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1
Haiko, Paula, Taija Makinen, Salla Keskitalo, Jussi Taipale, Marika J. Karkkainen, Megan E. Baldwin, Steven A. Stacker, Marc G. Achen e Kari Alitalo. "Deletion of Vascular Endothelial Growth Factor C (VEGF-C) and VEGF-D Is Not Equivalent to VEGF Receptor 3 Deletion in Mouse Embryos". Molecular and Cellular Biology 28, n. 15 (2 giugno 2008): 4843–50. http://dx.doi.org/10.1128/mcb.02214-07.
Abstract (sommario):
ABSTRACT Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3 −/− embryos, the Vegfc −/−; Vegfd −/− embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3 −/− embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3 neo hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc +/− mice in the K14-VEGF-D; Vegfc +/− compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo.
2
Eldrid, Charles, Mire Zloh, Constantina Fotinou, Tamas Yelland, Lefan Yu, Filipa Mota, David L. Selwood e Snezana Djordjevic. "VEGFA, B, C: Implications of the C-Terminal Sequence Variations for the Interaction with Neuropilins". Biomolecules 12, n. 3 (26 febbraio 2022): 372. http://dx.doi.org/10.3390/biom12030372.
Abstract (sommario):
Vascular endothelial growth factors (VEGFs) are the key regulators of blood and lymphatic vessels’ formation and function. Each of the proteins from the homologous family VEGFA, VEGFB, VEGFC and VEGFD employs a core cysteine-knot structural domain for the specific interaction with one or more of the cognate tyrosine kinase receptors. Additional diversity is exhibited by the involvement of neuropilins–transmembrane co-receptors, whose b1 domain contains the binding site for the C-terminal sequence of VEGFs. Although all relevant isoforms of VEGFs that interact with neuropilins contain the required C-terminal Arg residue, there is selectivity of neuropilins and VEGF receptors for the VEGF proteins, which is reflected in the physiological roles that they mediate. To decipher the contribution made by the C-terminal sequences of the individual VEGF proteins to that functional differentiation, we determined structures of molecular complexes of neuropilins and VEGF-derived peptides and examined binding interactions for all neuropilin-VEGF pairs experimentally and computationally. While X-ray crystal structures and ligand-binding experiments highlighted similarities between the ligands, the molecular dynamics simulations uncovered conformational preferences of VEGF-derived peptides beyond the C-terminal arginine that contribute to the ligand selectivity of neuropilins. The implications for the design of the selective antagonists of neuropilins’ functions are discussed.
3
Fountzilas, G., N. Angouridakis, R. M. Wirtz, S. Claas, A. Nikolaou e K. T. Kalogeras. "Prognostic value of VEGFC, HER2 and HER3 gene expression in recurrent squamous cell head and neck tumors". Journal of Clinical Oncology 24, n. 18_suppl (20 giugno 2006): 5538. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.5538.
Abstract (sommario):
5538 Background: The main prognostic variables of head and neck squamous cell carcinoma (HNSCC) are the location and size of the tumor and the presence of cervical lymph node metastases. Differential gene expression of members of the HER and VEGF families is a common feature in HNSCC. To elucidate the prognostic value and the interrelation of these factors we performed a detailed gene expression analysis within HNSCC tissue samples Methods: We analyzed fresh frozen tissue from 48 recurrent HNSCC tumors stored at -80oC. RNA was isolated with the RNeasy kit (Qiagen, Inc.), followed by kinetic one-step RT-PCR for the expression of 8 candidate genes (EGFR, HER2, HER3, HER4, VEGFA, VEGFB, VEGFC and VEGFD). Raw data (Ct values) were normalized to RPL37A expression (housekeeper gene) and candidate gene expression between patient groups with differential clinical outcomes was analyzed by using Genedata Expressionist and GraphPad Prism 4 software packages. Median patient follow-up from initial diagnosis was 27 months. Results: Overexpression of VEGFA and EGFR was prominent in most tumors, but did not appear to have any prognostic value. However, VEGFC expression was significantly higher (p = 0.0002) in the tumors of patients with poor overall survival (< 27 months). Interestingly, these tumors were further characterized by significantly lower expression levels of HER2 and HER3. Median survival of patients with tumor VEGFC expression levels of >600 was calculated to be 42 months from initial diagnosis (Kaplan-Meier Survival Analysis), compared to 182 months in the rest of the patients. Conclusions: We have found that elevated VEGFC expression and low expression of HER2 and HER3 correlate with poor outcome in recurrent HNSCC patients. VEGFC preferably binds to the VEGFR3, which is predominantly expressed on lymphatic vessels. Overexpression of VEGFC may therefore result in the establishment of intratumoral lymphatic vessels, which have been shown to facilitate the dissemination of tumor cells into lymph nodes and the formation of distant metastases. We conclude that the determination of VEGFC, HER2 and HER3 expression may be of high prognostic value in HNSCC patients and that it may serve in the early identification of aggressive HNSCC subtypes. No significant financial relationships to disclose.
4
Secker, Genevieve A., e Natasha L. Harvey. "Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update". International Journal of Molecular Sciences 22, n. 14 (20 luglio 2021): 7760. http://dx.doi.org/10.3390/ijms22147760.
Abstract (sommario):
The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.
5
Sanmartin, Elena, Eloisa Jantus-Lewintre, Rafael Sirera, Jose Javier Sanchez, Marta Usó, Sandra Gallach, Ana Blasco et al. "Prognostic value of “angiogenic” risk score in early-stage NSCLC." Journal of Clinical Oncology 30, n. 15_suppl (20 maggio 2012): 10594. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10594.
Abstract (sommario):
10594 Background: Angiogenesis is a key mechanism in tumor growth and dissemination mainly regulated by VEGF family members. We analyze the expression of 11 angiogenic genes in a cohort of resectable NSCLC patients and correlate them with clinico-pathological variables and prognosis. Methods: RNA was obtained from tumor and normal lung specimens from 175 NSCLC patients. RT-PCR was performed to assess the expression of HIF1-A, PIGF, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, NRP1 and NRP2. Relative expression was normalized by an endogenous gene (GUS) using the Pfaffl formulae. Differences were considered statistically significant at p<0.05. Results: We found that tumor samples had a significant higher expression of PIGF and lower expression of VEGFD, VEGFR2, and VEGFR3 compared with normal tissue (2.76X, 0.035X, 0.417X and 0.426X, respectively). The group of patients with higher expression levels of VEGFA or PlGF had a significantly reduced TTP (p=0.024 and p=0.027, respectively) and OS (p=0.055 and p=0.048, respectively) whereas those patients with values of VEGFB or VEGFD below the median had reduced TTP (p=0.020 and p=0.135, respectively) and OS (p=0.003 and p=0.089, respectively). The multivariate Cox regression analysis revealed that VEGFA, VEGFB and PlGF were independent prognostic markers for TTP and OS and based on these results we generated an “angiogenic” risk score model. TTP and OS were significantly different among the low, medium and high risk score patients (Table). Conclusions: VEGF family members are master control genes of the angiogenic process and have a crucial role in the prognostic of the disease. We found differences in the expression of four genes between tumor and normal lung samples. An “angiogenic” risk score (based on the expression of PlGF, VEGF-A and VEGF-B) significantly predicts OS and TTP in our cohort of early-stage NSCLC patients. Validation in an independent cohort is needed. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII. [Table: see text]
6
Jantus-Lewintre, Eloisa, Marta Usó, Elena Sanmartin, Sandra Gallach, Rafael Sirera, Ana Blasco, Cristina Hernando et al. "Ratios between VEGF ligands and receptors in tumor and stroma have impact on the outcome in resectable NSCLC." Journal of Clinical Oncology 31, n. 15_suppl (20 maggio 2013): e22147-e22147. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22147.
Abstract (sommario):
e22147 Background: In tumor angiogenesis there is a complex interplay between endothelial, stromal and tumor cells. Some key regulators of this process are the members of the vascular endothelial growth factor (VEGF) family of ligands and receptors and the neuropilins (NRP). This study analyzes the correlations between the expression of these angiogenic factors in tumor cells and tumor stroma, and their prognostic role in tissue samples from resected non-small cell lung cancer (NSCLC) patients. Methods: Representative tumor and stroma areas from FFPE tissue samples of 125 early-stage NSCLC patients were carefully micro-dissected. RNA isolated from the samples was retrotranscripted and preamplified. RTqPCR was performed using hydrolysis probes (TaqMan, Applied Biosystems) and relative quantification was calculated using GAPDH and CDKN1B as endogenous controls. Results were normalized against a human cDNA (Clontech) as a reference. All statistical analyses were considered significant at p<0.05. Results: Paired Wilcoxon test revealed differences between tumor and stroma gene expression for VEGFB (p<0.0001), VEGFC (p<0.0001), VEGFR-1 (p<0.0001), VEGFR-2 (p=0.020), VEGFR-3 (p< 0.0001), NRP-1 (p=0.001) and NRP-2 (p< 0.0001). Survival analyses showed that those patients with higher levels of the Ratio Stromal-VEGFA/ Tumoral-VEGFR-2 had worse time to progression (TTP) (median 26.23 months vs NR, p=0.013) and overall survival (OS) (median 29.50 months vs NR, p=0.001). Similarly, those patients with higher levels of the Ratio Stromal-VEGFC/Tumoral-VEGFR-3 had worse TTP (median 23.30 vs 70.53 months, p=0.015) and OS (median 37.20 months vs NR, p=0.023). Conclusions: Our results show significant differences in the expression of VEGF family members between tumor and stromal cells. This may indicate the importance of the tumor-stroma interaction when trying to understand the angiogenic process. Furthermore, the combination of the ligands expression in stroma and their receptors in tumor may have a prognostic value in NSCLC patients. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII.
7
Hunter, Stephanie, Braydon Nault, Kingsley Chukwunonso Ugwuagbo, Sujit Maiti e Mousumi Majumder. "Mir526b and Mir655 Promote Tumour Associated Angiogenesis and Lymphangiogenesis in Breast Cancer". Cancers 11, n. 7 (4 luglio 2019): 938. http://dx.doi.org/10.3390/cancers11070938.
Abstract (sommario):
MicroRNAs (miRNAs) are small endogenously produced RNAs, which regulate growth and development, and oncogenic miRNA regulate tumor growth and metastasis. Tumour-associated angiogenesis and lymphangiogenesis are processes involving the release of growth factors from tumour cells into the microenvioronemnt to communicate with endothelial cells to induce vascular propagation. Here, we examined the roles of cyclo-oxygenase (COX)-2 induced miR526b and miR655 in tumour-associated angiogenesis and lymphangiogenesis. Ectopic overexpression of miR526b and miR655 in poorly metastatic estrogen receptor (ER) positive MCF7 breast cancer cells resulted in upregulation of angiogenesis and lymphangiogenesis markers vascular endothelial growth factor A (VEGFA); VEGFC; VEGFD; COX-2; lymphatic vessel endothelial hyaluronan receptor-1 (LYVE1); and receptors VEGFR1, VEGFR2, and EP4. Further, miRNA-high cell free conditioned media promoted migration and tube formation by human umbilical vein endothelial cells (HUVECs), and upregulated VEGFR1, VEGFR2, and EP4 expression, showing paracrine stimulation of miRNA in the tumor microenvironment. The miRNA-induced migration and tube formation phenotypes were abrogated with EP4 antagonist or PI3K/Akt inhibitor treatments, confirming the involvement of the EP4 and PI3K/Akt pathway. Tumour supressor gene PTEN was found to be downregulated in miRNA high cells, confirming that it is a target of both miRNAs. PTEN inhibits hypoxia-inducible factor-1 (HIF1α) and the PI3K/Akt pathway, and loss of regulation of these pathways through PTEN results in upregulation of VEGF expression. Moreover, in breast tumors, angiogenesis marker VEGFA and lymphangiogenesis marker VEGFD expression was found to be significantly higher compared with non-adjacent control, and expression of miR526b and miR655 was positively correlated with VEGFA, VEGFC, VEGFD, CD31, and LYVE1 expression in breast tumour samples. These findings further strengthen the role of miRNAs as breast cancer biomarkers and EP4 as a potential therapeutic target to abrogate miRNA-induced angiogenesis and lymphangiogenesis in breast cancer.
