RESUMO
The discovery of vascular endothelial-derived growth factor (VEGF) has revolutionized our understanding of vasculogenesis and angiogenesis during development and physiological homeostasis. Over a short span of two decades, our understanding of the molecular mechanisms by which VEGF coordinates neurovascular homeostasis has become more sophisticated. The central role of VEGF in the pathogenesis of diverse cancers and blinding eye diseases has also become evident. Elucidation of the molecular regulation of VEGF and the transformative development of multiple therapeutic pathways targeting VEGF directly or indirectly is a powerful case study of how fundamental research can guide innovation and translation. It is also an elegant example of how agnostic discovery and can transform our understanding of human disease. This review will highlight critical nodal points in VEGF biology, including recent developments in immunotherapy for cancer and multitarget approaches in neovascular eye disease.
Assuntos
Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/fisiologia , Fatores de Crescimento do Endotélio Vascular/fisiologia , Animais , Humanos , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Vasos Retinianos/metabolismo , Vasos Retinianos/fisiologia , Transdução de Sinais/fisiologia , Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Anti-vascular endothelial growth factor (VEGF) cancer immunotherapy targets angiogenesis but development of resistance in patients is common. In this issue of Cell, Croci et al. identify a complex set of mechanisms by which galectin-1 prolongs cell-surface retention of VEGF receptor 2 (VEGFR2) and stimulates VEGF-independent tumor angiogenesis.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , HumanosRESUMO
The clinical benefit conferred by vascular endothelial growth factors (VEGF)-targeted therapies is variable, and tumors from treated patients eventually reinitiate growth. Here, we identify a glycosylation-dependent pathway that compensates for the absence of cognate ligand and preserves angiogenesis in response to VEGF blockade. Remodeling of the endothelial cell (EC) surface glycome selectively regulated binding of galectin-1 (Gal1), which upon recognition of complex N-glycans on VEGFR2, activated VEGF-like signaling. Vessels within anti-VEGF-sensitive tumors exhibited high levels of α2-6-linked sialic acid, which prevented Gal1 binding. In contrast, anti-VEGF refractory tumors secreted increased Gal1 and their associated vasculature displayed glycosylation patterns that facilitated Gal1-EC interactions. Interruption of ß1-6GlcNAc branching in ECs or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of α2-6-linked sialic acid conferred resistance to anti-VEGF. Disruption of the Gal1-N-glycan axis promoted vascular remodeling, immune cell influx and tumor growth inhibition. Thus, targeting glycosylation-dependent lectin-receptor interactions may increase the efficacy of anti-VEGF treatment.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Células Endoteliais/metabolismo , Galectina 1/genética , Galectina 1/metabolismo , Glicosilação , Humanos , Hipóxia , Camundongos , Receptores Mitogênicos/metabolismoRESUMO
Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR-interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth.
Assuntos
Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Fatores de Crescimento do Endotélio Vascular/fisiologia , Animais , Endocitose , Humanos , Neovascularização Fisiológica , Transporte Proteico , Receptor Cross-TalkRESUMO
Circadian clocks impose daily periodicities to behavior, physiology, and metabolism. This control is mediated by a central clock and by peripheral clocks, which are synchronized to provide the organism with a unified time through mechanisms that are not fully understood. Here, we characterized in Drosophila the cellular and molecular mechanisms involved in coupling the central clock and the peripheral clock located in the prothoracic gland (PG), which together control the circadian rhythm of emergence of adult flies. The time signal from central clock neurons is transmitted via small neuropeptide F (sNPF) to neurons that produce the neuropeptide Prothoracicotropic Hormone (PTTH), which is then translated into daily oscillations of Ca2+ concentration and PTTH levels. PTTH signaling is required at the end of metamorphosis and transmits time information to the PG through changes in the expression of the PTTH receptor tyrosine kinase (RTK), TORSO, and of ERK phosphorylation, a key component of PTTH transduction. In addition to PTTH, we demonstrate that signaling mediated by other RTKs contributes to the rhythmicity of emergence. Interestingly, the ligand to one of these receptors (Pvf2) plays an autocrine role in the PG, which may explain why both central brain and PG clocks are required for the circadian gating of emergence. Our findings show that the coupling between the central and the PG clock is unexpectedly complex and involves several RTKs that act in concert and could serve as a paradigm to understand how circadian clocks are coordinated.
