Mechanism of thrombin-induced angiogenesis

2002 ◽  
Vol 30 (2) ◽  
pp. 173-177 ◽  
Author(s):  
M. E. Maragoudakis ◽  
N. E. Tsopanoglou ◽  
P. Andriopoulou
Keyword(s):  
Endothelial Cells ◽  
Clinical Laboratory ◽  
Tumour Progression ◽  
Angiogenic Factor ◽  
Endothelial Cell Proliferation ◽  
Thrombin Receptor ◽  
Promoting Effect ◽  
Protease Activate Receptor ◽  
Increased Risk ◽  
Risk Of Cancer

Clinical, laboratory, histopathological and pharmacological evidence support the notion that a systemic activation of blood coagulation is often present in cancer patients. Additionally, thrombin was shown to promote tumour progression and metastasis in animals, and epidemiological studies suggest an increased risk of cancer diagnosis after primary thromboembolism. We have proposed that the aforementioned results may be related to our finding that thrombin is a potent activator of angiogenesis. This is a thrombin receptor-mediated event (the receptor is referred to as protease-activate receptor) and is independent of fibrin formation. Many cellular effects of thrombin on endothelial cells can contribute to the angiogenic action of thrombin. (i) Exposure of endothelial cells to thrombin cause a time- and dose-dependent decrease in the attachment of these cells to basement membrane components, with a concomitant increase in matrix metallo-proteinase 2 activation, (ii) Thrombin upregulates the expression of integrin αvβ3, the marker of the angiogenic phenotype of endothelial cells. (iii) Thrombin has chemotactic and aptotactic effects on endothelial cells and upregulates the expression of the vascular endothelial growth factor (VEGF) receptors (KDR and Flt1). Thus, thrombin synergizes with the key angiogenic factor VEGF in endothelial cell proliferation. Furthermore, thrombin enhances the secretion of VEGF and matrix metalloproteinase 9 of PC3 prostate cancer cells. These results can explain the angiogenic and tumour-promoting effect of thrombin and provide the basis for development of thrombin receptor mimetics or antagonists for therapeutic application.

scholarly journals Anti-seizure medication is not associated with an increased risk to develop cancer in epilepsy patients

2021 ◽  
Author(s):  
Jenny Stritzelberger ◽  
Johannes D. Lang ◽  
Tamara M. Mueller ◽  
Caroline Reindl ◽  
Vivien Westermayer ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Cancer Diagnosis ◽  
Index Date ◽  
Control Group ◽  
Protective Effects ◽  
Promoting Effect ◽  
Increased Risk ◽  
Comorbidity Index ◽  
Preclinical And Clinical Studies ◽  
Risk Of Cancer

Abstract Objective Whether anti-seizure medication (ASM) increases the risk for cancer has been debated for decades. While for some ASM, a carcinoma-promoting effect has been suspected, carcinoma-protective effects have been shown for other ASM. However, the issue remains unresolved as data from preclinical and clinical studies have been inconsistent and contradictory. Methods We collected anonymous patient data from practice neurologists throughout Germany between 2009 and 2018 using the IMS Disease Analyzer database (QuintilesIMS, Frankfurt, Germany). People with epilepsy (PWE) with an initial cancer diagnosis and antiepileptic therapy prior to the index date were 1:1 matched with a control group of PWE without cancer according to age, gender, index year, Charlson Comorbidity Index, and treating physician. For both groups, the risk to develop cancer under treatment with different ASMs was analyzed using three different models (ever use vs. never use (I), effect per one (II) and per five therapy years (III). Results A total of 3152 PWE were included (each group, n = 1,576; age = 67.3 ± 14.0 years). The risk to develop cancer was not significantly elevated for any ASM. Carbamazepine was associated with a decreased cancer risk (OR Model I: 0.699, p < .0001, OR Model II: 0.952, p = .4878, OR Model III: 0.758, p < .0004). Significance Our findings suggest that ASM use does not increase the risk of cancer in epilepsy patients.