8
McCarter, Anna L., e Michael T. Dellinger. "Trametinib Inhibits Lymphatic Vessel Invasion of Bone in a Mouse Model of Gorham-Stout Disease". Journal of Vascular Anomalies 4, n. 4 (15 novembre 2023): e070. http://dx.doi.org/10.1097/jova.0000000000000070.
Abstract (sommario):
Objective: Gorham-Stout disease (GSD) is a rare lymphatic anomaly that can be caused by somatic activating mutations in KRAS. This discovery has led investigators to suggest that MEK inhibitors could be a novel treatment for GSD. However, the effect of MEK inhibitors on bone disease in animal models of GSD has not been investigated. We recently reported that Osx-tTA;TetO-Vegfc mice exhibit a phenotype that resembles GSD. Osx-tTA;TetO-Vegfc mice overexpress vascular endothelial growth factor-C (VEGF-C) in bone, which stimulates the development of lymphatic vessels in bone and the gradual loss of cortical bone. The objective of this study was to characterize the effect of trametinib, an FDA-approved MEK1/2 inhibitor, on lymphangiogenesis and osteolysis in Osx-tTA;TetO-Vegfc mice. Methods: Immunoblotting was performed to assess the effect of trametinib on VEGF-C-induced phosphorylation of ERK1/2, AKT, and S6 in primary human lymphatic endothelial cells. Prevention and intervention experiments were performed to determine the effect of trametinib on lymphangiogenesis and osteolysis in Osx-tTA;TetO-Vegfc mice. Results: We found that trametinib blocked VEGF-C-induced phosphorylation of ERK1/2 in primary human lymphatic endothelial cells. We also found that trametinib prevented VEGF-C-induced lymphatic invasion of bone and cortical bone loss in Osx-tTA;TetO-Vegfc mice. Additionally, trametinib slowed the progression of disease in Osx-tTA;TetO-Vegfc mice with established disease. However, it did not reverse disease in Osx-tTA;TetO-Vegfc mice. Conclusion: Our results show trametinib impacts bone disease in Osx-tTA;TetO-Vegfc mice. These findings further support the testing of MEK inhibitors in patients with GSD and other RAS pathway-driven complex lymphatic anomalies with bone involvement.
9
Lim, Lillian, Hung Bui, Olivia Farrelly, Jisheng Yang, Li Li, David Enis, Wanshu Ma et al. "Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC". Blood 134, n. 20 (27 settembre 2019): 1764–75. http://dx.doi.org/10.1182/blood.2019001736.
Abstract (sommario):
Key Points Platelet activation supports lymphatic vessel growth during wound healing through release of the lymphangiogenic factor VEGFC. Thrombin and plasmin support lymphatic vessel growth through proteolytic activation of the lymphangiogenic factors VEGFC and VEGFD.
10
Dumond, Aurore, Christopher Montemagno, Valérie Vial, Renaud Grépin e Gilles Pagès. "Anti-Vascular Endothelial Growth Factor C Antibodies Efficiently Inhibit the Growth of Experimental Clear Cell Renal Cell Carcinomas". Cells 10, n. 5 (17 maggio 2021): 1222. http://dx.doi.org/10.3390/cells10051222.
Abstract (sommario):
Despite improvement during the last ten years in the longevity of patients with metastatic clear cell renal cell carcinoma (mccRCC) the disease remains incurable. Hence, new therapeutic strategies are urgently needed. Relapse following anti-angiogenic treatment depends on the over-expression of vascular endothelial growth factor C (VEGFC), one of the main drivers of lymphangiogenesis. Therefore, we developed specific mouse monoclonal antibodies and evaluated their therapeutic efficacy in vitro and in vivo. Immunization of mice with the domain of VEGFC that stimulates the VEGF receptor 3 (VEGFR3) led to the selection of one hybridoma producing specific anti-VEGFC monoclonal antibodies. The selected 1E9 antibodies were sequenced, and the corresponding variable light and heavy chains were subcloned into expression vectors in frame with sequences encoding the human IgG1 constant heavy and light chains. CHO cells were stably transfected and cloned to produce chimeric antibodies. These antibodies inhibited the activation of VEGFR3 signaling, and therefore the proliferation and migration of VEGFC-stimulated endothelial cells. Moreover, they inhibited the proliferation of VEGFC-expressing renal cancer cells through NRP2 signaling. 1E9 antibodies inhibited the growth of experimental RCC, and their therapeutic efficacy was enhanced by the anti-VEGF antibody bevacizumab. Hence, our results suggest that targeting VEGFC could have a relevant therapeutic impact on mccRCC that relapse following anti-angiogenic treatment.
11
Shi, Xinwei, Guoqiang Zheng, Hao Liu, Jing Cao, Wanlu Liu, Yuqi Li, Fuyuan Qiao, Dongrui Deng e Yuanyuan Wu. "Vascular endothelial growth factor C participates in regulation of maspin in extravillous trophoblast cell migration and invasion". Reproduction, Fertility and Development 31, n. 8 (2019): 1410. http://dx.doi.org/10.1071/rd18438.
Abstract (sommario):
Mammary serine protease inhibitor (maspin; also known as serpin family B member 5 (SERPINB5)) plays a vital role in regulating the biological functions of extravillous trophoblast (EVT) cells, but the mechanism remains unclear. Vascular endothelial growth factor (VEGF) C is a signature angiogenic molecule expressed and secreted by first-trimester trophoblasts, and bioinformatics analyses has revealed upregulation of VEGFC in pre-eclampsia. The aim of this study was to explore whether maspin regulates EVT cells by regulating the expression of VEGFC. Reverse transcription–polymerase chain reaction and western blotting were used to investigate the effects of hypoxia on the expression of VEGFC in EVT cells. Cells were treated with recombinant (r) maspin and decitabine (to selectively inhibit DNA methyltransferases and then upregulate maspin gene expression), and the effects on VEGFC expression evaluated. In addition, the effects of rVEGFC on the biological functions of EVT cells invitro were evaluated using cell migration and invasion assays. Hypoxia increased the expression of VEGFC in EVT cells. rMaspin upregulated the expression of VEGFC in normoxic EVT cells, and downregulated the expression of VEGFC in hypoxic EVT cells at 24h. Decitabine increased VEGFC expression in normoxic EVT cells, but had no significant effect on VEGFC expression in hypoxic EVT cells. rVEGFC promoted the migration and invasion of normoxic EVT cells and inhibited the invasion of hypoxic EVT cells. These results suggest that VEGFC is involved in the regulation of maspin in EVT cell migration and invasion. However, other molecular mechanisms may be involved and require further investigation.
12
Kim, Hyeong Su, Dae Young Zang, Sung-Hwa Sohn, Bohyun Kim e Hee Jung Sul. "Effect of tivantinib on VEGF signaling pathways and apoptosis of gastric cancer cells with c-MET or VEGFA amplification." Journal of Clinical Oncology 37, n. 15_suppl (20 maggio 2019): e14719-e14719. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14719.
Abstract (sommario):
e14719 Background: VEGFA is the key mediator of angiogenesis in cancer and previous studies reported that VEGFA expression was significantly up-regulated in gastric cancer tissues compared with matched normal tissues. We showed that increased levels of VEGFA are significantly associated with expression of hepatocyte growth factor receptor (MET) (r = 0.6255, P < 0.0001). In addition, it is well known that c-MET is potentially a highly plausible target for cancer therapy in gastric cancer. In this study, cytotoxic activity of tivantinib were evaluated in gastric cancer cells with high c-MET expression or VEGFA amplification. Methods: In this study, Western blot and quantitative real-time PCR analysis were used to detect the expression of protein and genes after treatment of tivantinib. In addition, MTS, flow cytometry, and migration assay were used. Results: Tivantinib inhibited growths of a high c-MET-expressed or VEGFA-amplified cell lines. Furthermore, in migration and apoptosis analysis, tivantinib induced apoptosis of SNU620, MKN45 (carried VEGFB mutation), AGS, and MKN28 cells but not in KATO III (carried VEGFB and VEGFC mutation) cells. We also found that tivantinib inhibited the VEGF signaling pathway and MYC expression in VEGFA-amplified gastric cancer cell lines. Conclusions: The data indicate that tivantinib could be a potential therapeutic agent for the treatment of gastric cancer with high c-MET expression or VEGFA amplification.
13
Xu, Kai, Chuan-ling Wu, Zhi-xin Wang, Hai-jiu Wang, Feng-jiao Yin, Wen-deng Li, Chu-chu Liu e Hai-ning Fan. "VEGF Family Gene Expression as Prognostic Biomarkers for Alzheimer’s Disease and Primary Liver Cancer". Computational and Mathematical Methods in Medicine 2021 (20 novembre 2021): 1–15. http://dx.doi.org/10.1155/2021/3422393.
Abstract (sommario):
Background. To analyze the expression of vascular endothelial growth factor (VEGF) in hepatocellular carcinoma (HCC) and cognitive impairment, explore the relationship between the expression of VEGF family genes and prognosis of patients with HCC, and evaluate the predictive ability of VEGF in cognitive impairment using computerized methods. Methods. VEGF expression in liver cancer tissues and normal tissues was analyzed using bioinformatics methods. The Kaplan-Meier survival analysis method was also used to analyze the relationship between VEGF expression and the prognosis of patients with HCC. Furthermore, immune infiltration assessment and gene set enrichment analysis were performed. Meanwhile, the differential expression of VEGF family genes between patients with Alzheimer’s disease (AD) and healthy controls was also checked. Results. Based on The Cancer Genome Atlas (TCGA) database, the VEGF family genes (VEFGA, VEGFB, VEGFC, and VEGFD) were highly expressed in cancer tissues and were significantly associated with poor prognosis in HCC. In HCC, the VEGF family genes showed significant heterogeneity in their functional and immune infiltration characteristics. Finally, VEGF family genes were identified as prognostic biomarkers in AD and risk prediction markers in HCC. Conclusions. VEGF is highly expressed in patients with HCC and lowly expressed in patients with AD. VEGF has opposite opposing roles in the treatment of tumors and cognitive impairment.
14
de Jonge, Hendrik JM, Peter Valk, Kim R. Kampen, Arja ter Elst, Gertjan Kaspers, Jacqueline Cloos, C. Michel Zwaan et al. "VEGFC Predicts Poor Outcome in Pediatric as Well as Adult Acute Myeloid Leukemia: Insights in Associated Gene Expression Profiles." Blood 114, n. 22 (20 novembre 2009): 997. http://dx.doi.org/10.1182/blood.v114.22.997.997.
