (CIN) and controls in this study. sPlGF and sFlt-1 were detected in 44 preoperative patients with cervical cancer, 18 cases with CIN, and 20 controls by ELISA. It was found that both sPlGF and sFlt-1 were significantly increased in the cervical cancer group as compared with those in CIN and control groups. sPlGF presented a high diagnostic ability of cervical cancer, with a sensitivity of 61.36% and a specificity of 89.47%; and sFlt-1 with a sensitivity of 50.00% and a specificity of 92.11%. Importantly, the combined use of sPlGF and sFlt-1 could increase the diagnostic rate of cervical cancer, with a sensitivity of 70.45% and a specificity of 92.11%. These results indicated that both sPlGF and sFlt-1 in circulation can serve as possible valuable diagnostic biomarkers for cervical cancer, and the combined use of them can be more valuable to diagnose the patients with early cervical cancer.
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Affiliation(s)
- Shou-Hua Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiao-Ling Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jing Cai
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shao-Hai Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Cheng LN, Lin YX, Liu L, Zhang XH, Xue YQ, Zhou SD, Liu ZL, Zhang H. Assessment of conbercept therapy for high myopia macular neovascularization by optical coherence tomography angiography. Sci Rep 2020; 10:16959. [PMID: 33046787 PMCID: PMC7550325 DOI: 10.1038/s41598-020-74073-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 08/31/2020] [Indexed: 11/09/2022] Open
Abstract
This study aimed to evaluate the efficacy and safety of the intravitreal injection of conbercept in the treatment of macular neovascularization (MNV) secondary to high myopia and to observe the application of optical coherence tomography angiography (OCTA) in the treatment follow-up. We reviewed the medical records of 20 patients (21 eyes) with MNV secondary to high myopia who were enrolled in the Department of Ophthalmology of the First Hospital of China Medical University between May 2018 and January 2020. Each patient received one or more intravitreal injections of conbercept (0.5 mg/0.05 mL). The treatment was conducted according to a 1 + PRN (pro re nata) regimen. The changes of best corrected visual acuity (BCVA), central macular thickness (CMT), and selected MNV and flow areas measured by OCTA were observed over a 6-month follow-up period. The mean logarithm of the minimum angle of resolution (logMAR) BCVA was 1.03 ± 0.61 before treatment and improved to 0.83 ± 0.59 (P = 0.007), 0.78 ± 0.62 (P = 0.001), 0.81 ± 0.73 (P = 0.027), and 0.79 ± 0.72 (P = 0.023) at 1 month, 2 months, 3 months, and 6 months after treatment, respectively. The mean CMT was 358.16 ± 206.11 μm before treatment and decreased to 295.38 ± 178.70 μm (P = 0.003), 288.34 ± 165.60 μm (P = 0.004), 284.36 ± 163.07 μm (P = 0.005), and 283.00 ± 160.32 μm (P = 0.004) at 1 month, 2 months, 3 months, and 6 months after treatment, respectively. Nineteen eyes (90.5%) had stable or improved vision at 6 months of follow-up. One month after conbercept injection, in OCTA images, the small-diameter blood vessels of the MNV decreased, the intertwined small blood vessels decreased or even disappeared, and the main or larger-diameter blood vessels were still present. The mean selected MNV and blood flow areas were 0.62 ± 0.81 and 0.22 ± 0.27 mm2, respectively, before treatment and decreased to 0.23 ± 0.33 and 0.07 ± 0.08 mm2 (P = 0.04 for both), respectively, 1 month after treatment. No drug-related systemic or ocular adverse effects were observed. Our results suggest that conbercept can effectively and safely improve BCVA and reduce CMT in patients with myopic MVN (mMNV). OCTA can be used to observe MNV area, blood flow area, and MNV morphological changes after treatment with conbercept, thus providing a reference for treatment follow-up.
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Affiliation(s)
- Lu-Na Cheng
- Department of Ophthalmology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, China
| | - Yu-Xi Lin
- Department of Ophthalmology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, China
| | - Lei Liu
- Department of Ophthalmology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, China.,Department of Public Service, The First Hospital of China Medical University, Shenyang, 110001, China
| | - Xu-He Zhang
- Department of Ophthalmology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, China
| | - Yan-Qi Xue
- Department of Ophthalmology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, China
| | - Sheng-Di Zhou
- Department of Ophthalmology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, China
| | - Zhe-Li Liu
- Department of Ophthalmology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, China
| | - Han Zhang
- Department of Ophthalmology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, China.