Abstract 554: Multimerin2 Influences Vascularization Through Modulation of Perlecan

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Petra E Burgisser ◽  
Dennie Tempel ◽  
Dorien Hermkens ◽  
Stefan Schulte-Merker ◽  
Caroline Cheng ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Blood Vessel ◽  
Angiogenic Factor ◽  
Endothelial Cell Proliferation ◽  
G1 Arrest ◽  
Blood Vessel Formation ◽  
Binding Partner ◽  
Vessel Formation

Vascular development is crucial in normal physiology and pathophysiology, and is in part orchestrated by a dynamic balance between extracellular matrix (ECM) and endothelial cells. The molecular mechanisms that govern this balance and as such play a role in the formation of new blood vessels remain largely unknown. In order to identify new genes involved in blood vessel formation, we performed a genome-wide gene expression array analysis in Flk1+ angioblasts during mouse development using a commercial platform (Affymetrix). Multimerin2 (Mmrn2) expression was found to be upregulated in angioblasts and in the developing vasculature of zebrafish and mice. In vitro , using immunofluorescence, Mmrn2 was detected outside of human aortic endothelial cells (HAECs), were it co-localized with the extracellular matrix components perlecan, laminin and fibronectin. Direct interaction with these proteins was confirmed using a combination of co-immunoprecipitation followed by proteomics (LC-MS), and western blot to identify possible binding partners. Mmrn2 gain-of-function and loss-of-function in vitro studies, using Mmrn2 siRNA and adenoviral constructs likewise decreased and increased the expression of its binding partner perlecan. Perlecan is a well known modulator of the pro-angiogenic factor, FGF2, and is required for further signaling through the FGF receptor. Therefore, Mmrn2 may influence FGF2 signaling through perlecan expression and complex formation. Subsequent in vitro studies using an adenoviral construct to induce Mmrn2 overexpression resulted in a G1-arrest in HAECs (P<0.001, N=8). In FGF2 depleted medium a G1 arrest was also observed (P<0.05, N=3), Mmrn2 overexpression combined with FGF2 depleted medium did not enhance the G1 arrest, suggesting a role of Mmrn2 in FGF2 signaling. In addition, Mmrn2 silencing or overexpression in HAECs led to a loss of ECM organization or improved organization, respectively. In line, the binding partner of Mmrn2, perlecan, has been shown to be involved in stabilization of the ECM. These findings suggest that Mmrn2 plays a role during blood vessel formation by binding to perlecan and the ECM, thereby modulating FGF2 signaling and ECM organization and subsequently, regulating endothelial cell proliferation.

MEKK3 is required for endothelium function but is not essential for tumor growth and angiogenesis

2007 ◽  
Vol 293 (4) ◽  
pp. C1404-C1411 ◽  
Author(s):  
Yong Deng ◽  
Jianhua Yang ◽  
Marya McCarty ◽  
Bing Su
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Critical Role ◽  
Embryonic Stem ◽  
Angiogenic Factor ◽  
Endothelial Cell Proliferation ◽  
Wild Type

Mitogen-activated protein kinase kinase kinase 3 (MEKK3) plays an essential role in embryonic angiogenesis, but its role in tumor growth and angiogenesis is unknown. In this study, we further investigated the role of MEKK3 in embryonic angiogenesis, tumor angiogenesis, and angiogenic factor production. We found that endothelial cells from Mekk3-deficient embryos showed defects in cell proliferation, apoptosis, and interactions with myocardium in the heart. We also found that MEKK3 is required for angiopoietin-1 (Ang1)-induced p38 and ERK5 activation. To study the role of MEKK3 in tumor growth and angiogenesis, we established both wild-type and Mekk3-deficient tumor-like embryonic stem cell lines and transplanted them subcutaneously into nude mice to assess their ability to grow and induce tumor angiogenesis. Mekk3-deficient tumors developed and grew similarly as control Mekk3 wild-type tumors and were also capable of inducing tumor angiogenesis. In addition, we found no differences in the production of VEGF in Mekk3-deficient tumors or embryos. Taken together, our results suggest that MEKK3 plays a critical role in Ang1/Tie2 signaling to control endothelial cell proliferation and survival and is required for endothelial cells to interact with the myocardium during early embryonic development. However, MEKK3 is not essential for tumor growth and angiogenesis.

scholarly journals Repulsive axon guidance molecule Slit3 is a novel angiogenic factor

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4300-4309 ◽  
Author(s):  
Bing Zhang ◽  
Ursula M. Dietrich ◽  
Jian-Guo Geng ◽  
Roy Bicknell ◽  
Jeffrey D. Esko ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Embryonic Development ◽  
Axon Guidance ◽  
Network Formation ◽  
Specific Activity ◽  
Angiogenic Factor ◽  
Endothelial Cell Proliferation ◽  
Axon Guidance Molecule ◽  
Guidance Molecule