Abstract (sommario):
Abstract Abstract 997 Poster Board I-19 A high vascular endothelial growth factor-C (VEGFC) mRNA level of primary blasts of pediatric Acute Myeloid Leukemia (AML) patients correlates with increased in vitro drug resistance and slow AML blast disappearance during induction therapy in vivo; measured by higher blast counts on day 15 in the bone marrow and a prolonged interval towards complete remission (HJM de Jonge et al. Clinical Cancer Research 2008). We set out to study both the effect of VEGFC on long term survival in AML and elucidate gene expression profiles associated with VEGFC expression by using Affymetrix HGU133Plus2.0 gene expression data of 100 pediatric and 525 adult AML patients. Pediatric AML patients with a high VEGFC mRNA expression level (i.e. above the median VEGFC expression level) showed a significantly shortened overall survival (P = .041, hazard ratio = 1,81). Among the adult cohort of 525 AML samples, patients with a high VEGFC mRNA level also had significantly reduced overall survival and event free survival (OS and EFS) compared to patients with a low VEGFC level (P < .001, hazard ratio = 1,41 for OS and P = .002, hazard ratio = 1,44 for EFS). The continuous variable VEGFC maintained its prognostic significance for OS and EFS in a multivariate cox-regression model after correction for possible confounding effects of age, white blood cell count, cytogenetic risk group (i.e. favorable, intermediate and unfavorable), NPM1 mutation and FLT3-ITD (P = .031, odds ratio 1.37 for OS and P = .008, odds ratio 1.42 for EFS). Differentially expressed probe sets were identified that distinguished patients with high from those with low VEGFC mRNA expression using a multivariate permutation test in Biometric Research Branch ArrayTools (BRB ArrayTools). Next, gene arrays of the pediatric AML cohort and a publicly available adult AML cohort of 180 gene arrays (Tomasson et al. Blood 2008) were used for validation of these probe sets. Finally, after two validation steps 569 probe sets were found to show differential high expression and 51 probe sets revealed differential low expression in AML with high mRNA levels of VEGFC, representative of distinctive biological processes (represented by GO-categories). Cell proliferation, VEGF receptor activity, signal transduction (e.g. PAK3 and SOS2 which are upstream activators of MEK1) and angiogenesis were upregulated, whereas genes associated with apoptosis (e.g. TIA1 and ANP32A) were found to be down regulated in AML with elevated VEGFC. In conclusion, high VEGFC mRNA expression levels are associated with reduced survival in adult and pediatric AML. Following the analysis of gene expression data in three independent AML cohorts the data suggest the involvement of specific biological processes in AML with (high) VEGFC expression with potential therapeutic impact. Disclosures: No relevant conflicts of interest to declare.
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Girling, Jane E., e Peter A. W. Rogers. "Regulation of endometrial vascular remodelling: role of the vascular endothelial growth factor family and the angiopoietin–TIE signalling system". REPRODUCTION 138, n. 6 (dicembre 2009): 883–93. http://dx.doi.org/10.1530/rep-09-0147.
Abstract (sommario):
Angiogenesis, lymphangiogenesis and vascular maturation occur on a regular, physiological basis in human endometrium. These processes form part of a continuum of vascular remodelling involving numerous regulatory factors. Key factors include vascular endothelial growth factor (VEGF)A, VEGFC and VEGFD, and their associated receptors VEGFR1, VEGFR2 and VEGFR3. A second group of vascular regulatory proteins belongs to the angiopoietin (ANG)–TIE system. Although members of the VEGF family and the ANG–TIE system are represented in the endometrium, our understanding of how these different molecules interact to regulate remodelling of the blood and lymphatic vasculature present in the endometrium is still limited. A review of the current information is provided.
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Zhang, Xufan, Qian Chen, Yuchen Li, Hongqing Chen, Qin Jiang e Qiongying Hu. "N-myc Downstream-Regulated Gene 1 (NDRG1) Regulates Vascular Endothelial Growth Factor A (VEGFA) and Malignancies in Glioblastoma Multiforme (GBM)". BioMed Research International 2022 (30 giugno 2022): 1–9. http://dx.doi.org/10.1155/2022/3233004.
Abstract (sommario):
Background. NDRG1 has been reported to exhibit relatively low expression levels in glioma tissues compared with adjacent brain tissues. Additionally, NDRG1 is reported to be a tumor suppressor with the potential to suppress the proliferation, invasion, and migration of cancer cells. However, its exact roles in GBM are still unknown. Methods. Gene Expression Profiling Interactive Analysis (GEPIA) was employed to evaluate the expression level of NDRG1 in GBM. After the introduction of NDRG1, proliferation, analyses of colony formation, migration, and invasion capacities were performed. A luciferase reporter assay was performed to detect the effect of NDRG1 on the vascular endothelial growth factor A (VEGFA) promoter. Results. In this study, data from GBM and healthy individuals were retrospectively collected by employing GBM, and VEGFA was found to be differentially expressed in GBM tissues compared with adjacent brain tissues. Furthermore, NDRG1 expression is positively correlated with VEGFA expression, but not expression of the other two VEGF isoforms, VEGFB and VEGFC. In the glioma cell lines U87MG and U118, overexpression of NDRG1 significantly upregulated VEGFA. By performing a dual-luciferase reporter assay, it was observed that overexpressed NDRG1 transcriptionally activated VEGFA. Expectedly, overexpression of NDRG1 decreased cell viability by blocking cell cycle phases at G1 phase. Additionally, overexpression of NDRG1 inhibited invasion, colony formation, and tumor formation in soft agar. Remarkably, VEGFA silencing or blockade of VEGF receptor 2 (VEGFR2) further inhibited malignant behaviors in soft agar, including proliferation, invasion, colony formation, and tumor formation. Conclusions. NDRG1-induced VEGFA exerts protective effects in GBM via the VEGFA/VEGFR2 pathway. Therefore, targeting both NDRG1 and VEGFA may represent a novel therapy for the treatment of GBM.
17
Nadarajah, Noeline, Dörte Schulte, Vivienne McConnell, Silvia Martin-Almedina, Christina Karapouliou, Peter Mortimer, Steve Jeffery et al. "A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon". International Journal of Molecular Sciences 19, n. 8 (1 agosto 2018): 2259. http://dx.doi.org/10.3390/ijms19082259.
Abstract (sommario):
Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.
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Marcozzi, Cristiana, Annalisa Frattini, Marina Borgese, Federica Rossi, Ludovica Barone, Eleonora Solari, Roberto Valli e Rosalba Gornati. "Paracrine effect of human adipose-derived stem cells on lymphatic endothelial cells". Regenerative Medicine 15, n. 9 (settembre 2020): 2085–98. http://dx.doi.org/10.2217/rme-2020-0071.
Abstract (sommario):
Aim: The proposal of this study was to evaluate, in vitro, the potential paracrine effect of human adipose-derived stem cells (hASCs) to promote lymphangiogenesis in lymphatic endothelial cells isolated from rat diaphragmatic lymphatic vessels. Materials & methods: ELISA on VEGFA, VEGFC and IL6 in hASC-conditioned medium; LYVE1 immunostaining; and gene expression of PROX1, VEGFR3, VEGFC, VEGFA and IL6 were the methods used. Results: In 2D culture, hASC-conditioned medium was able to promote lymphatic endothelial cell survival, maintenance of endothelial cobblestone morphology and induction to form a vessel-like structure. Conclusion: The authors' results represent in vitro evidence of the paracrine effect of hASCs on lymphatic endothelial cells, suggesting the possible role of hASC-conditioned medium in developing new therapeutic approaches for lymphatic system-related dysfunction such as secondary lymphedema.
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Hong, Kwang Dae, Youngseok Lee, Baek-Hui Kim, Sun Il Lee e Hong Young Moon. "Expression of GLI1 Correlates with Expression of Lymphangiogenesis Proteins, Vascular Endothelial Growth Factor C and Vascular Endothelial Growth Factor Receptor 3, in Colorectal Cancer". American Surgeon 79, n. 2 (febbraio 2013): 198–204. http://dx.doi.org/10.1177/000313481307900232.
Abstract (sommario):
Aberrant activation of the hedgehog (Hh) signaling pathway is associated with tumorigenesis in various tissues. In colorectal cancer (CRC), evidence for Hh activation is inconsistent, and the relationship between the Hh signaling pathway and lymphangiogenesis has not been studied. The aim of this study was to determine the relationship between Hh signaling and lymphangio-genesis and the association of this relationship with lymph node metastasis in CRC. We investigated 189 patients who underwent curative surgical resection for CRC between 2002 and 2004 at Korea University Guro Hospital. Paraffin-embedded specimens of colorectal adenocarcinoma and adjacent normal mucosa were evaluated. Immunohistochemical staining for Sonic hedgehog (Shh), Gli1, vascular endothelial growth factor C (VEGFC), and VEGF receptor 3 (VEGFR3) was performed for each specimen. Tumor specimen showed significantly strong staining of Shh, Gli1, VEGFC, and VEGFR3 compared with a normal specimen. Shh expression was not associated with Gli1 expression. Gli1 expression correlated positively with VEGFC and VEGFR3 expression ( P < 0.05 in both) but not with lymph node metastasis. Activation of the Hh signaling pathway associated with Gli1 promotes expression of lymphangiogenesis proteins, VEGFC and VEGFR3, in CRC. Further studies are necessary to determine the association of this relationship with lymph node metastasis in CRC.
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de Jonge, Hendrik J. M., Peter J. M. Valk, Nic J. G. M. Veeger, Arja ter Elst, Monique L. den Boer, Jacqueline Cloos, Valérie de Haas et al. "High VEGFC expression is associated with unique gene expression profiles and predicts adverse prognosis in pediatric and adult acute myeloid leukemia". Blood 116, n. 10 (9 settembre 2010): 1747–54. http://dx.doi.org/10.1182/blood-2010-03-270991.
Abstract (sommario):
Abstract High VEGFC mRNA expression of acute myeloid leukemia (AML) blasts is related to increased in vitro and in vivo drug resistance. Prognostic significance of VEGFC on long-term outcome and its associated gene expression profiles remain to be defined. We studied effect of VEGFC on treatment outcome and investigated gene expression profiles associated with VEGFC using microarray data of 525 adult and 100 pediatric patients with AML. High VEGFC expression appeared strongly associated with reduced complete remission rate (P = .004), reduced overall and event-free survival (OS and EFS) in adult AML (P = .002 and P < .001, respectively). Multivariable analysis established high VEGFC as prognostic indicator independent of cytogenetic risk, FLT3-ITD, NPM1, CEBPA, age, and white blood cell count (P = .038 for OS; P = .006 for EFS). Also, in pediatric AML high VEGFC was related to reduced OS (P = .041). A unique series of differentially expressed genes was identified that distinguished AML with high VEGFC from AML with low VEGFC, that is, 331 up-regulated genes (representative of proliferation, vascular endothelial growth factor receptor activity, signal transduction) and 44 down-regulated genes (eg, related to apoptosis) consistent with a role in enhanced chemoresistance. In conclusion, high VEGFC predicts adverse long-term prognosis and provides prognostic information in addition to well-known prognostic factors.
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Gula, Grzegorz, Sławomir Rumiński, Justyna Niderla-Bielińska, Agnieszka Jasińska, Ewelina Kiernozek, Ewa Jankowska-Steifer, Aleksandra Flaht-Zabost e Anna Ratajska. "Potential functions of embryonic cardiac macrophages in angiogenesis, lymphangiogenesis and extracellular matrix remodeling". Histochemistry and Cell Biology 155, n. 1 (1 novembre 2020): 117–32. http://dx.doi.org/10.1007/s00418-020-01934-1.