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Overexpression of Placental Growth Factor in Stromal Cells from Benign Prostatic Hyperplasia: Another Piece in the Puzzle? EUR UROL SUPPL 2020; 21:29-32. [PMID: 34337465 PMCID: PMC8317913 DOI: 10.1016/j.euros.2020.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2020] [Indexed: 11/30/2022] Open
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Leplina O, Smetanenko E, Tikhonova M, Batorov E, Tyrinova T, Pasman N, Ostanin A, Chernykh E. Binding of the placental growth factor to VEGF receptor type 1 modulates human T cell functions. J Leukoc Biol 2020; 108:1013-1024. [DOI: 10.1002/jlb.2a0420-723rr] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/02/2020] [Accepted: 04/06/2020] [Indexed: 01/02/2023] Open
Affiliation(s)
- Olga Leplina
- Laboratory of Cellular Immunotherapy Research Institute of Fundamental and Clinical Immunology Novosibirsk Russian Federation
| | - Ekaterina Smetanenko
- Laboratory of Cellular Immunotherapy Research Institute of Fundamental and Clinical Immunology Novosibirsk Russian Federation
| | - Marina Tikhonova
- Laboratory of Cellular Immunotherapy Research Institute of Fundamental and Clinical Immunology Novosibirsk Russian Federation
| | - Egor Batorov
- Laboratory of Cellular Immunotherapy Research Institute of Fundamental and Clinical Immunology Novosibirsk Russian Federation
| | - Tamara Tyrinova
- Laboratory of Cellular Immunotherapy Research Institute of Fundamental and Clinical Immunology Novosibirsk Russian Federation
| | - Natalya Pasman
- Department of Obstetrics and Gynecology Institute of Medicine and Psychology NSU Novosibirsk Russian Federation
| | - Alexander Ostanin
- Laboratory of Cellular Immunotherapy Research Institute of Fundamental and Clinical Immunology Novosibirsk Russian Federation
| | - Elena Chernykh
- Laboratory of Cellular Immunotherapy Research Institute of Fundamental and Clinical Immunology Novosibirsk Russian Federation
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Ma Q, Gu JT, Wang B, Feng J, Yang L, Kang XW, Duan P, Sun X, Liu PJ, Wang JC. PlGF signaling and macrophage repolarization contribute to the anti-neoplastic effect of metformin. Eur J Pharmacol 2019; 863:172696. [PMID: 31562866 DOI: 10.1016/j.ejphar.2019.172696] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 09/23/2019] [Accepted: 09/24/2019] [Indexed: 01/05/2023]
Abstract
Placental growth factor (PlGF) related signaling pathway has been shown to have close relationship with the progression of cancers. Metformin has been reported to have an inhibitory effect on PlGF expression in a breast cancer model. However, little is known about whether the anti-neoplastic activity of metformin is contributed by its inhibitory effect on PlGF expression. Protein, mRNA and secretion levels of PlGF were tested and the proliferation of cancer cells was determined. After treatment of metformin, BALB/c mice bearing 4T1 tumors were sacrificed and immunohistochemistry staining of the tumor sections was obtained. Baseline expression of autocrine PlGF varied between different breast cancer cell lines, while the expression of vascular endothelial growth factor receptor-1 (VEGFR-1) was comparable between cell lines. Other clinical data showed that the expression of PlGF other than VEGFR-1 had a prognostic value for patients with breast cancers. Metformin significantly decreased the secretion and mRNA levels of PlGF, which greatly contributed to its inhibitory effect on the proliferation of breast cancer cells with high P1GF expression. The unresponsiveness of tumor cells with low PlGF expression to genetic silencing was reversed by the supplementation of exogenous PlGF. Systemic metformin administration apparently inhibited the in vivo growth of 4T1 carcinoma, which was accompanied by the repolarization of macrophages from M2 to M1. These findings indicated that both autocrine and paracrine PlGF signaling and macrophage repolarization are involved in the progression of breast cancer, which could be targeted by metformin.
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Affiliation(s)
- Qiang Ma
- Department of peripheral vascular diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
| | - Jing-Tao Gu
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
| | - Bo Wang
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
| | - Jun Feng
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
| | - Lin Yang
- Department of psychiatry, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
| | - Xiao-Wei Kang
- Education Administration Office, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
| | - Peng Duan
- Emergency Department, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
| | - Xin Sun
- Department of Thoracic Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
| | - Pei-Jun Liu
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
| | - Ji-Chang Wang
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China; Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
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Bolukbasi S, Cakir A, Erden B, Karaca G. Comparison of the short-term effect of aflibercept and dexamethasone implant on serous retinal detachment in the treatment of naive diabetic macular edema. Cutan Ocul Toxicol 2019; 38:401-405. [DOI: 10.1080/15569527.2019.1657884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Selim Bolukbasi
- Department of Ophthalmology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Akin Cakir
- Department of Ophthalmology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Burak Erden
- Department of Ophthalmology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Gulderen Karaca
- Department of Ophthalmology, University of Health Sciences, Okmeydani Training and Research Hospital, Istanbul, Turkey
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Hua R, Ning H. Using optical coherence tomography angiography to guide the treatment of pathological myopic patients with submacular hemorrhage. Photodiagnosis Photodyn Ther 2019; 28:105-109. [PMID: 31470121 DOI: 10.1016/j.pdpdt.2019.08.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/24/2019] [Accepted: 08/26/2019] [Indexed: 11/29/2022]
Abstract
The present study aimed to investigate whether optical coherence tomography angiography (OCTA) could be used to guide the treatment of pathological myopic patients with submacular hemorrhage. Two pathological myopia patients with submacular hemorrhage were examined. Initially, choroidal neovascularization (CNV) was not observed during fundus angiography in both patients. However, based on OCTA, the first patient was diagnosed with myopic lacquer crack-related macular hemorrhage, and the second with CNV secondary to punctate inner choroidopathy. The first patient was treated with traditional Chinese medicine administered orally, and the second with intravitreal injections of anti-vascular endothelial growth factor (VEGF). Lesions in both patients were resolved. Submacular hemorrhage in pathological myopia patients could be caused by numerous mechanisms. OCTA is useful in differentiating inflammatory CNV from inflammatory lesions, particularly if CNV is not detected using other multimodal imaging techniques.
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Affiliation(s)
- Rui Hua
- Ophthalmology, The First Affiliated Hospital of China Medical University, No. 155, Nanjingbei Street, Shenyang, 110001, China
| | - Hong Ning
- Ophthalmology, The First Affiliated Hospital of China Medical University, No. 155, Nanjingbei Street, Shenyang, 110001, China.
