Vascular Endothelial Growth Factor Receptor Research Articles

New Thieno[2,3-d]pyrimidines as Anticancer VEGFR-2 Inhibitors with Apoptosis Induction: Design, Synthesis, and Biological and In Silico Studies.

Vascular endothelial growth factor receptor-2 (VEGFR-2) is a critical protein involved in tumor progression, making it an attractive target for cancer therapy. This study aimed to synthesize and evaluate novel thieno[2,3-d]pyrimidine analogues as potential anticancer VEGFR-2 inhibitors. The thieno[2,3-d]pyrimidine analogues were synthesized following the pharmacophoric features of VEGFR-2 inhibitors. The anticancer potential was assessed against PC3 and HepG2 cell lines. The VEGFR-2 inhibition was evaluated through IC50 determination. Cell cycle analysis and apoptosis assays were performed to elucidate the mechanisms of action. Molecular docking, molecular dynamics simulations, MM-GBSA, and PLIP studies were conducted to investigate the binding affinities and interactions with VEGFR-2. Additionally, in silico ADMET studies were performed. Compound 8b demonstrated significant anti-proliferative activities with IC50 values of 16.35 μM and 8.24 μM against PC3 and HepG2 cell lines, respectively, surpassing sorafenib and exhibiting enhanced selectivity indices. Furthermore, compound 8b showed an IC50 value of 73 nM for VEGFR-2 inhibition. Cell cycle analysis revealed G2-M phase arrest, while apoptosis assays demonstrated increased apoptosis in HepG2 cells. Molecular docking and dynamic simulations confirmed the binding affinity and interaction of compound 8b with VEGFR-2, supported by MMGBSA and PLIP studies. In silico ADMET studies indicated the drug development potential of the synthesized thieno[2,3-d]pyrimidines. The study highlights compound 8b as a promising VEGFR-2 inhibitor with potent anti-proliferative activities. Its mechanism of action involves cell cycle arrest and induction of apoptosis. Further, molecular docking and dynamic simulations support the strong binding affinity of compound 8b to VEGFR-2.

Rationale, in silico docking, ADMET profile, design, synthesis and cytotoxicity evaluations of phthalazine derivatives as VEGFR-2 inhibitors and apoptosis inducers.

New phthalazine derivatives as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors were synthesized joined to different spacers including pyrazole, α,β-unsaturated ketonic fragment, pyrimidinone and/or pyrimidinthione. A docking study was carried out to explore the suggested binding orientations of the novel derivatives inside the active site of VEGFR-2. The obtained biological data were extremely interrelated to that of the docking study. In particular, compounds 4b and 3e showed the highest activities against Michigan Cancer Foundation-7 (MCF-7) and Hepatocellular carcinoma G2 (HepG2) with half maximal inhibitory concentration (IC50) = 0.06, 0.06 μM and 0.08, 0.19 μM respectively. Our derivatives 3a-e, 4a,b and 5a,b were evaluated for their cytotoxicity against normal VERO cells. Our compounds exhibited low toxicity concerning normal VERO cells with IC50 = 3.00-4.75 μM. In addition, our final derivatives 3a-e, 4a, 4b, 5a and 5b were investigated for their VEGFR-2 inhibitory activities. Derivative 4b exhibited the highest VEGFR-2 inhibitory activities at an IC50 value of 0.09 ± 0.02 μM. Derivatives 3e, 4a and 5b demonstrated good activities with IC50 values = 0.12 ± 0.02, 0.15 ± 0.03 and 0.13 ± 0.03 μM respectively. Furthermore, the activities of 4b were assessed against MCF-7 cancer cells for apoptosis induction, cell cycle distribution and growth inhibition. Compound 4b caused cell growth arrest in growth 2-mitosis (G2-M) phase; accumulation of cells at that phase became 6.92% after being 13.2 in control cells. Moreover, our derivatives 3e, 4b and 5b revealed a good in silico considered absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile in comparison to sorafenib.

Recent updates on potential of VEGFR-2 small-molecule inhibitors as anticancer agents.