Abstract (sommario):
AbstractThe role of cardiac tissue macrophages (cTMs) during pre- and postnatal developmental stages remains in many aspects unknown. We aimed to characterize cTM populations and their potential functions based on surface markers. Our in situ studies of immunostained cardiac tissue specimens of murine fetuses (from E11to E17) revealed that a significant number of embryonic cTMs (phenotyped by CD45, CD68, CD64, F4/80, CD11b, CD206, Lyve-1) resided mostly in the subepicardial space, not in the entire myocardial wall, as observed in adult individuals. cTMs accompanied newly developed blood and lymphatic vessels adhering to vessel walls by cellular processes. A subpopulation of CD68-positive cells was found to form accumulations in areas of massive apoptosis during the outflow tract remodeling and shortening. Flow cytometry analysis at E14 and E17 stages revealed newly defined three subpopulations:CD64low, CD64highCD206-and CD64highCD206+. The levels of mRNA expression for genes related to regulation of angiogenesis (VEGFa, VEGFb, VEGFc, bFGF), lymphangiogenesis (VEGFc) and extracellular matrix (ECM) remodeling (MMP13, Arg1, Ym1/Chil3, Retlna/FIZZ1) differed among the selected populations and/or embryonic stages. Our results demonstrate a diversity of embryonic cTMs and their tissue-specific locations, suggesting their various potential roles in regulating angiogenesis, lymphangiogenesis and ECM remodeling.
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De Alarcon, Pedro, Manu Gnanamony e Jessica Garcia. "An in Vitro Study on the Role of Angiogenesis in Iron Deficiency Induced Reactive Thrombocytosis". Blood 132, Supplement 1 (29 novembre 2018): 2450. http://dx.doi.org/10.1182/blood-2018-99-115378.
Abstract (sommario):
Abstract Introduction: Iron deficiency (ID) is one of the recognized causes of reactive thrombocytosis in children. Factors that are commonly associated with megakaryopoiesis such as thrombopoietin (TPO), interleukin 6 (IL-6) and IL-11 are not altered in patients with iron deficiency and thrombocytosis suggesting the role of alternate mechanisms in controlling this process. We have previously shown using an ID rat model that ID increased the number of megakaryocytes in the bone marrow. We have also shown an increase in VEGFR (FLT1) and CXCR4 staining in bone marrow slides of ID rats. This data suggests that angiogenesis plays a vital role in the development of reactive thrombocytosis in response to ID. In this report, we have expanded our study to identify specific angiogenic signaling molecules associated with ID and used functional assays to validate it. Methods: For this study, we used the megakaryoblast cell line MEG-01 as an in vitro model of megakaryopoiesis. MEG-01 cells were adapted to grow in chemically defined serum free medium containing iron (iron replete media). For iron deficiency, serum free iron free media was mixed with iron replete media at a 1% v/v concentration (iron deplete media). For our experiments, MEG-01 cells were grown in both iron replete and depleted media for 7 days. Cell viability was measured using the trypan blue exclusion assay. Messenger-RNA expression of iron-related markers (TFR1, TFR2, FLT1, FLT3, FTL, FTH1, TF, HMOX1 and HMOX2) and angiogenic markers (VEGFA, VEGFB, VEGFC, PDGF, ANGPTL1, ANGPTL2, FGF2) was studied using real time PCR. We performed functional validation of angiogenesis with an in vitro tube formation assay using human umbilical vein endothelial (HUVEC) cells. For statistical analysis of the data we performed the t test using graph pad prism software and we considered p<0.05 as statistically significant. Results: In low iron conditions, MEG-01 cells showed a significant increase in FLT1 (4 fold) and FLT3 (3 fold) expression using real time PCR (p<0.001). Iron deficiency also induced a 2 fold increase in the mRNA expression of angiogenic molecules VEGFB, VEGFC, FGF2 and PDGFA (p<0.001). Using the tube formation assay, we also show that conditioned media collected from iron deficient MEG-01 cells induced increased vessel formation in endothelial cells. Conclusion: In this study, we were able to validate our earlier in vivo findings on iron deficiency induced reactive thrombocytosis. We show that cells adapt to low iron conditions by upregulating FLT1, FLT3 and FTL. We also show that several markers in the angiogenesis pathway like VEGFB, VEGFC, FGF2 and PDGFA are upregulated in response to iron deficiency. We were also able to show that an increase in these angiogenic molecules induced increased vessel formation in endothelial cells. This report, along with our previous findings, points to the importance of the angiogenic pathway in reactive thrombocytosis induced by iron deficiency. Disclosures No relevant conflicts of interest to declare.
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Zhao, Liangyu, Chencheng Yao, Zijue Zhu, Nachuan Liu, Jing Zhai, Yizhou Wang, Chao Yang et al. "Intra-Seminiferous Tubular Injection of Vascular Endothelial Growth Factor C Sustained-Release Ultrafine Particles: A Novel Method for Improving the Regeneration of Spermatogenesis After Chemotherapy". Journal of Biomedical Nanotechnology 15, n. 12 (1 dicembre 2019): 2376–92. http://dx.doi.org/10.1166/jbn.2019.2857.
Abstract (sommario):
Busulfan and other chemotherapeutic drugs used in the treatment of cancer may result in temporary or even permanent damage to spermatogenesis. During spermatogenesis, the rapidly dividing spermatogonia are highly susceptible to chemotherapy. Consequently, there is significant interest in developing an approach that could provide stimulation and regenerate spermatogenesis after chemotherapy. In a previous study, we suggested the potential application for vascular endothelial growth factor C (VEGFC) because of its key role in stimulating the proliferation of spermatogonia. However, methods to facilitate the recovery of spermatogenesis in such patients using VEGFC, or other regulatory factors, are sorely lacking because of the rapid degradation of these proteins and restrictions created by the blood-testis-barrier. To this end, we loaded VEGFC into polyanion dextran sulfate incorporated in a polycation chitosan shell to produce VEGFC sustained-release ultrafine particles (UFPs, CS-DS-VEGFC). We tested such particles in an azoospermic mouse model, created using busulfan. For each mouse, CS-DS-VEGFC was injected into the seminiferous tubules of one testis, while unloaded UFPs (CS-DS), or the VEGFC protein alone, was injected into the opposite testis as a control. All mice were sacrificed and evaluated 5 weeks later. Spermatogenesis in the tubules that were injected with CS-DS-VEGFC was clearly better than those injected with controls, and contained more spermatogonia and spermatocytes, along with Ki67 and PCNA positive-cells per tubule. In addition, the phosphorylation levels of AKT and MAPK in these tubules were also higher than in controls, indicating that CS-DS-VEGFC could induce the sustained activation of these pathways. In conclusion, CS-DS-VEGFC, combined with the efferent tubule injection technique, is a feasible approach with which to improve the regeneration of spermatogenesis in busulfan-induced azoospermic mice.
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Bui, Hung M., David Enis, Marius R. Robciuc, Harri J. Nurmi, Jennifer Cohen, Mei Chen, Yiqing Yang et al. "Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD". Journal of Clinical Investigation 126, n. 6 (9 maggio 2016): 2167–80. http://dx.doi.org/10.1172/jci83967.
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Morfoisse, Florent, Fabienne De Toni, Jeremy Nigri, Mohsen Hosseini, Audrey Zamora, Florence Tatin, Françoise Pujol et al. "Coordinating Effect of VEGFC and Oleic Acid Participates to Tumor Lymphangiogenesis". Cancers 13, n. 12 (8 giugno 2021): 2851. http://dx.doi.org/10.3390/cancers13122851.
Abstract (sommario):
In cancer, the lymphatic system is hijacked by tumor cells that escape from primary tumor and metastasize to the sentinel lymph nodes. Tumor lymphangiogenesis is stimulated by the vascular endothelial growth factors-C (VEGFC) after binding to its receptor VEGFR-3. However, how VEGFC cooperates with other molecules to promote lymphatics growth has not been fully determined. We showed that lymphangiogenesis developed in tumoral lesions and in surrounding adipose tissue (AT). Interestingly, lymphatic vessel density correlated with an increase in circulating free fatty acids (FFA) in the lymph from tumor-bearing mice. We showed that adipocyte-released FFA are uploaded by lymphatic endothelial cells (LEC) to stimulate their sprouting. Lipidomic analysis identified the monounsaturated oleic acid (OA) as the major circulating FFA in the lymph in a tumoral context. OA transporters FATP-3, -6 and CD36 were only upregulated on LEC in the presence of VEGFC showing a collaborative effect of these molecules. OA stimulates fatty acid β-oxidation in LECs, leading to increased AT lymphangiogenesis. Our results provide new insights on the dialogue between tumors and adipocytes via the lymphatic system and identify a key role for adipocyte-derived FFA in the promotion of lymphangiogenesis, revealing novel therapeutic opportunities for inhibitors of lymphangiogenesis in cancer.
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Wu, Lichuang, Chenxian Su, Chuanhua Yang, Jinxing Liu e Yiheng Ye. "TBX3 regulates the transcription of VEGFA to promote osteoblasts proliferation and microvascular regeneration". PeerJ 10 (11 luglio 2022): e13722. http://dx.doi.org/10.7717/peerj.13722.
Abstract (sommario):
Objective Osteochondral decellularization can promote local vascular regeneration, but the exact mechanism is unknown. The aim of this study is to study osteogenic microvascular regeneration in single cells. Methods The scRNA-seq dataset of human periosteal-derived cells (hPDCs) were analyzed by pySCENIC. To examine the role of TBX3 in osteogenesis and vascularization, cell transfection, qRT-PCR, western blot, and CCK-8 cell proliferation assays were performed. Results TCF7L2, TBX3, FLI1, NFKB2, and EZH2 were found to be transcription factors (TFs) most closely associated with corresponding cells. The regulatory network of these TFs was then visualized. Our study knocked down the expression of TBX3 in human osteoblast cell lines. In the TBX3 knockdown group, we observed decreased expression of VEGFA, VEGFB, and VEGFC. Moreover, Western blot analysis showed that downregulating TBX3 resulted in a reduction of VEGFA expression. And TBX3 stimulated osteoblast proliferation in CCK-8 assays. Conclusion TBX3 regulates VEGFA expression and promotes osteoblast proliferation in skeletal microvasculature formation. The findings provide a theoretical basis for investigating the role of TBX3 in promoting local vascular regeneration.
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Çoban, Zehra Dilşad, Mustafa Yener, Ahmet Samed Benli, Kerim Amanov, Ertan Altaylı, Halide Demir, Özgür Kılıçarslan, Emre Çavana e Şefik Güran. "KANTARON YAĞI VEGFA, VEGFB, VEGFC ve FGF2 GENLERİ ÜZERİNDEN ERKEN DÖNEM KULLANILDIĞINDA YARA İYİLEŞMESİNDE OLUMLU ETKİ GÖSTERMEKTEDİR". Cumhuriyet Medical Journal 38, n. 4 (25 novembre 2016): 231. http://dx.doi.org/10.7197/cmj.v38i4.5000101540.
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Fang, Shentong, Shuo Chen, Harri Nurmi, Veli-Matti Leppänen, Michael Jeltsch, David Scadden, Lev Silberstein, Hanna Mikkola e Kari Alitalo. "VEGF-C protects the integrity of the bone marrow perivascular niche in mice". Blood 136, n. 16 (15 ottobre 2020): 1871–83. http://dx.doi.org/10.1182/blood.2020005699.