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Placental growth factor regulates the generation of T H17 cells to link angiogenesis with autoimmunity. Nat Immunol 2019; 20:1348-1359. [PMID: 31406382 DOI: 10.1038/s41590-019-0456-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 06/28/2019] [Indexed: 02/06/2023]
Abstract
Helper T cells actively communicate with adjacent cells by secreting soluble mediators, yet crosstalk between helper T cells and endothelial cells remains poorly understood. Here we found that placental growth factor (PlGF), a homolog of the vascular endothelial growth factor that enhances an angiogenic switch in disease, was selectively secreted by the TH17 subset of helper T cells and promoted angiogenesis. Interestingly, the 'angio-lymphokine' PlGF, in turn, specifically induced the differentiation of pathogenic TH17 cells by activating the transcription factor STAT3 via binding to its receptors and replaced the activity of interleukin-6 in the production of interleukin-17, whereas it suppressed the generation of regulatory T cells. Moreover, T cell-derived PlGF was required for the progression of autoimmune diseases associated with TH17 differentiation, including experimental autoimmune encephalomyelitis and collagen-induced arthritis, in mice. Collectively, our findings provide insights into the PlGF-dictated links among angiogenesis, TH17 cell development and autoimmunity.
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Falkowski S. Résistance aux inhibiteurs des tyrosines kinases dans le cancer du rein. Bull Cancer 2019; 105 Suppl 3:S255-S260. [PMID: 30595154 DOI: 10.1016/s0007-4551(18)30380-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
FOCUS ON RESISTANCE TO TYROSINE KINASE INHIBITORS IN RENAL CANCER: The last decade has seen significant advances in understanding the biology and genetics of kidney cancer, some of which have radically changed treatment standards, including the emergence of targeted therapies. TKIs have significantly improved outcome in patients with metastatic disease. Nevertheless, a subset of patients (approximately 25 %) does not show any clinical benefit from targeted therapies. In many cases, patients initially respond to therapy but resistance to targeted agents has been shown to develop after a median of 6-12 months of treatment. Two general models of tumor resistance to anti-angiogenic agents targeting the VEGF pathway have been proposed: an adaptive (evasive) resistance, which occurs after a prolonged application of a drug (providing a period of tumor control), or intrinsic one (preexisting) non-responsiveness despite the presence of an active agent, showing no therapeutic benefit. Intrinsic resistance is related to tumor redundancy of pro-angiogenic pathways. Acquired resistance is associated with activation of alternative pathways either by upregulation of the VEGF pathway or by recruitment of alternative angiogenic factors responsible for tumor revascularization. Because different combinations and sequences of TKI are tested in clinical trials and immunotherapy (alone or in combination) radically alters patient management in its metastatic disease, the current effort aims at identifying resistance processes, evaluating their importance and proposing rational therapeutic approaches in order to obtain an additional clinical benefit. Our article summarizes the different mechanisms of resistance described in the literature.
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Affiliation(s)
- Sabrina Falkowski
- Service oncologie, polyclinique de Limoges, site Chénieux, 18, rue du Général-Catroux, 87000 Limoges, France.
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The role of placental growth factor (PlGF) and its receptor system in retinal vascular diseases. Prog Retin Eye Res 2018; 69:116-136. [PMID: 30385175 DOI: 10.1016/j.preteyeres.2018.10.006] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 10/23/2018] [Accepted: 10/26/2018] [Indexed: 12/20/2022]
Abstract
Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. Upon binding to VEGF- and neuropilin-receptor sub-types, PlGF modulates a range of neural, glial and vascular cell responses that are distinct from VEGF-A. As PlGF expression is selectively associated with pathological angiogenesis and inflammation, its blockade does not affect the healthy vasculature. PlGF actions have been extensively described in tumor biology but more recently there has been accumulating preclinical evidence that indicates that this growth factor could have an important role in retinal diseases. High levels of PlGF have been found in aqueous humor, vitreous and/or retina of patients exhibiting retinopathies, especially those with diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD). Expression of this growth factor seems to correlate closely with many of the key pathogenic features of early and late retinopathy in preclinical models. For example, studies using genetic modification and/or pharmacological treatment to block PlGF in the laser-induced choroidal neovascularization (CNV) model, oxygen-induced retinopathy model, as well as various murine diabetic models, have shown that PlGF deletion or inhibition can reduce neovascularization, retinal leakage, inflammation and gliosis, without affecting vascular development or inducing neuronal degeneration. Moreover, an inhibitory effect of PlGF blockade on retinal scarring in the mouse CNV model has also been recently demonstrated and was found to be unique for PlGF inhibition, as compared to various VEGF inhibition strategies. Together, these preclinical results suggest that anti-PlGF therapy might have advantages over anti-VEGF treatment, and that it may have clinical applications as a standalone treatment or in combination with anti-VEGF. Additional clinical studies are clearly needed to further elucidate the role of PlGF and its potential as a therapeutic target in ocular diseases.
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Carola C, Ghiringhelli F, Kim S, André T, Barlet J, Bengrine-Lefevre L, Marijon H, Garcia-Larnicol ML, Borg C, Dainese L, Steuer N, Richa H, Benetkiewicz M, Larsen AK, Gramont AD, Chibaudel B. FOLFIRI3-aflibercept in previously treated patients with metastatic colorectal cancer. World J Clin Oncol 2018; 9:110-118. [PMID: 30254966 PMCID: PMC6153125 DOI: 10.5306/wjco.v9.i5.110] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/11/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy and safety of the modified FOLFIRI3-aflibercept as second-line therapy in patients with metastatic colorectal cancer.