The vascular endothelial growth factor receptor (VEGFR) system is the key component for controlling angiogenesis in cancer cells. Blocking vascular endothelial growth factor receptor 2 (VEGFR2) signalling is one of the most promising approaches to hindering angiogenesis and the subsequent growth of cancer cells. The USFDA-approved small-molecule drugs targeting VEGFR-2 are developing drug resistance over the course of chemotherapy, and cardiac-related side effects are consistently being reported; hence, there is an urgent need for more safe and effective anticancer molecules. The present review focuses on the structure and physiology of VEGFR-2 and its involvement in the progression of cancer cells. The recent updates from the last five years through papers and patents on structure-activity relationships, pharmacophoric attributes, molecular docking interactions, antiangiogenic assays, cancer cell line studies, and the potencies (IC50) of VEGFR-2 inhibitors are discussed herein. The common structural framework requirements, such as the Asp-Phe-Gly (DFG) motif of VEGFR-2 interacting with the HBD-HBA region in the ligand molecules, the central aryl ring occupying the linker region, and a variety of bio-isosteres, can enhance activity against VEGFR-2. At one end, the heteroaryl moiety is essential for interaction within the ATP-binding site of VEGFR-2, while the terminal hydrophobic tail occupies the allosteric binding site. Three to five bond spacers between the heteroaryl and HBD-HBA regions provided a better result towards VEGFR-2 inhibition, mirroring the behaviors of standard drugs. The in-depth analysis of recent updates on VEGFR-2 inhibitors presented in this paper will help prospective synthetic and medicinal chemists to discover new lead molecules for the treatment of various cancers.

Data-driven derivation of an adverse outcome pathway linking vascular endothelial growth factor receptor (VEGFR), endocrine disruption, and atherosclerosis.

Dysregulation of vascular endothelial growth factor (VEGF) and its receptor (VEGFR) contributes to atherosclerosis and cardiovascular disease (CVD), making it a potential target for CVD risk assessment. High-throughput screening (HTS) approaches have resulted in large-scale in vitro data, providing mechanistic information that can help assess chemical toxicity and identify molecular ini­tiating events (MIEs) of adverse outcome pathways (AOPs). AOPs represent a logical sequence of biological responses contributing to toxicity and are valuable tools to inform chemical risk assessment. Here, we used HTS data to formulate an AOP relating VEGF signaling perturbation to atheroscle­rosis. ToxCast, Tox21, and PubChem data were evaluated to obtain bioprofiles of 4165 compounds active in assays targeting VEGFR. Cheminformatics analysis identified 109 enriched structural fin­gerprints. Applying a subspace clustering approach based on chemical structure bioactivity yielded 12 primary targets, whose relevance to CVD was confirmed by an AI-assisted literature review. An AOP was hypothesized by coupling mechanistic relationships highlighted by HTS data with literature review findings, linking serotonin receptor (HTR), estrogen receptor alpha (ERα), and vasopressin receptor (AVPR) targets with VEGFR activity, angiogenic signaling, and atherosclerosis. Several endocrine disrupting chemicals (EDCs), e.g., bisphenols, triclosan, dichlorodiphenyltrichloroethane (DDT), and polychlorinated biphenyls (PCBs), were identified as relevant chemical stressors. Sub­space clustering of these chemicals evaluated potential MIEs and highlighted associations with use case classes. By applying computational methods to profile HTS data and hypothesize a mechanistic AOP, this study proposes a data-driven approach to evaluating environmental cardiotoxicity, which could eventually supplement and reduce the need for animal testing in toxicological assessments.

Expression of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, cyclooxygenase-2, survivin, E-cadherin and Ki-67 in canine nasal carcinomas and sarcomas - a pilot study.

Malignant (intra-) nasal tumors (NTs) are the most common cause of chronic nasal discharge in dogs. Besides radiation therapy, palliative therapy is necessary in some dogs. Therefore, studies on receptor expression have supported the utility of tyrosine kinase inhibitors (TKI) in dogs with nasal carcinomas. However, studies on receptor expression in nasal sarcomas are lacking. This study evaluated the expression of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR), cyclooxigenase-2 (COX-2), Ki-67, survivin and E-cadherin in nasal carcinomas and sarcomas and compared it with tumor (T) categories based on computed tomography (CT). In 26 dogs with NTs, cross sectional imaging and upper airway endoscopy with guided biopsy collection were performed, followed by histopathological examination of NTs, revealing 19 epithelial and 7 mesenchymal tumors. While EGFR and E-cadherin were only expressed by carcinomas, the following markers were expressed by both carcinomas and sarcomas without significant differences between tumor types and T-categories: VEGFR-2 (carcinomas and sarcomas 100%), COX-2 (carcinomas 63%, sarcomas 57%), survivin (carcinomas 100%, sarcomas 86%) and Ki-67 (median expression of 28.5% in carcinomas and 17.3% in sarcomas). Based on similarities in marker expression between canine carcinomas and sarcomas, clinical studies should further elucidate the use of TKI or COX-2 inhibitors as additional therapy in dogs with nasal sarcomas.