Abstract (sommario):
Abstract Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) stem cell niche, which provides a vital source of HSC regulatory signals. Radiation and chemotherapy disrupt the HSC niche, including its sinusoidal vessels and perivascular cells, contributing to delayed hematopoietic recovery. Thus, identification of factors that can protect the HSC niche during an injury could offer a significant therapeutic opportunity to improve hematopoietic regeneration. In this study, we identified a critical function for vascular endothelial growth factor-C (VEGF-C), that of maintaining the integrity of the BM perivascular niche and improving BM niche recovery after irradiation-induced injury. Both global and conditional deletion of Vegfc in endothelial or leptin receptor–positive (LepR+) cells led to a disruption of the BM perivascular niche. Furthermore, deletion of Vegfc from the microenvironment delayed hematopoietic recovery after transplantation by decreasing endothelial proliferation and LepR+ cell regeneration. Exogenous administration of VEGF-C via an adenoassociated viral vector improved hematopoietic recovery after irradiation by accelerating endothelial and LepR+ cell regeneration and by increasing the expression of hematopoietic regenerative factors. Our results suggest that preservation of the integrity of the perivascular niche via VEGF-C signaling could be exploited therapeutically to enhance hematopoietic regeneration.
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Cohen, Batya, Hanoch Tempelhof, Tal Raz, Roni Oren, Julian Nicenboim, Filip Bochner, Ron Even et al. "BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression". Life Science Alliance 3, n. 4 (4 marzo 2020): e202000666. http://dx.doi.org/10.26508/lsa.202000666.
Abstract (sommario):
Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physiological and pathological conditions. Vascular endothelial growth factor C (VEGFC), the ligand for both VEGFR2 and VEGFR3, is a central lymphangiogenic regulator that also drives angiogenesis. Here, we report that members of the highly conserved BACH (BTB and CNC homology) family of transcription factors regulate VEGFC expression, through direct binding to its promoter. Accordingly, down-regulation of bach2a hinders blood vessel formation and impairs lymphatic sprouting in a Vegfc-dependent manner during zebrafish embryonic development. In contrast, BACH1 overexpression enhances intratumoral blood vessel density and peritumoral lymphatic vessel diameter in ovarian and lung mouse tumor models. The effects on the vascular compartment correlate spatially and temporally with BACH1 transcriptional regulation of VEGFC expression. Altogether, our results uncover a novel role for the BACH/VEGFC signaling axis in lymphatic formation during embryogenesis and cancer, providing a novel potential target for therapeutic interventions.
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Kampen, Kim R., Arja ter Elst, André B. Mulder, Megan E. Baldwin, Klupacs Robert e Evelina S. J. M. de Bont. "Anti-VEGFC Treatment Reduces the Leukemic Outgrowth of Primary CD34+ Pediatric Acute Myeloid Leukemia Cells". Blood 118, n. 21 (18 novembre 2011): 1425. http://dx.doi.org/10.1182/blood.v118.21.1425.1425.
Abstract (sommario):
Abstract Abstract 1425 Previously, it was demonstrated that exogenous addition of vascular endothelial growth factor C (VEGFC) increased the leukemic cell viability, reduced apoptosis via activation of Bcl-2, and decreased chemotherapy induced apoptosis via its receptor FLT-4 (Further revert to as VEGFR3) (Dias et al. Blood 2002). Furthermore, it was shown that VEGFC promotes angiogenesis by induction of COX-2 through VEGFR3 activation in THP-1 cells (Chien et al. Carcinogenesis 2005). We have previously found that endogenous VEGFC expression is associated with decreased drug responsiveness in childhood acute myeloid leukemia (AML), both in vitro as well as in vivo (de Jonge et al. Clinical Cancer Research 2008). In addition, high VEGFC mRNA expression is strongly associated with reduced complete remission and overall survival in adult as well as pediatric AML (de Jonge et al. Blood 2010). It was thought that the leukemic blast population is organized as a hierarchy, whereby leukemia initiating cells (LICs) reside at the top of this hierarchy, and it is only these cells that have the capacity to engraft in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The LIC is thought to be enriched in the CD34+ leukemic cell fraction and is shown to expand in vitro using a myeloid cytokine mix of IL-3, TPO, and G-CSF in colony forming cell (CFC) assays and long-term culture-initiating cell (LTC-IC) assays (Guan et al. Exp. Hematol. 2002, van Gosliga et al. Exp. Hematol. 2007). Moreover, LTC-IC assays performed in limiting dilution detect the in vitro outgrowth potential of stem-like cells that reside underneath the stromal cell layer. In this study, we set out to investigate the potential of anti-VEGFC treatment as an inhibitor of the outgrowth of LICs within the CD34+ fraction of primary AML samples. First, we determined the possibility of an autocrine loop for VEGFC in AML. Pediatric AML cell (n=7) derived VEGFC levels were found to be 1.4-fold increased (P =.008) compared to secreted VEGFC levels from normal bone marrow (NBM) cells (n=4). Pediatric AML blast cells showed KDR (further revert to as VEGFR2) membrane expression in 44 out of 50 patient samples (varying 8–99% of the total blast population), whereas on NBM cells VEGFR2 expression was below 5%. VEGFR3 expression was below 5% on both leukemic blasts and NBM cells. We evaluated the effect of anti-VEGFC (VGX-100, kindly provided by Vegenics, used at a concentration of 30 μg/ml) treatment on the CD34+ isolated compartment of pediatric AML bone marrow samples. Anti-VEGFC treatment reduced the outgrowth potential of AML derived CD34+ cells (n=2) with >25% in CFC assays. Interestingly, morphological analysis revealed a 3-fold enhanced formation of macrophages. LTC-IC assays demonstrated a (15% to 50%) decrease in the long-term growth of CD34+ isolated AML cells in 3 out of 4 patient samples. Morphological characterization of the suspension cells suggested a shift in development along the myelomonocytic lineage after two weeks of anti-VEGFC treatment. With FACS analysis, these cells showed a higher number of cells stained positive for CD11b, and CD14, and lower numbers where positive for CD34. Anti-VEGFC treated LTC-IC assays in limiting dilution demonstrated a (44% and 74%) reduction in the outgrowth potential of long-term cultured CD34+ isolated AML cells and blocked the erythroid colony formation in 2 out of 3 patient samples. Anti-VEGFC treatment did not have an effect on the outgrowth of CD34+ sorted NBM cells in the various assays (n=2). In conclusion, anti-VEGFC treatment of the CD34+ isolated fraction from primary pediatric AML samples showed a reduction of AML outgrowth. Differentiating cells are skewed to the myelomonocytic lineage upon anti-VEGFC treatment. We hypothesize that deprivation of VEGFC in primary CD34+ AML cell cultures results in enhanced leukemic cell death and abates an important proliferation signal for AML cells. Yet, further investigations are warranted.Figure 1.Skewing of LTC-IC assay suspension cells towards the myelomonocytic lineage upon anti-VEGFC treatment. MGG stained cytospins of suspension cells of the LTC-IC co-culture obtained during demi-depopulation at week 2.Figure 1. Skewing of LTC-IC assay suspension cells towards the myelomonocytic lineage upon anti-VEGFC treatment. MGG stained cytospins of suspension cells of the LTC-IC co-culture obtained during demi-depopulation at week 2. Disclosures: Baldwin: Circadian Technologies Limited: Employment. Robert:Circadian Technologies Limited: Employment, Membership on an entity's Board of Directors or advisory committees.
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Fang, Shentong, Harri Nurmi, Krista Heinolainen, Shuo Chen, Essi Salminen, Pipsa Saharinen, Hanna K. A. Mikkola e Kari Alitalo. "Critical requirement of VEGF-C in transition to fetal erythropoiesis". Blood 128, n. 5 (4 agosto 2016): 710–20. http://dx.doi.org/10.1182/blood-2015-12-687970.
Abstract (sommario):
Key Points Vegfc is essential for mobilization, maturation, and enucleation of primitive erythroblasts. Vegfc deletion compromises liver colonization by erythro-myeloid progenitors and subsequent macrophage/erythroid expansion.
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García-Pérez, Omar, Leticia Melgar-Vilaplana, Inés Sifaoui, Aleksandra Śmietańska, Elizabeth Córdoba-Lanús e Ricardo Fernández-de-Misa. "VEGFC Gene Expression Is Associated with Tumor Progression and Disease-Free Survival in Cutaneous Squamous Cell Carcinoma". International Journal of Molecular Sciences 25, n. 1 (27 dicembre 2023): 379. http://dx.doi.org/10.3390/ijms25010379.
Abstract (sommario):
Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers in the skin. CSCC belongs to the non-melanoma skin cancers, and its incidence is increasing every year around the world. The principal routes of tumor progression are related to angiogenesis and lymphangiogenesis. In this study, we assess the gene expression of the relevant biomarkers of both routes in 49 formalin-fixed paraffin-embedded (FFPE) CSCC samples in an attempt to determine a molecular profile that correlates with the tumor progression and disease-free survival (DFS). The results were enhanced by a posttranscriptional analysis using an immunofluorescence assay. Overexpression of the vascular endothelial growth factor C (VEGFC) gene was found in patients with tumor progression (p = 0.022) and in patients with perineural invasion (p = 0.030). An increased expression of protein VEGFC in samples with tumor progression supported these results (p = 0.050). In addition, DFS curves showed differences (p = 0.027) for tumors with absent-low VEGFC expression versus those with high levels of VEGFC expression. No significant influence on DFS was detected for the remaining analyzed genes. VEGFC expression was found to be a risk factor in the disease progression (HR = 2.675; 95% CI: 1.089–6.570; p = 0.032). Our main results suggest that VEGFC gene expression is closely related to tumor progression, DFS, and the presence of perineural invasion.
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Shibuya, Masabumi. "Unique signal transduction of the VEGF family members VEGF-A and VEGF-E". Biochemical Society Transactions 37, n. 6 (19 novembre 2009): 1161–66. http://dx.doi.org/10.1042/bst0371161.
Abstract (sommario):
Both VEGF (vascular endothelial growth factor)-A and Orf-virus-encoded VEGF-E bind and activate VEGFR (VEGF receptor)-2; however, only VEGF-A binds VEGFR-1. To understand the biological differences between VEGF-A and VEGF-E in vivo, we established transgenic mouse models. K14 (keratin-14)-promoter-driven VEGF-E transgenic mice showed a significant increase in mature blood vessels. However, K14–VEGF-A transgenic mice exhibited severe inflammation and oedema with increased angiogenesis, as well as lymphangiogenesis and lymph vessel dilatation. K14–VEGF-A transgenic mice deficient in VEGFR-1 signalling (K14–VEGF-A-tg/VEGFR-1 TK−/− mice) showed decreases in oedema and inflammation with less recruitment of macrophage-lineage cells, suggesting an involvement of VEGFR-1 in these adverse effects. VEGFE might be more useful than VEGFA for pro-angiogenic therapy.
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El-Sammak, Hadil, Bingyuan Yang, Stefan Guenther, Wenbiao Chen, Rubén Marín-Juez e Didier Y. R. Stainier. "A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration". Circulation Research 130, n. 7 (aprile 2022): 1014–29. http://dx.doi.org/10.1161/circresaha.121.319929.