METHODS This is a retrospective multicenter cohort, evaluating the efficacy and safety of the association of aflibercept with FOLFIRI3 (day 1: aflibercept 4 mg/kg, folinic acid 400 mg/m2, irinotecan 90 mg/m2, 5-fluorouracil infusion 2400 mg/m2 per 46 h; day 3: irinotecan 90 mg/m2) in patients with previously treated metastatic colorectal cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS Among 74 patients treated in four French centers, nine were excluded due to prior use of aflibercept (n = 3), more than one prior treatment line in irinotecan-naïve patients (n = 3), and inadequate liver function (n = 3). In the “irinotecan-naïve” patients (n = 30), ORR was 43.3% and DCR was 76.7%. Median PFS and OS were 11.3 mo (95%CI: 6.1-29.0) and 17.0 mo (95%CI: 13.0-17.3), respectively. The most common (> 5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), and hypertension (6.7%). In the “pre-exposed irinotecan” patients (n = 35), 20 (57.1%) received ≥ 2 prior lines of treatment. ORR was 34.3% and DCR was 60.0%. Median PFS and OS were 5.7 mo (95%CI: 3.9-10.4) and 14.3 mo (95%CI: 12.8-19.5), respectively.
CONCLUSION Minimally modified FOLFIRI has improvement dramatically the FOLFIRI3-aflibercept efficacy, whatever prior use of irinotecan. A prospective randomized trial is warranted to compare FOLFIRI-aflibercept to FOLFIRI3-aflibercept.
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Affiliation(s)
- Candice Carola
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret 92300, France
| | | | - Stefano Kim
- Department of Medical Oncology, CHU Besançon, Besançon 25030, France
| | - Thierry André
- Department of Medical Oncology, Saint-Antoine Hospital, and Sorbonne Universités, UMPC, Paris 75012, France
| | - Juliette Barlet
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret 92300, France
| | | | - Hélène Marijon
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret 92300, France
| | - Marie-Line Garcia-Larnicol
- Department of Medical Oncology, Saint-Antoine Hospital, and Sorbonne Universités, UMPC, Paris 75012, France
| | - Christophe Borg
- Department of Medical Oncology, CHU Besançon, Besançon 25030, France
| | - Linda Dainese
- Department of Anatomy-Pathology, Paris Pathology Institute, Malakoff 92240, France
| | - Nils Steuer
- Department of Medical Oncology, Saint-Antoine Hospital, and Sorbonne Universités, UMPC, Paris 75012, France
| | - Hubert Richa
- Department of Gastrointestinal Surgery, Franco-British Institute, Levallois-Perret 92300, France
| | | | - Annette K Larsen
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938, Faculté de Médecine Sorbonne Université, Paris 75012, France
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret 92300, France
| | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret 92300, France
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Srivastava A, Shukla V, Tiwari D, Gupta J, Kumar S, Kumar A. Targeted therapy of chronic liver diseases with the inhibitors of angiogenesis. Biomed Pharmacother 2018; 105:256-266. [PMID: 29859468 DOI: 10.1016/j.biopha.2018.05.102] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 05/09/2018] [Accepted: 05/21/2018] [Indexed: 01/09/2023] Open
Abstract
Angiogenesis appears to be intrinsically associated with the progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several studies have suggested that this association is relevant for chronic liver disease (CLD) progression, with angiogenesis. The fact that angiogenesis plays a pivotal role in CLDs gives rise to new opportunities for treating CLDs. Inhibitor of angiogenesis has proved effective for the treatment of patients suffering from CLD. However, it is limited in diagnosis. The last decade has witnessed a plethora of publications which elucidate the potential of angiogenesis inhibitors for the therapy of CLD. The close relationship between the progression of CLDs and angiogenesis emphasizes the need for anti-angiogenic therapy to block/slow down CLD progression. The present review summarizes all these discussions, the results of the related studies carried out to date and the future prospects in this field. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role and future use of angiogenic factors as second-line treatment of CLD. This review compiles relevant findings and offers opinions that have emerged in last few years relating liver angiogenesis and its treatment using anti-angiogenic factors.
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Affiliation(s)
- Ankita Srivastava
- Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Barabanki, Uttar Pradesh, India
| | - Vanistha Shukla
- Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Barabanki, Uttar Pradesh, India
| | - Deepika Tiwari
- Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Barabanki, Uttar Pradesh, India
| | - Jaya Gupta
- Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Barabanki, Uttar Pradesh, India
| | - Sunil Kumar
- Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Barabanki, Uttar Pradesh, India.
| | - Awanish Kumar
- Department of Biotechnology, National Institute of Technology, Raipur, Chhattisgarh, India.