Application of Support Vector Machine Classification Model to Identification of Vascular Endothelial Growth Factor Receptor Inhibitors.

Nowadays, with the increasing prevalence of cancer mortality, finding the best cancer inhibitors is vital. Angiogenesis, which refers to the formation of new blood vessels from existing ones, undergoes abnormal changes in the physiological process of solid tumors. Vascular endothelial growth factor receptor (VEGFR) plays a crucial role in angiogenesis. Hence, one of the suggestions in cancer treatment has been inhibiting VEGFR signaling to prevent angiogenesis. The computational approach as an in vitro alternative method is crucial to reduce time and cost. This study aimed to use classification algorithm to separate potent inhibitors from inactive ones. In order to apply the machine learning model, biological compounds were extracted from the BindingDB database. Due to the large number of molecular features, the classification model was susceptible to overfitting. To address this issue, a correlation-based feature selection algorithm was proposed as a means of feature reduction. Subsequently, for the classification step, a support vector machine model that utilizes both linear and non-linear kernels was employed. The implementation of the support vector machine model with the radial basis function kernel, along with the correlation-based feature selection method, resulted in a higher accuracy (81.8%, P value = 0.008) compared to other feature selection methods used in this study. Finally, two structures were introduced with the highest binding affinity to inhibit the second VEGFR. According to the results, the correlation-based feature selection method is more accurate than other methods.

Comprehensive structural and functional analysis of hVEGFR1: Insights into phosphorylation, molecular interactions, and potential inhibitors through docking and dynamics simulations

Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), is an enzyme with tyrosine kinase activity that plays a pivotal role in angiogenesis, the process of new blood vessel formation. This receptor is of significant clinical importance as it is implicated in various cancers, particularly non-small cell lung cancer (NSCLC), where its dysregulation leads to uncontrolled cell growth through ligand-induced phosphorylation. While commercially available drugs target VEGFR1, their prolonged use often leads to drug resistance and the emergence of mutations in cancer patients. To address these challenges, researchers have identified the human tyrosine kinase (hTK) domain of VEGFR1 as a potential therapeutic marker for lung malignancies. The 3D crystal structure of the hTK domain, obtained from Protein Data Bank (PDB ID: 3HNG), has provided vital structural insights of hVEGFR1. This study has revealed variations within the hVEGFR1 tyrosine kinase domain, distinguishing between regions associated with phosphorylase kinase and transferase activities. We identified numerous potential phosphorylation sites within the TK domain, shedding light on the protein's regulation and signaling possible. Detailed molecular interaction analyses have elucidated the binding forces between lead molecules and hVEGFR1, including hydrogen bonds, electrostatic, hydrophobic, and π-sigma interactions. The stability observed during molecular dynamics simulations further underscores the biological relevance of these interactions. Furthermore, docked complexes has highlighted localized structural fluctuations, offering insight into potential allosteric effects and dynamic conformational changes induced by lead molecules. These findings not only provide a comprehensive characterization of hVEGFR1 but also pave the way for the development of targeted therapies. Eventually, this study has the potential in identifying drug to combat diseases associated with hVEGFR1 dysregulation, including cancer and angiogenesis-related disorders, contributing to effective treatment strategies.

Causal effect of vascular endothelial growth factor on the risk of atrial fibrillation: a two-sample Mendelian randomization study.