Abstract Slits are large, secreted repulsive axon guidance molecules. Recent genetic studies revealed that the Slit3 is dispensable for neural development but required for non-neuron–related developmental processes, such as the genesis of the diaphragm and kidney. Here we report that Slit3 potently promotes angiogenesis, a process essential for proper organogenesis during embryonic development. We observed that Slit3 is expressed and secreted by both endothelial cells and vascular smooth muscle cells in vasculature and that the Slit cognate receptors Robo1 and Robo4 are universally expressed by endothelial cells, suggesting that Slit3 may act in paracrine and autocrine manners to regulate endothelial cells. Cellular function studies revealed that Slit3 stimulates endothelial-cell proliferation, promotes endothelial-cell motility and chemotaxis via interaction with Robo4, and accelerates endothelial-cell vascular network formation in vitro with a specific activity comparable with vascular endothelial growth factor. Furthermore, Slit3 stimulates neovessel sprouting ex vivo and new blood vessel growth in vivo. Consistent with these observations, the Slit3 knockout mice display disrupted angiogenesis during embryogenesis. Taken together, our studies reveal that the repulsive axon guidance molecule Slit3 is a novel and potent angiogenic factor and functions to promote angiogenesis in coordinating organogenesis during embryonic development.

Naturally Produced Extracellular Matrix Is an Excellent Substrate for Canine Endothelial Cell Proliferation and Resistance to Shear Stress on PTFE Vascular Grafts

1997 ◽  
Vol 78 (05) ◽  
pp. 1392-1398 ◽  
Author(s):  
A Schneider ◽  
M Chandra ◽  
G Lazarovici ◽  
I Vlodavsky ◽  
G Merin ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Cell ◽  
Cell Attachment ◽  
Thrombus Formation ◽  
Endothelial Cell Proliferation ◽  
Ptfe Graft ◽  
Vascular Prostheses ◽  
Endothelial Cell Attachment

SummaryPurpose: Successful development of a vascular prosthesis lined with endothelial cells (EC) may depend on the ability of the attached cells to resist shear forces after implantation. The present study was designed to investigate EC detachment from extracellular matrix (ECM) precoated vascular prostheses, caused by shear stress in vitro and to test the performance of these grafts in vivo. Methods: Bovine aortic endothelial cells were seeded inside untreated polytetrafluoro-ethylene (PTFE) vascular graft (10 X 0.6 cm), PTFE graft precoated with fibronectin (FN), or PTFE precoated with FN and a naturally produced ECM (106 cells/graft). Sixteen hours after seeding the medium was replaced and unattached cells counted. The strength of endothelial cell attachment was evaluated by subjecting the grafts to a physiologic shear stress of 15 dynes/cm2 for 1 h. The detached cells were collected and quantitated. PTFE or EC preseeded ECM coated grafts were implanted in the common carotid arteries of dogs. Results: While little or no differences were found in the extent of endothelial cell attachment to the various grafts (79%, 87% and 94% of the cells attached to PTFE, FN precoated PTFE, or FN+ECM precoated PTFE, respectively), the number of cells retained after a shear stress was significanly increased on ECM coated PTFE (20%, 54% and 85% on PTFE, FN coated PTFE, and FN+ECM coated PTFE, respectively, p <0.01). Implantation experiments in dogs revealed a significant increase in EC coverage and a reduced incidence of thrombus formation on ECM coated grafts that were seeded with autologous saphenous vein endothelial cells prior to implantation. Conclusion: ECM coating significantly increased the strength of endothelial cell attachment to vascular prostheses subjected to shear stress. The presence of adhesive macromolecules and potent endothelial cell growth promoting factors may render the ECM a promising substrate for vascular prostheses.