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Chen Y, Hua R. Therapeutic Efficacy of Conbercept for Inflammatory Choroidal Neovascularization. J Ocul Pharmacol Ther 2018; 34:235-236. [PMID: 29185839 DOI: 10.1089/jop.2017.0097] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Yutong Chen
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Rui Hua
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China
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Tan RP, Chan AHP, Lennartsson K, Miravet MM, Lee BSL, Rnjak-Kovacina J, Clayton ZE, Cooke JP, Ng MKC, Patel S, Wise SG. Integration of induced pluripotent stem cell-derived endothelial cells with polycaprolactone/gelatin-based electrospun scaffolds for enhanced therapeutic angiogenesis. Stem Cell Res Ther 2018; 9:70. [PMID: 29562916 PMCID: PMC5863387 DOI: 10.1186/s13287-018-0824-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/19/2018] [Accepted: 03/05/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Induced pluripotent stem-cell derived endothelial cells (iPSC-ECs) can be generated from any somatic cell and their iPSC sources possess unlimited self-renewal. Previous demonstration of their proangiogenic activity makes them a promising cell type for treatment of ischemic injury. As with many other stem cell approaches, the low rate of in-vivo survival has been a major limitation to the efficacy of iPSC-ECs to date. In this study, we aimed to increase the in-vivo lifetime of iPSC-ECs by culturing them on electrospun polycaprolactone (PCL)/gelatin scaffolds, before quantifying the subsequent impact on their proangiogenic function. METHODS iPSC-ECs were isolated and stably transfected with a luciferase reporter to facilitate quantification of cell numbers and non-invasive imaging in-vivo PCL/gelatin scaffolds were engineered using electrospinning to obtain woven meshes of nanofibers. iPSC-ECs were cultured on scaffolds for 7 days. Subsequently, cell growth and function were assessed in vitro followed by implantation in a mouseback subcutaneous model for 7 days. RESULTS Using a matrix of conditions, we found that scaffold blends with ratios of PCL:gelatin of 70:30 (PG73) spun at high flow rates supported the greatest levels of iPSC-EC growth, retention of phenotype, and function in vitro. Implanting iPSC-ECs seeded on PG73 scaffolds in vivo improved their survival up to 3 days, compared to cells directly injected into control wounds, which were no longer observable within 1 h. Enhanced engraftment improved blood perfusion, observed through non-invasive laser Doppler imaging. Immunohistochemistry revealed a corresponding increase in host angiogenic mechanisms characterized by the enhanced recruitment of macrophages and the elevated expression of proangiogenic cytokines vascular endothelial growth factor and placental growth factor. CONCLUSIONS Knowledge of these mechanisms combined with a deeper understanding of the scaffold parameters influencing this function provides the groundwork for optimizing future iPSC-EC therapies utilizing engraftment platforms. The development of combined scaffold and iPSC-EC therapies could ultimately improve therapeutic angiogenesis and the treatment of ischemic injury.
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Affiliation(s)
- Richard P Tan
- The Heart Research Institute, Sydney, NSW, 2042, Australia. .,Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
| | - Alex H P Chan
- The Heart Research Institute, Sydney, NSW, 2042, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | | | | | - Bob S L Lee
- The Heart Research Institute, Sydney, NSW, 2042, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
| | - Jelena Rnjak-Kovacina
- Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Zoe E Clayton
- The Heart Research Institute, Sydney, NSW, 2042, Australia
| | - John P Cooke
- Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, 77030, USA
| | - Martin K C Ng
- The Heart Research Institute, Sydney, NSW, 2042, Australia.,Royal Prince Alfred Hospital, Sydney, NSW, 2042, Australia
| | - Sanjay Patel
- The Heart Research Institute, Sydney, NSW, 2042, Australia.,Royal Prince Alfred Hospital, Sydney, NSW, 2042, Australia
| | - Steven G Wise
- The Heart Research Institute, Sydney, NSW, 2042, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
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41
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Doello K. The role of trophoblastic epigenetic reprogrammation in benign tumor cells on malignant progression: A molecular hypothesis. Med Hypotheses 2018. [PMID: 29523298 DOI: 10.1016/j.mehy.2018.02.019] [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: 11/26/2022]
Abstract
Cancer tissues and placental ones share many properties such as invasiveness, metastasis and local immunosuppressive effects. The goal of the present article is to hypothesize a theory about cancer origin that links placental and cancerous tissues at molecular level. This hypothesis explain that cancer origin could be due to low hypoxic conditions in the peripheral zones of benign tumors which might up-regulate the expression of IGF2, and, consequently, trophoblastic genes. In fact, many phenotypic characteristics and molecular markers are shared between these two cell types (cancerous and trophoblastics ones), providing evidences to support this hypothesis. As a consequence, it could be interesting to demonstrate whether cancer start with a cellular reprogrammation towards a trophoblastic fate in order to design new antitumoral strategies focused on this fact.
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Affiliation(s)
- Kevin Doello
- Medical Oncology Service, Virgen de las Nieves Hospital (Granada), Av. Fuerzas Armadas, sn, 18014 Granada, Spain.
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42
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Graziani G, Ruffini F, Tentori L, Scimeca M, Dorio AS, Atzori MG, Failla CM, Morea V, Bonanno E, D'Atri S, Lacal PM. Antitumor activity of a novel anti-vascular endothelial growth factor receptor-1 monoclonal antibody that does not interfere with ligand binding. Oncotarget 2018; 7:72868-72885. [PMID: 27655684 PMCID: PMC5341950 DOI: 10.18632/oncotarget.12108] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/12/2016] [Indexed: 11/29/2022] Open
Abstract
Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase transmembrane receptor that has also a soluble isoform containing most of the extracellular ligand binding domain (sVEGFR-1). VEGF-A binds to both VEGFR-2 and VEGFR-1, whereas placenta growth factor (PlGF) interacts exclusively with VEGFR-1. In this study we generated an anti-VEGFR-1 mAb (D16F7) by immunizing BALB/C mice with a peptide that we had previously reported to inhibit angiogenesis and endothelial cell migration induced by PlGF. D16F7 did not affect binding of VEGF-A or PlGF to VEGFR-1, thus allowing sVEGFR-1 to act as decoy receptor for these growth factors, but it hampered receptor homodimerization and activation. D16F7 inhibited both the chemotactic response of human endothelial, myelomonocytic and melanoma cells to VEGFR-1 ligands and vasculogenic mimicry by tumor cells. Moreover, D16F7 exerted in vivo antiangiogenic effects in a matrigel plug assay. Importantly, D16F7 inhibited tumor growth and was well tolerated by B6D2F1 mice injected with syngeneic B16F10 melanoma cells. The antitumor effect was associated with melanoma cell apoptosis, vascular abnormalities and decrease of both monocyte/macrophage infiltration and myeloid progenitor mobilization. For all the above, D16F7 may be exploited in the therapy of metastatic melanoma and other tumors or pathological conditions involving VEGFR-1 activation.