Observational studies have found that vascular endothelial growth factor (VEGF) levels are associated with the risk of cardiovascular disease. However, it remains unclear whether VEGF levels have a causal effect on the risk of atrial fibrillation. A two-sample Mendelian randomization (MR) study was conducted to explore the causal relationship between VEGF levels and the risk of atrial fibrillation. Genetic variants associated with VEGF [VEGF-A, VEGF-C, VEGF-D, VEGF receptor-2 (VEGFR-2), VEGFR-3] and atrial fibrillation (atrial fibrillation, atrial fibrillation and flutter) were used as instrumental variables. Data on genetic variants were obtained from published genome-wide association studies (GWAS) or the IEU Open GWAS project. Inverse-variance weighted (IVW) analysis was used as the primary basis for the results, and sensitivity analyses were used to reduce bias. Causal relationships were expressed as odds ratio (OR) with 95% confidence interval (CI), and a P-value of <0.1 corrected for False Discovery Rate (FDR) (PFDR < 0.1) was considered to have a significant causal relationship. Genetically predicted high levels of VEGF-A [OR = 1.025 (95%CI: 1.004-1.047), PFDR = 0.060] and VEGF-D [OR = 1.080 (95%CI: 1.039-1.123), PFDR = 0.001]] were associated with an increased risk of atrial fibrillation, while no causal relationship was observed between VEGF-C (PFDR = 0.419), VEGFR-2 (PFDR = 0.784), and VEGFR-3 (PFDR = 0.899) and atrial fibrillation risk. Moreover, only genetically predicted high levels of VEGF-D [OR = 1.071 (95%CI: 1.014-1.132), PFDR = 0.087] increased the risk of atrial fibrillation and flutter. Sensitivity analysis demonstrated that the relationship between VEGF-D levels and the risk of atrial fibrillation was robust. This study supports a causal association between high VEGF-D levels and increased risk of atrial fibrillation.

Lack of RAMP1 Signaling Suppresses Liver Regeneration and Angiogenesis Following Partial Hepatectomy in Mice.

The liver effectively restores both size and function following partial hepatectomy (PHx). Angiogenesis is crucial for the repair and regeneration of liver tissue post-PHx. Calcitonin gene-related peptide (CGRP) released from sensory nerves and its receptor-receptor activity-modifying protein 1 (RAMP1) are involved in angiogenesis. This study aimed to assess the role of RAMP1 signaling in angiogenesis during liver regeneration following PHx. RAMP1 deficient (RAMP1-/-) and wild-type (WT) mice were subjected to PHx. RAMP1-/- mice demonstrated delayed liver regeneration, indicated by lower liver-to-body weight ratios compared to WT mice. This was associated with lower levels of Ki67+ hepatocytes and hepatic trophic growth factors. Additionally, RAMP1-/- mice exhibited lower levels of endothelial cell markers, including CD31, compared to WT mice. This reduction was associated with reduced levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor 3 (VEGFR3). In WT mice with PHx, the administration of a VEGFR3 inhibitor reduced the liver-to-body weight ratio, Ki67+ hepatocytes, and VEGF-C/VEGFR3 expression levels in the liver compared to those in the vehicle-treated group. The deletion of RAMP1 signaling suppresses liver regeneration and angiogenesis through VEGFR3. Specific activation of RAMP1 signaling may represent a potential therapeutic strategy for liver regeneration following PHx.

Effect of vitamin B12 on methotrexate-induced cardiotoxicity in rats.

Methotrexate (MTX) is a drug with anti-inflammatory and immunosuppressive effects and is also a folic acid antagonist. Our aim in this study is to determine the molecular mechanisms of cardiotoxicity caused by MTX, a chemotherapeutic drug, and to evaluate the protective effects of vitamin B12 on this toxicity. A total of 32 rats were used in our study and 4 groups were formed. Control group, Vit B12 group (3 μg/kg B12 for 15 days, IP), MTX group (20 mg/kg MTX single dose on day 8 of the experiment, IP), MTX +Vit B12 group (3 μg/kg, IP ), Vit B12 throughout the 15 days, and a single dose of 20 mg/kg MTX (IP) on day 8 of the experiment. Immunohistochemically, expressions of hypoxia-inducible factor 1α (HIF1-α), vascular endothelial growth factor receptor-2 (VEGFR-2), erythropoietin (EPO), and interleukin-6 (IL-6) were evaluated in the heart tissue. Total catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were measured in the heart tissue. At the same time, ANP and NT-proBNP levels were measured in the blood serum. In the study, the expression of HIF1-α and VEGFR-2 increased significantly in the MTX group, while IL-6 and EPO significantly decreased. At the same time, CAT and SOD levels were significantly decreased and MDA levels increased significantly in the MTX group. While vitamin B12 significantly corrected all these values, it also greatly reduced the increases in ANP and NT-proBNP levels caused by MTX. It is important to use Vit B12 before and after MTX administration to replace the folate that MTX has reduced.