Abstract (sommario):
Background: Ischemic heart disease following the obstruction of coronary vessels leads to the death of cardiac tissue and the formation of a fibrotic scar. In contrast to adult mammals, zebrafish can regenerate their heart after injury, enabling the study of the underlying mechanisms. One of the earliest responses following cardiac injury in adult zebrafish is coronary revascularization. Defects in this process lead to impaired cardiomyocyte repopulation and scarring. Hence, identifying and investigating factors that promote coronary revascularization holds great therapeutic potential. Methods: We used wholemount imaging, immunohistochemistry and histology to assess various aspects of zebrafish cardiac regeneration. Deep transcriptomic analysis allowed us to identify targets and potential effectors of Vegfc (vascular endothelial growth factor C) signaling. We used newly generated loss- and gain-of-function genetic tools to investigate the role of Emilin2a (elastin microfibril interfacer 2a) and Cxcl8a (chemokine (C-X-C) motif ligand 8a)-Cxcr1 (chemokine (C-X-C) motif receptor 1) signaling in cardiac regeneration. Results: We first show that regenerating coronary endothelial cells upregulate vegfc upon cardiac injury in adult zebrafish and that Vegfc signaling is required for their proliferation during regeneration. Notably, blocking Vegfc signaling also significantly reduces cardiomyocyte dedifferentiation and proliferation. Using transcriptomic analyses, we identified emilin2a as a target of Vegfc signaling and found that manipulation of emilin2a expression can modulate coronary revascularization as well as cardiomyocyte proliferation. Mechanistically, Emilin2a induces the expression of the chemokine gene cxcl8a in epicardium-derived cells, while cxcr1 , the Cxcl8a receptor gene, is expressed in coronary endothelial cells. We further show that Cxcl8a-Cxcr1 signaling is also required for coronary endothelial cell proliferation during cardiac regeneration. Conclusions: These data show that after cardiac injury, coronary endothelial cells upregulate vegfc to promote coronary network reestablishment and cardiac regeneration. Mechanistically, Vegfc signaling upregulates epicardial emilin2a and cxcl8a expression to promote cardiac regeneration. These studies aid in understanding the mechanisms underlying coronary revascularization in zebrafish, with potential therapeutic implications to enhance revascularization and regeneration in injured human hearts.
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Astin, J. W., M. J. L. Haggerty, K. S. Okuda, L. Le Guen, J. P. Misa, A. Tromp, B. M. Hogan, K. E. Crosier e P. S. Crosier. "Vegfd can compensate for loss of Vegfc in zebrafish facial lymphatic sprouting". Development 141, n. 13 (5 giugno 2014): 2680–90. http://dx.doi.org/10.1242/dev.106591.
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Litke, Christian, Hilmar Bading e Daniela Mauceri. "Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D". Journal of Biological Chemistry 293, n. 21 (9 aprile 2018): 8196–207. http://dx.doi.org/10.1074/jbc.ra117.001613.
Abstract (sommario):
Nucleo-cytoplasmic shuttling of class IIa histone deacetylases (i.e. HDAC4, -5, -7, and -9) is a synaptic activity- and nuclear calcium–dependent mechanism important for epigenetic regulation of signal-regulated gene expression in hippocampal neurons. HDAC4 in particular has been linked to the regulation of genes important for both synaptic structure and plasticity. Here, using a constitutively nuclear-localized, dominant-active variant of HDAC4 (HDAC4 3SA), we demonstrate that HDAC4 accumulation in the nucleus severely reduces both the length and complexity of dendrites of cultured mature hippocampal neurons, but does not affect the number of dendritic spines. This phenomenon appeared to be specific to HDAC4, as increasing the expression of HDAC3 or HDAC11, belonging to class I and class IV HDACs, respectively, did not alter dendritic architecture. We also show that HDAC4 3SA decreases the expression of vascular endothelial growth factor D (VEGFD), a key protein required for the maintenance of dendritic arbors. The expression of other members of the VEGF family and their receptors was not affected by the nuclear accumulation of HDAC4. VEGFD overexpression or administration of recombinant VEGFD, but not VEGFC, the closest VEGFD homologue, rescued the impaired dendritic architecture caused by the nuclear-localized HDAC4 variant. These results identify HDAC4 as an epigenetic regulator of neuronal morphology that controls dendritic arborization via the expression of VEGFD.
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Gao, Chaoqun, Jie Zhu, Qiu Qin, Xiaorong Yang, Yanfei Jiang e Jinan Zhang. "The Relationship between VEGFC Gene Polymorphisms and Autoimmune Thyroiditis". BioMed Research International 2022 (12 luglio 2022): 1–8. http://dx.doi.org/10.1155/2022/2603519.
Abstract (sommario):
Background. Autoimmune thyroid diseases (AITDs), representative autoimmune diseases, mainly consist of Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). In this passage, we investigated the association between vascular endothelial growth factor C (VEGFC) gene polymorphisms and AITDs. Methods. A total of 1084 patients with AITDs and 794 healthy controls were tested for VEGFC gene genotypes in four single nucleotide polymorphisms (SNPs) by high-throughput sequencing, and the correlation between VEGFC gene polymorphisms and AITDs was statistically analyzed. Results. The genotype distribution of rs3775194 was statistically associated with AITDs compared with the control group. Rs3775194 was associated with AITDs under the overdominant model, both before and after adjusting for confounding factors, while the other three SNPs were not associated with GD and HT. There was a prominent discrepancy between male healthy controls and male AITD patients under overdominant model in rs3775194 and the recessive model in rs11947611. The genotype distribution of rs3775194 was statistically related to male HT. Conclusion. These results reveal the correlation between VEGFC mutation and AITD susceptibility.
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Verbiest, Annelies, Benoit Beuselinck, Gabrielle Couchy, Sylvie Job, Aurelien De Reynies, Clément Meiller, Maarten Albersen et al. "Metastatic clear cell renal cell carcinoma: Proangiogenic gene expression and outcome on sunitinib." Journal of Clinical Oncology 35, n. 15_suppl (20 maggio 2017): e16085-e16085. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e16085.
Abstract (sommario):
e16085 Background: Clear cell renal cell carcinomas (ccRCC) are hypervascular tumors that respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. They can be divided into 4 mRNA-expression based subgroups (ccrcc 1-4) with different outcomes on sunitinib. We hypothesized that the expression of proangiogenic genes is predictive for response to sunitinib. Methods: Retrospective series of metastatic ccRCC-patients treated with sunitinib as first line targeted therapy (n = 104). We studied expression of genes involved in angiogenesis and the immune-suppressive microenvironment (qRT-PCR) and mutational status of Von Hippel Lindau and Polybromo (PBRM) 1 (sequencing) on primary tumor samples. Outcome parameters were response rate (Response Evaluation Criteria in Solid Tumors), progression free survival (PFS) and overall survival (OS). Gene expression levels were tested in multivariate analysis (MV) against the IMDC risk criteria, presence of bone metastases and sarcomatoid dedifferentiation ≥25%. Results: Expression of Hypoxia Inducible Factor (HIF) 2A, Platelet Derived Growth Factor Receptor B, VEGFC, VEGFR1 and VEGFR2 was significantly correlated with PFS on MV and expression of HIF1A, HIF2A and VEGFR2 with OS. VEGFR2-expression was also correlated with partial response (p = 0.03) and anti-correlated with early progressive disease (p = 0.008). HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3-expression was higher in ccrcc2-tumors compared to others. Expression of genes involved in angiogenesis and in the immune-suppressive microenvironment was not directly correlated nor anti-correlated. In tumors with a bi-allelic PBRM1-inactivation, HIF2A, VEGFA, VEGFR1 and VEGFR2-expression were higher compared to tumors with 1 or 2 functional PBRM1-alleles. This did not translate in different outcome on sunitinib. Conclusions: Tumoral expression of genes involved in the HIF-VEGF-VEGFR proangiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in metastatic ccRCC. Expression of these genes was high in the molecular ccrcc2-subgroup, known to be sensitive to sunitinib. These findings could be used for patient selection in future clinical trials.
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Rei, Nádia, Cláudia A. Valente, Sandra H. Vaz, Miguel Farinha-Ferreira, Joaquim A. Ribeiro e Ana M. Sebastião. "Changes in adenosine receptors and neurotrophic factors in the SOD1G93A mouse model of amyotrophic lateral sclerosis: Modulation by chronic caffeine". PLOS ONE 17, n. 12 (14 dicembre 2022): e0272104. http://dx.doi.org/10.1371/journal.pone.0272104.
Abstract (sommario):
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of corticospinal tract motor neurons. Previous studies showed that adenosine-mediated neuromodulation is disturbed in ALS and that vascular endothelial growth factor (VEGF) has a neuroprotective function in ALS mouse models. We evaluated how adenosine (A1R and A2AR) and VEGF (VEGFA, VEGFB, VEGFR-1 and VEGFR-2) system markers are altered in the cortex and spinal cord of pre-symptomatic and symptomatic SOD1G93A mice. We then assessed if/how chronic treatment of SOD1G93A mice with a widely consumed adenosine receptor antagonist, caffeine, modulates VEGF system and/or the levels of Brain-derived Neurotrophic Factor (BDNF), known to be under control of A2AR. We found out decreases in A1R and increases in A2AR levels even before disease onset. Concerning the VEGF system, we detected increases of VEGFB and VEGFR-2 levels in the spinal cord at pre-symptomatic stage, which reverses at the symptomatic stage, and decreases of VEGFA levels in the cortex, in very late disease states. Chronic treatment with caffeine rescued cortical A1R levels in SOD1G93A mice, bringing them to control levels, while rendering VEGF signaling nearly unaffected. In contrast, BDNF levels were significantly affected in SOD1G93A mice treated with caffeine, being decreased in the cortex and increased in spinal the cord. Altogether, these findings suggest an early dysfunction of the adenosinergic system in ALS and highlights the possibility that the negative influence of caffeine previously reported in ALS animal models results from interference with BDNF rather than with the VEGF signaling molecules.
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Frantsiyants, Elena M., Oleg I. Kit, Irina V. Kaplieva, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Elena A. Dzhenkova, Nikolay S. Samoylenko, Petr N. Gabrichidze, Anton G. Milakin e Sergey I. Poluektov. "Role of angiogenesis factors in formation of metastatic niches." Journal of Clinical Oncology 37, n. 15_suppl (20 maggio 2019): e15534-e15534. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15534.
Abstract (sommario):
e15534 Background: A metastatic niche indicates a particular location with a specific cell type, epidermal-mesenchymal transition proteins and diffuse signals that are necessary for the growth of metastases. The purpose of the study was to determine levels of VEGFs, their receptors and TGFβ1 in tissues of gastric cancer (GC) and its metastatic niches: the peritoneum and omentum. Methods: The main group included 21 patients with metastatic GC T3-4аN0-3M1; comparison group – 17 non-cancer patients. Levels of VEGFA, VEGFC, sVEGFR1, sVEGFR3 and TGFβ1 in tissues were determined by standard ELISA methods. Results: Levels of growth factors in GC tissues were higher than in controls: VEGFA in T3-4аN0-3M1 – by 2.7 times, in T3-4аN0-3M0 – by 2.5 times; TGFβ1 in T3-4аN0-3M1 – by 5.6 times, in T3-4аN0-3M0 – by 3.5 times. VEGFA levels in primary gastric tumors were similar in all patients, while TGFβ1 in T3-4аN0-3M1 was 1.6 times (p < 0.05) higher than in T3-4аN0-3M0. VEGFA levels in T3-4аN0-3M1 exceeded control values: in the omentum – by 2.8, in the peritoneum – by 4.2 times. TGFβ1 in the omentum and peritoneum in T3-4аN0-3M1 was increased by 2.5 and 3.1 times respectively, compared to controls. Statistically significant differences in VEGFA and TGFβ1 levels in the omentum and peritoneum in T3-4аN0-3M0 were not found. Conclusions: GC is characterized by equally elevated levels of VEGFA, regardless of the presence or absence of metastases. In the omentum and peritoneum with metastases, high VEGF levels can be considered as one of the primary factors for the formation of signaling pathways between metastatic tumor cells and local non-tumor cells in premetastatic niches. Levels of TGFβ1 in the omentum and peritoneum increase only in patients with metastases, and in GC tissue they are increased to a greater extent than in patients without metastases. Probably, in case of T3-4aN0-3M0, the factor produced by the primary tumor was insufficient for its paracrine induction in the metastatic niche, and scattered cells could not transit from “sleeping” to the active state.