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Affiliation(s)
- Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Federica Ruffini
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy
| | - Lucio Tentori
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Manuel Scimeca
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Annalisa S Dorio
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | | | - Cristina M Failla
- Laboratory of Experimental Immunology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy
| | - Veronica Morea
- National Research Council of Italy (CNR), Institute of Molecular Biology and Pathology, Rome, Italy
| | - Elena Bonanno
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Stefania D'Atri
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy
| | - Pedro M Lacal
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy
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43
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Skoda M, Stangret A, Szukiewicz D. Fractalkine and placental growth factor: A duet of inflammation and angiogenesis in cardiovascular disorders. Cytokine Growth Factor Rev 2018; 39:116-123. [DOI: 10.1016/j.cytogfr.2017.12.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 12/18/2017] [Accepted: 12/19/2017] [Indexed: 12/11/2022]
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44
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Atzori MG, Tentori L, Ruffini F, Ceci C, Bonanno E, Scimeca M, Lacal PM, Graziani G. The Anti-Vascular Endothelial Growth Factor Receptor-1 Monoclonal Antibody D16F7 Inhibits Glioma Growth and Angiogenesis In Vivo. J Pharmacol Exp Ther 2018; 364:77-86. [PMID: 29025978 DOI: 10.1124/jpet.117.244434] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 10/10/2017] [Indexed: 03/08/2025] Open
Abstract
The vascular endothelial growth factor (VEGF) receptor-1 (VEGFR-1) is a tyrosine kinase receptor that does not play a relevant role in physiologic angiogenesis in adults, whereas it is important in tumor angiogenesis. In high-grade glioma VEGFR-1 expression by tumor endothelium and neoplastic cells contributes to the aggressive phenotype. We recently generated an anti-VEGFR-1 monoclonal antibody (D16F7 mAb) characterized by a novel mechanism of action, since it hampers receptor activation without interfering with ligand binding. The mAb is able to inhibit chemotaxis and extracellular matrix invasion of glioma cells in vitro stimulated by VEGF-A and by the VEGFR-1-selective ligand placental growth factor (PlGF). In this study, we have investigated the influence of D16F7 on glioma growth and angiogenesis in vivo using C6 glioma cells transfected with the human VEGFR-1. D16F7 was able to inhibit receptor activation and migration and extracellular matrix invasion of C6 cells overexpressing the receptor in response to PlGF and VEGF-A. In nude mice, treatment with 10 and 20 mg/kg D16F7 as a single agent was well tolerated and significantly inhibited glioma growth (P < 0.001). Strikingly, in an intracranial orthotopic model, mice dosed with 20 mg/kg D16F7 demonstrated a 65% increase in median survival time compared with vehicle-treated controls (P < 0.001) with a high percentage of long-term survivors (46%). These effects were associated with glioma cell apoptosis and decreased tumor-associated vessel formation. Overall, these results highlight the therapeutic potential of D16F7 in glioma treatment, deserving further investigation after a humanization process as single agent or in combination therapies.
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Affiliation(s)
- Maria Grazia Atzori
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Lucio Tentori
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Federica Ruffini
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Claudia Ceci
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Elena Bonanno
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Manuel Scimeca
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Pedro Miguel Lacal
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
| | - Grazia Graziani
- Departments of Systems Medicine (M.G.A., L.T., C.C., G.G.) and Experimental Medicine and Surgery (E.B., M.S.), University of Rome Tor Vergata, Rome, Italy; and Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (F.R., P.M.L.)
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Duran I, Lambea J, Maroto P, González-Larriba JL, Flores L, Granados-Principal S, Graupera M, Sáez B, Vivancos A, Casanovas O. Resistance to Targeted Therapies in Renal Cancer: The Importance of Changing the Mechanism of Action. Target Oncol 2017; 12:19-35. [PMID: 27844272 DOI: 10.1007/s11523-016-0463-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Renal cell carcinoma (RCC) is a complex disease characterized by mutations in several genes. Loss of function of the von Hippel-Lindau (VHL) tumour suppressor gene is a very common finding in RCC and leads to up-regulation of hypoxia-inducible factor (HIF)-responsive genes accountable for angiogenesis and cell growth, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Binding of these proteins to their cognate tyrosine kinase receptors on endothelial cells promotes angiogenesis. Promotion of angiogenesis is in part due to the activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway. Inhibition of this pathway decreases protein translation and inhibits both angiogenesis and tumour cell proliferation. Although tyrosine kinase inhibitors (TKIs) stand as the main first-line treatment option for advanced RCC, eventually all patients will become resistant to TKIs. Resistance can be overcome by using second-line treatments with different mechanisms of action, such as inhibitors of mTOR, c-MET, programmed death 1 (PD-1) receptor, or the combination of an mTOR inhibitor (mTORi) with a TKI. In this article, we briefly review current evidence regarding mechanisms of resistance in RCC and treatment strategies to overcome resistance with a special focus on the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- I Duran
- Sección de Oncología Médica, Hospital Universitario Virgen del Rocío, Sevilla, Spain.,Laboratorio de Terapias Avanzadas y Biomarcadores en Oncología, Instituto de Biomedicina de Sevilla, Sevilla, Spain
| | - J Lambea
- Servicio de Oncología Médica, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - P Maroto
- Servicio de Oncología Médica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | | | - S Granados-Principal
- Servicio de Oncología Médica, Complejo Hospitalario de Jaén, Jaén, Spain.,GENYO, Centre for Genomics and Oncological Research (Pfizer/University of Granada/Andalusian Regional Government), PTS Granada, Granada, Spain
| | - M Graupera
- Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, Barcelona, Spain
| | - B Sáez
- Departmento de Bioquímica, Biología Molecular y Celular, Instituto Universitario de Investigación en Nanociencia de Aragón, Universidad de Zaragoza, Zaragoza, Spain
| | - A Vivancos
- Departamento de Bioquímica y Biología Molecular, Universidad Pompeu Fabra, Barcelona, Spain
| | - O Casanovas
- ProCURE Research Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Avinguda Gran Via, 199-203, 08907, Barcelona, Spain.