Thrombopoietin mimetic therapy alleviates radiation-induced bone marrow vascular injury in a bone marrow transplant mouse model.

There is a need for therapies that can mitigate bone marrow dysfunction and organ toxicity that occur following myeloablative injury and reduced intensity conditioning regimens used in patients undergoing bone marrow transplantation (BMT). The pathogenesis of adverse effects from BMT conditioning has been linked to injury to the vascular endothelium, bone marrow (BM), and other organs. To evaluate the impact of the thrombopoietin mimetic drug JNJ-26366821 (TPOm) on BM vascular recovery in mice undergoing myeloablative radiation conditioning followed by BMT. TPOm (doses: 0 µg, 300 µg, 1000 µg per Kg body weight) was administered on Days 0 and 7 after BMT, in mice receiving a total body irradiation (TBI) conditioning regimen (5.5 Gy x 2) before congenic BMT. BM donner cell engraftment was analyzed using flow cytometry on Days 7, 14, and 30 post-BMT. The morphological and biophysical properties of the BM vasculature were evaluated by intravital multiphoton microscopy (MPM) and immunofluorescence confocal imaging. Herein, morphological properties involve microvascular density (MVD), vessel diameter, and vascular area, while biophysical properties include transfer rate (Ktrans) of contrast within the BM vascular niche, as well as the fractional volume (vec ) of extracellular extravascular tissue (EES). No significant difference in donor chimerism was observed at days 7, 14, and 30 post-BMT, between TPOm and PBS-treated mice. TPOm intervention improved BM vasculature regeneration in transplanted mice. The MVD, Ktrans, and BM vasculature as well as vascular endothelial growth factor receptor-2 (VEGFR2) in the BM, showed a dose dependent improvement in mice treated with TPOm. On day 14 post-BMT, the group receiving 1000 µg/Kg TPOm showed significant shifts (p-value < 0.05) in MVD, Ktrans, and VEGFR2 expression from their corresponding control types (TPOm dose 0 µg) towards levels comparable to healthy controls. TPOm intervention augments BM vascular structure and function, which may be important for hematopoietic recovery and bone marrow function in radiation conditioned hematopoietic stem cell transplant patients, in addition to enhancing platelet recovery.

Eucommia granules activate Wnt/β-catenin pathway, and improve oxidative stress, inflammation, and endothelial injury in preeclampsia rats.

Pre-eclampsia (PE) is a pregnancy-related complication. Eucommia is effective in the treatment of hypertensive disorders in pregnancy, but the specific effects and possible mechanisms of Eucommia granules (EG) in PE remain unknown. The aim of this study was to investigate the effects and possible mechanisms of EG in PE rats. Pregnant Sprague Dawley rats were divided into five groups (n = 6): the control group, the model group, the low-dose group, the medium-dose group, and the high-dose group of EG. The PE model was established by subcutaneous injection of levonitroarginine methyl ester. Saline was given to the blank and model groups, and the Eucommia granules were given by gavage to the remaining groups. Blood pressure and urinary protein were detected. The body length and weight of the pups and the weight of the placenta were recorded. Superoxide dismutase (SOD) activity and levels of malondialdehyde (MDA), placental growth factor (PIGF), and soluble vascular endothelial growth factor receptor-1 (sFIt-1) were measured in the placenta. Pathological changes were observed by hematoxylin-eosin staining. Wnt/β-catenin pathway-related protein expression was detected using Western blot. Compared with the model group, the PE rats treated with EG had lower blood pressure and urinary protein. The length and weight of the pups and placental weight were increased. Inflammation and necrosis in the placental tissue was improved. SOD level increased, MDA content and sFIt-1/PIGF ratio decreased, and Wnt/β-catenin pathway-related protein expression level increased. Moreover, the results of EG on PE rats increased with higher doses of EG. EG may activate the Wnt/β-catenin pathway and inhibit oxidative stress, inflammation, and vascular endothelial injury in PE rats, thereby improving the perinatal prognosis of preeclamptic rats. EG may inhibit oxidative stress, inflammation, and vascular endothelial injury through activation of the Wnt/β-catenin pathway in preeclampsia rats, thereby improving perinatal outcomes in PE rats.