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Yu, Huapeng, Cuixia Xu e Qirong Li. "Clinical Efficacy and Safety of Tumor Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy for Ovarian Cancer". Evidence-Based Complementary and Alternative Medicine 2023 (12 aprile 2023): 1–8. http://dx.doi.org/10.1155/2023/6412679.
Abstract (sommario):
Objective. To assess the clinical efficacy and safety of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer. Methods. From April 2018 to November 2021, 66 patients with ovarian cancer were admitted to our hospital and randomly allocated to undergo intravenous chemotherapy following CRS (the observation group) or CRS with HIPEC (the experimental group) using a parallel randomized technique, with 33 cases in each group. Clinical effectiveness, intraoperative and postoperative recovery, VEGF level, T-lymphocyte subpopulation cell level, adverse events, and patient survival were all outcome metrics. Results. CRS plus HIPEC was associated with significantly higher clinical efficacy versus CRS alone ( P < 0.05 ). The difference in the intraoperative bleeding and operative time between the two groups did not meet the statistical standard ( P > 0.05 ). Patients in the experimental group experienced shorter postoperative chemotherapy and length of hospital stay than those in the observation group ( P < 0.05 ). CRS plus HIPEC resulted in significantly lower levels of VEGFA, VEGFB, and VEGFC and higher levels of CD3+, CD4+, and CD3+/CD4+ than CRS alone ( P < 0.05 ). The two groups of patients had a similar incidence of adverse events ( P > 0.05 ). The experimental group showed a longer median survival (25 months) and a 1-year survival rate (79.55%) than the observation group (22 months, 49.56%) (log rank = 20.411, P < 0.05 ). A significantly lower 1-year recurrence rate was observed in the experimental group than in the observation group ( P < 0.05 ). Conclusion. CRS plus HIPEC effectively improves the clinical efficacy of ovarian cancer patients, prolongs the survival of patients, and improves the level of VEGF and T-lymphocyte subpopulation cells, with a manageable safety. In addition, the treatment method can improve the therapeutic effect, reduce the toxic and side effects, and improve the immunity of the body, which is worthy of clinical promotion.
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Pamies Corts, A., D. Llop, D. Ibarretxe, D. Taverner, R. Rosales, N. Plana, L. Masana, J. C. Vallve e S. Paredes. "AB0053 ANGIOPOIETIN-2, VEGFA, VEGFC, VEGFD, EGF, PLGF AND HB-EGF ARE GROWTH FACTORS ASSOCIATED WITH SUBCLINICAL ARTERIOSCLEROSIS IN A COHORT OF PATIENTS WITH RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 82, Suppl 1 (30 maggio 2023): 1205.2–1206. http://dx.doi.org/10.1136/annrheumdis-2023-eular.4465.
Abstract (sommario):
BackgroundPatients with rheumatoid arthritis (RA) present increased risk of cardiovascular (CV) disease compared to the general population. Moreover, CV risk factors that have causal relationship with atherosclerosis do not seem to fully explain the accelerated process that they exhibit[1]. Over the years, several serum growth factors have been associated with atherosclerosis and some of them have been targeted as potential immunotherapy targets for the treatment of CV disease[2,3]. However, very few studies have studied these associations in RA patients.ObjectivesWe evaluated the association of 8 plasmatic growth factors (angiopoietin-2, EGF, HB-EGF, PLGF, TGF-α, VEGFa, VEGFc, VEGFd) with surrogate markers of subclinical arteriosclerosis (carotid intima media thickness (cIMT), carotid plaque presence (cPP) and pulse wave velocity (PWV)) in a cohort of RA patients.MethodsA total of 199 patients with RA were included. Subclinical markers of arteriosclerosis, (cIMT, cPP and PWV) were measured with the My Lab 50 X-Vision sonogram. The different plasmatic growth factors were measured with Bio-Plex Pro Human Cancer Biomarker Panel 2, from BIO-RAD. Multivariate models and Partial Least Square Discriminant Analysis (PLS-DA) were used for analysis. Analyses were performed in the overall cohort and stratified by sex.ResultsThe multivariate models showed that angiopoietin-2 was significantly associated with cPP and PWV in the overall cohort. Moreover, VEGFc was also associated with PWV. Stratified analyses showed that VEGFa, VEGFd, EGF, PLGF, HB-EGF were associated with cPP in men patients. In this direction, PLS-DA analysis showed that the mentioned growth factors properly classified patients with and without cPP (Figure 1). Furthermore, angiopoietin-2, EGF, VEGFc, VEGFa, HB-EGF were associated with PWV. Regarding women, angiopoietin-2 was associated with PWV. Result from the lineal and logistic regressions are summarized in Table 1.ConclusionPlasmatic growth factors, especially in men, are highly associated with subclinical arteriosclerosis surrogate markers and could be potential predictors of CV disease in patients with RA.References[1]Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: A meta-analysis of observational studies. Arthritis Care Res. 2008;59:1690–7.[2]Mindur JE, Swirski FK. Growth Factors as Immunotherapeutic Targets in Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2019;39:1275–87.[3]Domouzoglou EM, Naka KK, Vlahos AP, Papafaklis MI, Michalis LK, Tsatsoulis A, et al. Fibroblast growth factors in cardiovascular disease: The emerging role of FGF21. Am J Physiol - Hear Circ Physiol. 2015;309:H1029.Table 1.Summaries of the multivariate lineal and logistic regression models to estimate the associations between growth factors (GF) and cPP and PWV in the overall cohort and stratified by sex. Basal models are adjusted for age, sex, body mass index, disease onset, disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, corticosteroids, biological drugs and DAS28. GF = growth factor, β = beta coefficient, OR = odds ratio, p = p-valueGF associations with subclinical arteriosclerosisORpR2(%)cPPOVERALL COHORTBasal Model24+ angiopoietin-21.00050.0226MENBasal Model33+ VEGFa1.0020.0439+ VEGFd1.0020.0438+ EGF1.020.0240+ PLGF1.010.0339+ HB-EGF1.020.0438BpR2(%)PWVOVERALL COHORTBasal Model32+ angiopoietin-20.00060.00136+ VEGFc0.00050.0434MENBasal Model33+ angiopoietin-20.00070.0240+ VEGFa0.0020.0239+ VEGFc0.0010.00841+ HB-EGF0.010.0438WOMENBasal Model36+ angiopoietin-20.00050.0139Figure 1.PLS-DA of men with cPP and without cPP, adjusted for the significant growth factors and age, body mass index, disease onset, disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, corticosteroids, biological drugs and DAS. 28 0 = no cPP, 1 = cPPAcknowledgementsWe would like to thank all patients for their essential collaboration.Disclosure of InterestsANNA PAMIES CORTS Speakers bureau: Novartis, Galapagos, Didac Llop: None declared, Daiana Ibarretxe Speakers bureau: Sanofi, Sobi, Genzyme, Rubio, Delia Taverner Speakers bureau: Galapagos, Amgen, Roser Rosales: None declared, Nuria Plana Speakers bureau: Amgen, Sanofi, Servier, Consultant of: Servier, Luis Masana Speakers bureau: Amgen, Sanofi, Servier, Consultant of: Servier, Amgen, Joan Carles Vallve: None declared, Silvia Paredes Speakers bureau: Lilly, Bristol, Amgen, Consultant of: Galapagos, Sanofi, Bristol.
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Zalewski, Daniel, Paulina Chmiel, Przemysław Kołodziej, Grzegorz Borowski, Marcin Feldo, Janusz Kocki e Anna Bogucka-Kocka. "Dysregulations of Key Regulators of Angiogenesis and Inflammation in Abdominal Aortic Aneurysm". International Journal of Molecular Sciences 24, n. 15 (28 luglio 2023): 12087. http://dx.doi.org/10.3390/ijms241512087.
Abstract (sommario):
Abdominal aortic aneurysm (AAA) is a chronic vascular disease caused by localized weakening and broadening of the abdominal aorta. AAA is a clearly underdiagnosed disease and is burdened with a high mortality rate (65–85%) from AAA rupture. Studies indicate that abnormal regulation of angiogenesis and inflammation contributes to progression and onset of this disease; however, dysregulations in the molecular pathways associated with this disease are not yet fully explained. Therefore, in our study, we aimed to identify dysregulations in the key regulators of angiogenesis and inflammation in patients with AAA in peripheral blood mononuclear cells (using qPCR) and plasma samples (using ELISA). Expression levels of ANGPT1, CXCL8, PDGFA, TGFB1, VEGFB, and VEGFC and plasma levels of TGF-alpha, TGF-beta 1, VEGF-A, and VEGF-C were found to be significantly altered in the AAA group compared to the control subjects without AAA. Associations between analyzed factors and risk factors or biochemical parameters were also explored. Any of the analyzed factors was associated with the size of the aneurysm. The presented study identified dysregulations in key angiogenesis- and inflammation-related factors potentially involved in AAA formation, giving new insight into the molecular pathways involved in the development of this disease and providing candidates for biomarkers that could serve as diagnostic or therapeutic targets.
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Baker, A. F., T. Dragovich, A. Cui, D. Laheru, C. Campen, D. D. Von Hoff e M. Hidalgo. "Plasma IL-6 level and survival of pancreatic cancer patients treated with a VEGFR inhibitor, vatalanib (PTK/ZK)". Journal of Clinical Oncology 27, n. 15_suppl (20 maggio 2009): e15514-e15514. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15514.
Abstract (sommario):
e15514 Background: Use of anti-angiogenesis drugs in pancreatic cancer has not yet resulted in significant clinical improvements and it is unknown if there are subsets of patients with pancreatic cancer that may benefit from this therapeutic approach. We have reported on a phase II trial of PTK/ZK (VEGFR inhibitor) in patients (n=65) who have failed or progressed on gemcitabine. The 6- month OS met the primary endpoint of 29 % and there were 2 partial responses. We investigated some of the plasma proteins relevant for angiogenesis in correlation with clinical outcomes on this trial. Methods: Plasma samples were obtained prior to and after 4 weeks of therapy with PTK/ZK, aliquoted and frozen until assayed. Patient plasma was assayed for: VEGFA, VEGFC, VEGFR1, VEGFR2, FGFb, PDGFBB, OPN, ANG2, IL-6, and sIL-6R (SearchLight, Pierce Biotechnology Multiplex ELISA and IL-6 and sIL-6R using R&D Systems).The Spearmen correlation was utilized to look for correlations and changes from baseline compared to post-treatment levels. The correlation of baseline levels with survival were analyzed using the Cox proportional hazard model. Results: Thirty eight paired patient samples were assayed. A significant correlation of baseline values was found between VEGF-C and VEGFR1 (p=0.0496), VEGF-C and VEGF (0.0092), PDGFB and ANG2 (p=0.0003), IL-6 and ANG2 (p=0.0089), and FGFb and OPN (p=0.0281). A correlation in post-treatment change was observed between VEGF-C and PDGFB (p=0.0008), FGFb and OPN (p=0.0374), PDGFB and ANG2 (p=0.0005), IL-6 and ANG-2 (p=0.0464), and VEGF and IL-6 (p=0.0546). Lower baseline IL-6 levels correlated with longer survival (p=0.0227). A post-treatment decrease in plasma IL-6 levels was significantly associated with improvement in survival (p=0.0457). IL-6 mediates multiple effects including angiogenic and pro-survival signaling and has been proposed as a potential prognostic factor in different malignancies. Conclusions: Of all angiogenesis markers analyzed only a post-treatment decrease in plasma IL-6 correlated with improved survival on study. IL-6 warrants further investigation as a potential marker of sensitivity to anti-angiogenesis therapy, especially in patients with pancreatic cancer. Supported by: 1P50 CA95060; 1PO1CA109552–01A1 [Table: see text]
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Ad, Michal, e Arin K. Greene. "Prenatal Lymphedema: A Genotype-Phenotype Analysis". Journal of Vascular Anomalies 5, n. 1 (5 gennaio 2024): e073. http://dx.doi.org/10.1097/jova.0000000000000073.