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46
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Accelerated growth of hemangioblastoma in pregnancy: the role of proangiogenic factors and upregulation of hypoxia-inducible factor (HIF) in a non-oxygen-dependent pathway. Neurosurg Rev 2017; 42:209-226. [DOI: 10.1007/s10143-017-0910-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 09/16/2017] [Accepted: 09/19/2017] [Indexed: 12/28/2022]
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47
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Wang Z, Liu T. Placental growth factor signaling regulates isoform splicing of vascular endothelial growth factor A in the control of lung cancer cell metastasis. Mol Cell Biochem 2017; 439:163-169. [PMID: 28861767 DOI: 10.1007/s11010-017-3145-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 08/02/2017] [Indexed: 12/13/2022]
Abstract
Vascular endothelial growth factor (VEGF) family members play critical and complex roles in the regulation of cancer vascularization and metastasis. The exact molecular control of lung cancer metastasis by VEGF family members is not completely understood. Here, we showed that specimens from non-small cell lung cancer (NSCLC) contained significantly higher levels of placental growth factor (PlGF) than paired non-cancer tissue (p < 0.05, N = 25). Moreover, higher levels of PlGF were detected in NSCLC specimens from the patients who had distal metastases than those who had not. High-PlGF levels appeared to be associated with poor patient survival. In vitro, PlGF dose-dependently increased the ratio of pro-angiogenic VEGF isoform (VEGF165) versus anti-angiogenic VEGF isoform (VEGF165b), seemingly through induction of expression of splicing regulatory factor SRp40, resulting in the enhancement of the cancer cell metastatic potential. Higher levels of SRp40 were detected in NSCLC specimens, compared to paired non-cancer tissue (p < 0.05, N = 25). Finally, a strong correlation was detected between the levels of PlGF and SRp40 in NSCLC specimens (r = 0.83, p < 0.0001, N = 25). Together, these data suggest that PlGF may increase NSCLC metastasis through SRp40-mediated mRNA splicing of VEGF.
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Affiliation(s)
- Zanfeng Wang
- Department of Respiratory Medicine, First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, China.
| | - Tingwei Liu
- Department of Respiratory Medicine, First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, China
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48
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Placenta growth factor mediated gene regulation in sickle cell disease. Blood Rev 2017; 32:61-70. [PMID: 28823762 DOI: 10.1016/j.blre.2017.08.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 08/08/2017] [Accepted: 08/15/2017] [Indexed: 01/07/2023]
Abstract
Sickle cell anemia (SCA) is an autosomal recessive disorder caused by mutation in the β-globin gene. Pulmonary hypertension (PH), a complication of SCA, results in severe morbidity and mortality. PH is a multifactorial disease: systemic vasculopathy, pulmonary vasoconstriction, and endothelial dysfunction and remodeling. Placenta growth factor (PlGF), an angiogenic growth factor, elaborated from erythroid cells, has been shown to contribute to inflammation, pulmonary vasoconstriction and airway hyper-responsiveness (AH) in mouse models of sickle cell disease. In this review, we summarize the cell-signaling mechanism(s) by which PlGF regulates the expression of genes involved in inflammation, PH and AH in cell culture and corroborate these findings in mouse models of SCA and in individuals with SCA. The role of microRNAs (miRNAs) in the post-transcriptional regulation of these genes is presented and how these miRNAs located in their host genes are transcriptionally regulated. An understanding of the transcriptional regulation of these miRNAs provides a new therapeutic approach to ameliorate the clinical manifestations of SCA.