Advances in Predictive Biomarkers for Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer.

This study aimed to explore advances in biomarkers related to anti-angiogenic therapy in patients with non-small cell lung cancer (NSCLC), thereby enhancing treatment selection, advancing personalized and precision medicine to improve treatment outcomes and patient survival rates. This article reviews key discoveries in predictive biomarkers for anti-angiogenic therapy in NSCLC in recent years, such as (1) liquid biopsy predictive biomarkers: studies have identified activated circulating endothelial cells (aCECs) via liquid biopsy as potential predictive biomarkers for the efficacy of anti-angiogenic therapy; (2) imaging biomarkers: advanced imaging technologies, such as dynamic contrast-enhanced integrated magnetic resonance positron emission tomography (MR-PET), are used to assess tumor angiogenesis in patients with NSCLC and evaluate the clinical efficacy of anti-angiogenic drugs; (3) genetic predictive biomarkers: research has explored polymorphisms of Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) and vascular endothelial growth factor-A (VEGF-A), as well as how plasma levels of VEGF-A can predict the outcomes and prognosis of patients with non-squamous NSCLC undergoing chemotherapy combined with bevacizumab. Despite progress in identifying biomarkers related to anti-angiogenic therapy, several challenges remain, including limitations in clinical trials, heterogeneity in NSCLC, and technical hurdles. Future research will require extensive clinical validation and in-depth mechanistic studies to fully exploit the potential of these biomarkers for personalized treatment.

Inhibitory effect of ink derived from Indian Loligo duvauceli squid against HIF1α induced angiogenesis

Squids are one of the most important commercial marine resources having high human consumption and market value. An Indian squid, Loligo duvauceli is a valuable species among them. They contain ink sacs which are discarded before using them for consumption. This study for the first time reports its potent ability to inhibit angiogenesis in vitro and in vivo. The melanin-free extract (MFI) of squid ink was assessed for antiproliferative effect on cancer and human umbilical vein endothelial (HUVEC) cell lines. Its antiangiogenic activity was investigated in HUVEC-based tube formation and chick chorioallantoic membrane (CAM) assays. The MFI displayed a prominent reduction in the mean vascular density of the CAM membrane, the viability of HUVEC cells, and its tube formation on the Matrigel base. Influence on the expression of angiogenesis effector genes HIF 1 α, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptors (VEGFR), and COX 2 in HUVEC cell line denoted prominent downregulation of HIF 1 α, VEGF, and VEGFR gene expression. Overall, the results indicated a remarkable potential of L. duvauceli ink to serve as a negative mediator of angiogenesis with probable selective HIF1α induced molecular mechanism for exerting its effect. This waste product of sea food processing industry thus presented itself as a promising natural candidate for arresting angiogenesis.

The Prognostic Significance of Transient Receptor Potential Canonical 1 and Its Association with Vascular Endothelial Growth Factor Receptor 2 in Papillary Thyroid Carcinoma Patients.

The Prognostic Significance of Transient Receptor Potential Canonical 1 and Its Association with Vascular Endothelial Growth Factor Receptor 2 in Papillary Thyroid Carcinoma Patients.

Data-driven derivation of an adverse outcome pathway linking vascular endothelial growth factor receptor (VEGFR), endocrine disruption, and atherosclerosis_suppl2

Data-driven derivation of an adverse outcome pathway linking vascular endothelial growth factor receptor (VEGFR), endocrine disruption, and atherosclerosis_suppl2