Abstract (sommario):
Primary lymphedema most commonly affects the lower extremities, is progressive, and is not curable. The condition is associated with mutations in approximately 30 genes. Patients usually present with edema during infancy or adolescence. Four of 364 (1%) patients with primary lymphedema in our database were diagnosed by prenatal imaging. Three children did not exhibit lymphedema after birth, 2 had a VEGFC mutation, and 2 exhibited normal lymphatic function by lymphoscintigraphy. Lymphedema identified prenatally is associated with a VEGFC mutation and can resolve postnatally.
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Matas-Céspedes, Alba, Vanina Rodriguez, Susana Kalko, Eva Gine, Elias Campo, Gael Roue, Armando Lopez-Guillermo, Dolors Colomer e Perez-Galan Patricia. "Follicular Dendrytic Cells Deliver Angiogenesis Signaling To Follicular Lymphoma Cells That Is Hampered By The Pan-PI3K Inhibitor NVP-BKM120". Blood 122, n. 21 (15 novembre 2013): 3072. http://dx.doi.org/10.1182/blood.v122.21.3072.3072.
Abstract (sommario):
Abstract Follicular Lymphoma (FL) is the paradigm of a neoplasia depending on the microenvironment for proliferation and survival. In the lymphoid follicle, FL cells are surrounded by follicular dendrytic cells (FDCs) that function as antigen presenting cells delivering survival and proliferation signaling. FDCs together with macrophages are associated to poor FL survival. Our aim was to uncover the signaling pathways underlying FL-FDC crosstalk and its validation as new targets for therapy using specific inhibitors. Global gene expression profiling of FL-FDC co-cultures yield a marked modulation of FL transcriptome by FDCs. The Principal Component Analysis (PCA) showed that HK-cocultured FL cells clustered together,independently of the patient origin. Then, pathways assignmentwas performed by DAVID and GSEA softwares, both of themuncovering an overrepresentation on genes related toangiogenesis. In the DAVID analysis, we found significant(False Discovery Rate (FDR)<5%,) angiogenesis–related GOterms such as, blood vessel development, blood vessel morphogenesis, VEGFR signaling pathway, sprouting angiogenesis, positive regulation of angiogenesis, patterning of blood vessels among others. In the GSEA analysis, our dataset was interrogated for enrichment of genesets belonging to C2 data base together with custom-derived ones. In accordance with DAVID results, genesets related to angiogenesis were enriched (FDR< 5%) in HK-cocultured FLcells, such as HumanAngiogenesis, Weston_VEGFA_targtes, PID_VEGFR1_2 and PID_lymphangiogenesis. As PI3K pathway is known to play a determinant role in angiogenesis, we explored if NVP-BKM120, a pan-PI3K inhibitor in clinical trials for solid tumors, could interfere with this signaling. First, by using Taqman Angiogenesis Array®containing 94 probes against genes related to angiogenesis, we analyzed if the modulation of genes in FL cells cocultured with HK could be inhibited by NVP-BKM120. Effectively, we found a group of genes that were positively regulated by HK and inhibited by NVP-BKM120, among them ANGPT1, CXCL12, EPHB2, VEGFA, VEGFC, ADAMST1, NRP1, NRP2, HSPG2,COL4A1, PDGFRA and PDGFRB. In addition, by ELISA analysis of cell culture supernatants, we found that NVP-BKM120 reduced VEGFA and VEGFC secretion of FL cells alone or co-cultured with HK. Then, we analyzed if this reduction of proangiogenic factors effectively reduced angiogenesis. To this aim we performed HUVEC tube formation assay with the supernatants of FL cells co-cultured or not with HK, in the presence or absence of the PI3K inhibitor. We demonstrated that, as expected, supernatants derived fromFL-HK-cocultures increased the number of tubes formed, and NVP-BKM120 reduced these numbers. Then, we investigated the impact of NVP-BKM120 treatment on FL cell signalling and proliferation. NVP-BKM120 efficiently blocks both constitutive activation of PI3K/AKT pathway in FL cells and that derived from B-cell receptor stimulation or HK co-culture, reducing cell proliferation of FL cells and inducing apoptosis in a portion of FL cell lines and primary cells. NVP-BKM120 also impedes signaling and migration induced by the chemokine SDF1α. In vivo, NVP-BKM120 significantly (p<0.05) reduces tumor outgrowth in subcutaneous and systemic FL mouse models. We isolated RNA from mouse tumors and run TaqmanAngiogenesis array as before. NVP-BKM120 downmodulated the expresion of genes related to angiogenesis already found in vitro such a VEGFA, HSPGB2, NRP2 ,PDGFRA and PDGFRB, but also novel genes, including SERPINC1, FST,PDGFB, TGFB1, TNF, VEGFB, COL18A1, ANGPT4 and PECAM(CD31). In addition, the reduction on VEGFA and CD31 was also validated by IHC in these tumors. These results warrant further investigation of pan-PI3K inhibitors for FL therapy in the context of microenvironment survival signaling inhibition. Disclosures: Lopez-Guillermo: Roche: Membership on an entity’s Board of Directors or advisory committees.
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Ericson, Marna E., Edward B. Breitschwerdt, Paul Reicherter, Cole Maxwell, Ricardo G. Maggi, Richard G. Melvin, Azar H. Maluki et al. "Bartonella henselae Detected in Malignant Melanoma, a Preliminary Study". Pathogens 10, n. 3 (10 marzo 2021): 326. http://dx.doi.org/10.3390/pathogens10030326.
Abstract (sommario):
Bartonella bacilliformis (B. bacilliformis), Bartonella henselae (B. henselae), and Bartonella quintana (B. quintana) are bacteria known to cause verruga peruana or bacillary angiomatosis, vascular endothelial growth factor (VEGF)-dependent cutaneous lesions in humans. Given the bacteria’s association with the dermal niche and clinical suspicion of occult infection by a dermatologist, we determined if patients with melanoma had evidence of Bartonella spp. infection. Within a one-month period, eight patients previously diagnosed with melanoma volunteered to be tested for evidence of Bartonella spp. exposure/infection. Subsequently, confocal immunohistochemistry and PCR for Bartonella spp. were used to study melanoma tissues from two patients. Blood from seven of the eight patients was either seroreactive, PCR positive, or positive by both modalities for Bartonella spp. exposure. Subsequently, Bartonella organisms that co-localized with VEGFC immunoreactivity were visualized using multi-immunostaining confocal microscopy of thick skin sections from two patients. Using a co-culture model, B. henselae was observed to enter melanoma cell cytoplasm and resulted in increased vascular endothelial growth factor C (VEGFC) and interleukin 8 (IL-8) production. Findings from this small number of patients support the need for future investigations to determine the extent to which Bartonella spp. are a component of the melanoma pathobiome.
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Chédeville, Agathe L., Anbarasu Lourdusamy, Ana Rita Monteiro, Richard Hill e Patricia A. Madureira. "Investigating Glioblastoma Response to Hypoxia". Biomedicines 8, n. 9 (27 agosto 2020): 310. http://dx.doi.org/10.3390/biomedicines8090310.
Abstract (sommario):
Glioblastoma (GB) is the most common and deadly type of primary malignant brain tumor with an average patient survival of only 15–17 months. GBs typically have hypoxic regions associated with aggressiveness and chemoresistance. Using patient derived GB cells, we characterized how GB responds to hypoxia. We noted a hypoxia-dependent glycolytic switch characterized by the up-regulation of HK2, PFKFB3, PFKFB4, LDHA, PDK1, SLC2A1/GLUT-1, CA9/CAIX, and SLC16A3/MCT-4. Moreover, many proangiogenic genes and proteins, including VEGFA, VEGFC, VEGFD, PGF/PlGF, ADM, ANGPTL4, and SERPINE1/PAI-1 were up-regulated during hypoxia. We detected the hypoxic induction of invasion proteins, including the plasminogen receptor, S100A10, and the urokinase plasminogen activator receptor, uPAR. Furthermore, we observed a hypoxia-dependent up-regulation of the autophagy genes, BNIP-3 and DDIT4 and of the multi-functional protein, NDRG1 associated with GB chemoresistance; and down-regulation of EGR1 and TFRC (Graphical abstract). Analysis of GB patient cohorts’ revealed differential expression of these genes in patient samples (except SLC16A3) compared to non-neoplastic brain tissue. High expression of SLC2A1, LDHA, PDK1, PFKFB4, HK2, VEGFA, SERPINE1, TFRC, and ADM was associated with significantly lower overall survival. Together these data provide important information regarding GB response to hypoxia which could support the development of more effective treatments for GB patients.
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Zalewski, Daniel, Paulina Chmiel, Przemysław Kołodziej, Marcin Kocki, Marcin Feldo, Janusz Kocki e Anna Bogucka-Kocka. "Key Regulators of Angiogenesis and Inflammation Are Dysregulated in Patients with Varicose Veins". International Journal of Molecular Sciences 25, n. 12 (20 giugno 2024): 6785. http://dx.doi.org/10.3390/ijms25126785.
Abstract (sommario):
Varicose veins (VVs) are the most common manifestation of chronic venous disease (CVD) and appear as abnormally enlarged and tortuous superficial veins. VVs result from functional abnormalities in the venous circulation of the lower extremities, such as venous hypertension, venous valve incompetence, and venous reflux. Previous studies indicate that enhanced angiogenesis and inflammation contribute to the progression and onset of VVs; however, dysregulations in signaling pathways associated with these processes in VVs patients are poorly understood. Therefore, in our study, we aimed to identify key regulators of angiogenesis and inflammation that are dysregulated in patients with VVs. Expression levels of 18 genes were analyzed in peripheral blood mononuclear cells (PBMC) using real-time PCR, as well as plasma levels of 6 proteins were investigated using ELISA. Higher levels of CCL5, PDGFA, VEGFC, TGF-alpha, TGF-beta 1, and VEGF-A, as well as lower levels of VEGFB and VEGF-C, were found to be statistically significant in the VV group compared to the control subjects without VVs. None of the analyzed factors was associated with the venous localization of the varicosities. The presented study identified dysregulations in key angiogenesis- and inflammation-related factors in PBMC and plasma from VVs patients, providing new insight into molecular mechanisms that could contribute to the development of VVs and point out promising candidates for circulatory biomarkers of this disease.
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Nagai, Nao, e Takashi Minami. "Emerging Role of VEGFC in Pathological Angiogenesis". EBioMedicine 2, n. 11 (novembre 2015): 1588–89. http://dx.doi.org/10.1016/j.ebiom.2015.11.006.