Neuroradiology Manifestations of Li-Fraumeni Syndrome: Epidemiology, Genetics, Imaging Findings, and Management

Neurographics ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 228-235
Author(s):  
S. Naganawa ◽  
T. Donohue ◽  
A. Capizzano ◽  
Y. Ota ◽  
J. Kim ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Soft Tissue Sarcomas ◽  
Suppressor Gene ◽  
Imaging Findings ◽  
Li Fraumeni Syndrome ◽  
Increased Risk ◽  
Li Fraumeni ◽  
Risk Of Cancer

Li-Fraumeni syndrome is a familial cancer predisposition syndrome associated with germline mutation of the tumor suppressor gene 53, which encodes the tumor suppressor p53 protein. Affected patients are predisposed to an increased risk of cancer development, including soft-tissue sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma, among other malignancies. The tumor suppressor gene TP53 plays an important, complex role in regulating the cell cycle, collaborating with transcription factors and other proteins. The disruption of appropriate cell cycle regulation by mutated TP53 is considered to be the cause of tumorigenesis in Li-Fraumeni syndrome. Appropriate surveillance, predominantly by using MR imaging, is used for early malignancy screening in an effort to improve the survival rate among individuals who are affected. Patients with Li-Fraumeni syndrome are also at increased risk for neoplasm development after radiation exposure, and, therefore, avoiding unnecessary radiation in both the diagnostic and therapeutic settings is paramount. Here, we review the epidemiology, genetics, imaging findings, and the current standard surveillance protocol for Li-Fraumeni syndrome from the National Comprehensive Cancer Network as well as potential treatment options.Learning Objective: Describe the cause of second primary malignancy among patients with Li-Fraumeni syndrome.

scholarly journals Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 621
Author(s):  
Maria Grazia Muoio ◽  
Marianna Talia ◽  
Rosamaria Lappano ◽  
Andrew H. Sims ◽  
Veronica Vella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Bioinformatic Analysis ◽  
Tube Formation ◽  
Endothelial Cell Proliferation ◽  
Diabetic Patients ◽  
Obesity And Diabetes ◽  
Er Positive

Background: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. Methods: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. Results: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. Conclusions: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.

scholarly journals Cognitive impact of COVID-19: looking beyond the short term

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Scott Miners ◽  
Patrick G. Kehoe ◽  
Seth Love
Keyword(s):  
Endothelial Cells ◽  
Immune Activation ◽  
Angiotensin Receptor Blockers ◽  
Amyloid Β ◽  
Neurological Complications ◽  
Cerebral Hypoperfusion ◽  
Cerebral White Matter ◽  
Ischaemic Damage ◽  
Hospitalised Patients ◽  
Increased Risk

AbstractCOVID-19 is primarily a respiratory disease but up to two thirds of hospitalised patients show evidence of central nervous system (CNS) damage, predominantly ischaemic, in some cases haemorrhagic and occasionally encephalitic. It is unclear how much of the ischaemic damage is mediated by direct or inflammatory effects of virus on the CNS vasculature and how much is secondary to extracranial cardiorespiratory disease. Limited data suggest that the causative SARS-CoV-2 virus may enter the CNS via the nasal mucosa and olfactory fibres, or by haematogenous spread, and is capable of infecting endothelial cells, pericytes and probably neurons. Extracranially, SARS-CoV-2 targets endothelial cells and pericytes, causing endothelial cell dysfunction, vascular leakage and immune activation, sometimes leading to disseminated intravascular coagulation. It remains to be confirmed whether endothelial cells and pericytes in the cerebral vasculature are similarly targeted. Several aspects of COVID-19 are likely to impact on cognition. Cerebral white matter is particularly vulnerable to ischaemic damage in COVID-19 and is also critically important for cognitive function. There is accumulating evidence that cerebral hypoperfusion accelerates amyloid-β (Aβ) accumulation and is linked to tau and TDP-43 pathology, and by inducing phosphorylation of α-synuclein at serine-129, ischaemia may also increase the risk of development of Lewy body disease. Current therapies for COVID-19 are understandably focused on supporting respiratory function, preventing thrombosis and reducing immune activation. Since angiotensin-converting enzyme (ACE)-2 is a receptor for SARS-CoV-2, and ACE inhibitors and angiotensin receptor blockers are predicted to increase ACE-2 expression, it was initially feared that their use might exacerbate COVID-19. Recent meta-analyses have instead suggested that these medications are protective. This is perhaps because SARS-CoV-2 entry may deplete ACE-2, tipping the balance towards angiotensin II-ACE-1-mediated classical RAS activation: exacerbating hypoperfusion and promoting inflammation. It may be relevant that APOE ε4 individuals, who seem to be at increased risk of COVID-19, also have lowest ACE-2 activity. COVID-19 is likely to leave an unexpected legacy of long-term neurological complications in a significant number of survivors. Cognitive follow-up of COVID-19 patients will be important, especially in patients who develop cerebrovascular and neurological complications during the acute illness.