Long-term survival of a cat with a metastatic gastrointestinal stromal tumor

Case summary An 8-year-old spayed female mixed-breed cat presented with a 2-year history of recurrent vomiting and hyporexia. Physical examination revealed a palpable mass in the mesogastric abdominal region without discomfort upon touch. Abdominal ultrasonography revealed an intramural mass in the small intestine (duodenum) that caused a decrease in the segment lumen. A complete blood count revealed leukocytosis with marked neutrophilia, eosinophilia and mild hypoalbuminemia. Enterectomy was performed with 3 cm margins and end-to-end anastomosis at the duodenal site of the mass. Histology revealed neoplastic elongated spindle cells that were poorly confined, originating within the muscle layers and that had a mitotic index of 2/10 high-power field (hpf) (at 400×), human epidermal growth factor receptor-type 2 (HER-2) supporting the diagnosis of low-grade sarcoma. Immunohistochemical analysis was positive for KIT, confirming a gastrointestinal stromal tumor (GIST) with a Ki67 level of 15%. Furthermore, multikinase profile biomarkers revealed that the neoplastic cells expressed HER-2 (65%), epidermal growth factor receptor-1 (50%), vascular endothelial growth factor receptor 2 (35%), platelet-derived growth factor receptor beta (15%) and c-KIT (15%). Six months after the original surgery, CT revealed presumptive hepatic, splenic and peritoneal metastases. Toceranib phosphate was prescribed at a dose of 2.75 mg/kg and progressive disease was observed at 8 weeks of follow-up. Relevance and novel information To the best of our knowledge, this is the first case report to characterize the proliferation biomarker profile of a feline GIST in veterinary oncology. However, despite KIT expression in this tumor, the target drug did not inhibit tumor proliferation, providing new insights into this rare tumor in the feline species.

Knockdown of MUC1 by RNA Interference (siRNA) Influenced Vascular Endothelial Growth Factor Receptor (VEGFR2) and Suppression of Growth of Pancreatic Cancer Cells (PANC1)

MUC1 is overexpressed approximately in most of pancreatic adenocarcinomas and has been revealed to be linked with a worse prognosis, beside effectiveness, MUC1 hold for regulating cellular and developmental pathways. The objective of the current study is to downregulate the overexpression of MUC1 by small interfering RNA (siRNA) on PANC1 and to investigate its effect on vascular endothelial growth factor (VEGFR-2) expression. Besides MUC1, the expression levels of VEGFR2 were investigated in PANC1. Then the expression level of MUC1 was downregulated by using MUC1 specific siRNA approach to identify whether MUC1 is involved in the regulation of VEGFR-2 mRNA and protein, which were determined by QRT-PCR and Western blot, respectively. Interestingly, siRNA is considered an emerging approach in cancer cell therapy. Furthermore, the impact of MUC1 silencing in pancreatic adenocarcinoma cell lines was investigated. Transwell and Matrigel assays were performed to study the functional significance of MUC1 activity on cell migration and invasion, respectively. The present study indicates that targeting MUC1 by siRNA in pancreatic adenocarcinoma cells is associated with silencing of VEGFR-2 expression in both mRNA and protein levels, demonstrating that MUC1 regulates the main driver of angiogenesis and metastasis. The current study showed that targeting MUC1 with siRNA decreases pancreatic cancer cell proliferation, migration, and invasion, by significantly decreasing the expression of the potent angiogenic receptor VEGFR-2. Therefore, targeting MUC1 with siRNA can be exploited as a therapeutic option for pancreatic cancer treatment.

Monocyte/macrophage-mediated venous thrombus resolution.

Venous thromboembolism (VTE) poses a notable risk of morbidity and mortality. The natural resolution of the venous thrombus might be a potential alternative treatment strategy for VTE. Monocytes/macrophages merge as pivotal cell types in the gradual resolution of the thrombus. In this review, the vital role of macrophages in inducing inflammatory response, augmenting neovascularization, and facilitating the degradation of fibrin and collagen during thrombus resolution was described. The two phenotypes of macrophages involved in thrombus resolution and their dual functions were discussed. Macrophages expressing various factors, including cytokines and their receptors, adhesion molecules, chemokine receptors, vascular endothelial growth factor receptors, profibrinolytic- or antifibrinolytic-related enzymes, and other elements, are explored for their potential to promote or attenuate thrombus resolution. Furthermore, this review provides a comprehensive summary of new and promising therapeutic candidate drugs associated with monocytes/macrophages that have been demonstrated to promote or impair thrombus resolution. However, further clinical trials are essential to validate their efficacy in VTE therapy.

Data-driven derivation of an adverse outcome pathway linking vascular endothelial growth factor receptor (VEGFR), endocrine disruption, and atherosclerosis_suppl1

Data-driven derivation of an adverse outcome pathway linking vascular endothelial growth factor receptor (VEGFR), endocrine disruption, and atherosclerosis_suppl1