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49
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Atzori MG, Tentori L, Ruffini F, Ceci C, Lisi L, Bonanno E, Scimeca M, Eskilsson E, Daubon T, Miletic H, Ricci Vitiani L, Pallini R, Navarra P, Bjerkvig R, D'Atri S, Lacal PM, Graziani G. The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:106. [PMID: 28797294 PMCID: PMC5553938 DOI: 10.1186/s13046-017-0577-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 08/02/2017] [Indexed: 01/09/2023]
Abstract
BACKGROUND Glioblastoma (GBM) is a highly migratory, invasive, and angiogenic brain tumor. Like vascular endothelial growth factor-A (VEGF-A), placental growth factor (PlGF) promotes GBM angiogenesis. VEGF-A is a ligand for both VEGF receptor-1 (VEGFR-1) and VEGFR-2, while PlGF interacts exclusively with VEGFR-1. We recently generated the novel anti-VEGFR-1 monoclonal antibody (mAb) D16F7 that diminishes VEGFR-1 homodimerization/activation without affecting VEGF-A and PlGF binding. METHODS In the present study, we evaluated the expression of VEGFR-1 in human GBM tissue samples (n = 42) by immunohistochemistry, in cell lines (n = 6) and GBM stem cells (GSCs) (n = 18) by qRT-PCR and/or western blot analysis. In VEGFR-1 positive GBM or GSCs we also analyzed the ability of D16F7 to inhibit GBM invasiveness in response to VEGF-A and PlGF. RESULTS Most of GBM specimens stained positively for VEGFR-1 and all but one GBM cell lines expressed VEGFR-1. On the other hand, in GSCs the expression of the receptor was heterogeneous. D16F7 reduced migration and invasion of VEGFR-1 positive GBM cell lines and patient-derived GSCs in response to VEGF-A and PlGF. Interestingly, this effect was also observed in VEGFR-1 positive GSCs transfected to over-express wild-type EGFR (EGFRwt+) or mutant EGFR (ligand binding domain-deficient EGFRvIII+). Furthermore, D16F7 suppressed intracellular signal transduction in VEGFR-1 over-expressing GBM cells by reducing receptor auto-phosphorylation at tyrosine 1213 and downstream Erk1/2 activation induced by receptor ligands. CONCLUSION The results from this study suggest that VEGFR-1 is a relevant target for GBM therapy and that D16F7-derived humanized mAbs warrant further investigation.
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Affiliation(s)
- Maria Grazia Atzori
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Lucio Tentori
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Federica Ruffini
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Via dei Monti di Creta, 104, 00167, Rome, Italy
| | - Claudia Ceci
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Lucia Lisi
- Istituto di Farmacologia, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italia
| | - Elena Bonanno
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Manuel Scimeca
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Eskil Eskilsson
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Thomas Daubon
- INSERM U1029, University of Bordeaux, Pessac, France.,Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Hrvoje Miletic
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Lucia Ricci Vitiani
- Department of Hematology, Oncology and Molecular Medicine, "Istituto Superiore di Sanità" (ISS), Rome, Italy
| | - Roberto Pallini
- Department of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Pierluigi Navarra
- Istituto di Farmacologia, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italia.,UOC di Farmacologia, Fondazione Policlinico Universitario Agostino Gemelli, Largo Francesco Vito 1, 00168, Roma, Italia
| | - Rolf Bjerkvig
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Stefania D'Atri
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Via dei Monti di Creta, 104, 00167, Rome, Italy
| | - Pedro Miguel Lacal
- Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Via dei Monti di Creta, 104, 00167, Rome, Italy.
| | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
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50
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Li X, Jin Q, Yao Q, Zhou Y, Zou Y, Li Z, Zhang S, Tu C. Placental Growth Factor Contributes to Liver Inflammation, Angiogenesis, Fibrosis in Mice by Promoting Hepatic Macrophage Recruitment and Activation. Front Immunol 2017; 8:801. [PMID: 28744285 PMCID: PMC5504098 DOI: 10.3389/fimmu.2017.00801] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 06/26/2017] [Indexed: 12/17/2022] Open
Abstract
Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, mediates wound healing and inflammatory responses, exerting an effect on liver fibrosis and angiogenesis; however, the precise mechanism remains unclear. The aims of this study are to identify the role of PlGF in liver inflammation and fibrosis induced by bile duct ligation (BDL) in mice and to reveal the underlying molecular mechanism. PlGF small interfering RNA (siRNA) or non-targeting control siRNA was injected by tail vein starting 2 days after BDL. Liver inflammation, fibrosis, angiogenesis, macrophage infiltration, and hepatic stellate cells (HSCs) activation were examined. Our results showed that PlGF was highly expressed in fibrotic livers and mainly distributed in activated HSCs and macrophages. Furthermore, PlGF silencing strongly reduced the severity of liver inflammation and fibrosis, and inhibited the activation of HSCs. Remarkably, PlGF silencing also attenuated BDL-induced hepatic angiogenesis, as evidenced by attenuated liver endothelial cell markers CD31 and von Willebrand factor immunostaining and genes or protein expression. Interestingly, these pathological ameliorations by PlGF silencing were due to a marked reduction in the numbers of intrahepatic F4/80+, CD68+, and Ly6C+ cell populations, which were reflected by a lower expression of these macrophage marker molecules in fibrotic livers. In addition, knockdown of PlGF by siRNA inhibited macrophages activation and substantially suppressed the expression of pro-inflammatory cytokines and chemokines in fibrotic livers. Mechanistically, evaluation of cultured RAW 264.7 cells revealed that VEGF receptor 1 (VEGFR1) mainly involved in mediating the role of PlGF in macrophages recruitment and activation, since using VEGFR1 neutralizing antibody blocking PlGF/VEGFR1 signaling axis significantly inhibited macrophages migration and inflammatory responses. Together, these findings indicate that PlGF plays an important role in liver inflammation, angiogenesis, and fibrosis by promoting hepatic macrophage recruitment and activation, and suggest that blockage of PlGF could be a promising novel therapy for chronic fibrotic liver diseases.
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Affiliation(s)
- Xi Li
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qianwen Jin
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Shanghai, China
| | - Qunyan Yao
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Shanghai, China
| | - Yi Zhou
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Shanghai, China
| | - Yanting Zou
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Shanghai, China
| | - Zheng Li
- Laboratory Animal Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shuncai Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Shanghai, China
| | - Chuantao Tu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Liver Diseases, Shanghai, China
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