scholarly journals Exploring the Epidemiology of Cancer after Solid Organ Transplantation (EpCOT): an observational cohort study

BMJ Open ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. e043731
Author(s):  
Adnan Sharif ◽  
Javeria Peracha ◽  
David Winter ◽  
Raoul Reulen ◽  
Mike Hawkins
Keyword(s):  
Organ Transplantation ◽  
Record Linkage ◽  
Solid Organ Transplantation ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Study Cohort ◽  
Solid Organ ◽  
Post Transplantation ◽  
Increased Risk ◽  
Risk Of Cancer

IntroductionSolid organ transplant patients are counselled regarding increased risk of cancer (principally due to their need for lifelong immunosuppression) and it ranks as one of their biggest self-reported worries. Post-transplantation cancer is common, associated with increased healthcare costs and emerging as a leading cause of post-transplant mortality. However, epidemiology of cancer post-transplantation remains poorly understood, with limitations including translating data from different countries and national data being siloed across different registries and/or data warehouses.Methods and analysisStudy methodology for Epidemiology of Cancer after Solid Organ Transplantation involves record linkage between the UK Transplant Registry (from NHS Blood and Transplant), Hospital Episode Statistics (for secondary care episodes from NHS Digital), National Cancer Registry (from cancer registration data hosted by Public Health England) and the National Death Registry (from NHS Digital). Deterministic record linkage will be conducted by NHS Digital, with a fully anonymised linked dataset available for analysis by the research team. The study cohort will consist of up to 85 410 solid organ transplant recipients,who underwent a solid organ transplant in England between 1 January 1985 and 31 December 2015, with up-to-date outcome data.Ethics and disseminationThis study has been approved by the Confidentiality Advisory Group (reference: 16/CAG/0121), Research Ethics Committee (reference: 15/YH/0320) and Institutional Review Board (reference: RRK5471). The results of this study will be presented at national and international conferences, and manuscripts with results will be submitted for publication in high-impact peer-reviewed journals. The information produced will also be used to develop national evidence-based clinical guidelines to inform risk stratification to enable risk-based clinical follow-up.Trial registration numberNCT02991105.

scholarly journals Antihypertensive Drugs and the Risk of Cancer: A Nationwide Cohort Study

2021 ◽  
Vol 10 (4) ◽  
pp. 771
Author(s):  
In-Jeong Cho ◽  
Jeong-Hun Shin ◽  
Mi-Hyang Jung ◽  
Chae Young Kang ◽  
Jinseub Hwang ◽  
...  
Keyword(s):  
Antihypertensive Drugs ◽  
Beta Blockers ◽  
Angiotensin Receptor Blockers ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Channel Blockers ◽  
Antihypertensive Medications ◽  
Converting Enzyme Inhibitors ◽  
Incident Cancer ◽  
Increased Risk ◽  
Risk Of Cancer

We sought to assess the association between common antihypertensive drugs and the risk of incident cancer in treated hypertensive patients. Using the Korean National Health Insurance Service database, the risk of cancer incidence was analyzed in patients with hypertension who were initially free of cancer and used the following antihypertensive drug classes: Angiotensin-converting enzyme inhibitors (ACEIs); angiotensin receptor blockers (ARBs); beta blockers (BBs); calcium channel blockers (CCBs); and diuretics. During a median follow-up of 8.6 years, there were 4513 (6.4%) overall cancer incidences from an initial 70,549 individuals taking antihypertensive drugs. ARB use was associated with a decreased risk for overall cancer in a crude model (hazard ratio (HR): 0.744, 95% confidence interval (CI): 0.696–0.794) and a fully adjusted model (HR: 0.833, 95% CI: 0.775–0.896) compared with individuals not taking ARBs. Other antihypertensive drugs, including ACEIs, CCBs, BBs, and diuretics, did not show significant associations with incident cancer overall. The long-term use of ARBs was significantly associated with a reduced risk of incident cancer over time. The users of common antihypertensive medications were not associated with an increased risk of cancer overall compared to users of other classes of antihypertensive drugs. ARB use was independently associated with a decreased risk of cancer overall compared to other antihypertensive drugs.

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