Assuntos
Antígenos de Grupos Sanguíneos , Relógios Circadianos , Animais , Relógios Circadianos/genética , Drosophila , Transdução de Sinais , Receptores Proteína Tirosina Quinases/genética , Fosforilação , Fatores de Crescimento do Endotélio VascularRESUMO
Blockade of vascular endothelial growth factor (VEGF) signaling with bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), or with receptor tyrosine kinase inhibitors, has improved progression-free survival and, in some indications, overall survival across several types of cancers by interrupting tumor angiogenesis. However, the clinical benefit conferred by these therapies is variable, and tumors from treated patients eventually reinitiate growth. Previously we demonstrated, in mouse tumor models, that galectin-1 (Gal1), an endogenous glycan-binding protein, preserves angiogenesis in anti-VEGF-resistant tumors by co-opting the VEGF receptor (VEGFR)2 signaling pathway in the absence of VEGF. However, the relevance of these findings in clinical settings is uncertain. Here, we explored, in a cohort of melanoma patients from AVAST-M, a multicenter, open-label, randomized controlled phase 3 trial of adjuvant bevacizumab versus standard surveillance, the role of circulating plasma Gal1 as part of a compensatory mechanism that orchestrates endothelial cell programs in bevacizumab-treated melanoma patients. We found that increasing Gal1 levels over time in patients in the bevacizumab arm, but not in the observation arm, significantly increased their risks of recurrence and death. Remarkably, plasma Gal1 was functionally active as it was able to reprogram endothelial cell biology, promoting migration, tubulogenesis, and VEGFR2 phosphorylation. These effects were prevented by blockade of Gal1 using a newly developed fully human anti-Gal1 neutralizing mAb. Thus, using samples from a large-scale clinical trial from stage II and III melanoma patients, we validated the clinical relevance of Gal1 as a potential mechanism of resistance to bevacizumab treatment.
Assuntos
Melanoma , Fator A de Crescimento do Endotélio Vascular , Animais , Camundongos , Humanos , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Galectina 1 , Melanoma/tratamento farmacológico , Melanoma/patologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Células Endoteliais/patologia , Fatores de Crescimento do Endotélio Vascular , Biologia , Inibidores da Angiogênese/farmacologiaRESUMO
BACKGROUND: Dkk3 (Dickkopf-3) is a secreted glycoprotein known for its proapoptotic and angiogenic activity. The role of Dkk3 in cardiovascular homeostasis is largely unknown. Remarkably, the Dkk3 gene maps within a chromosome segment linked to the hypertensive phenotype in spontaneously hypertensive rats (SHR). METHODS: We used Dkk3-/- mice or stroke-resistant (sr) and stroke-prone (sp) SHR to examine the role of Dkk3 in the central and peripheral regulation of blood pressure (BP). We used lentiviral expression vector to rescue Dkk3 in knockout mice or to induce Dkk3 overexpression or silencing in SHR. RESULTS: Genetic deletion of Dkk3 in mice enhanced BP and impaired endothelium-dependent acetylcholine-induced relaxation of resistance arteries. These alterations were rescued by restoring Dkk3 expression either in the periphery or in the central nervous system (CNS). Dkk3 was required for the constitutive expression of VEGF (vascular endothelium growth factor), and the action of Dkk3 on BP and endothelium-dependent vasorelaxation was mediated by VEGF-stimulated phosphatidylinositol-3-kinase pathway, leading to eNOS (endothelial NO synthase) activation both in resistance arteries and the CNS. The regulatory function of Dkk3 on BP was confirmed in SHR stroke-resistant and SHR stroke-prone in which was blunted in both resistance arteries and brainstem. In SHR stroke-resistant, lentiviral expression vector-induced Dkk3 expression in the CNS largely reduced BP, whereas Dkk3 knock-down further enhanced BP. In SHR stroke-prone challenged with a hypersodic diet, lentiviral expression vector-induced Dkk3 expression in the CNS displayed a substantial antihypertensive effect and delayed the occurrence of stroke. CONCLUSIONS: These findings demonstrate that Dkk3 acts as peripheral and central regulator of BP by promoting VEGF expression and activating a VEGF/Akt (protein kinase B)/eNOS hypotensive axis.
Assuntos
Hipertensão , Acidente Vascular Cerebral , Animais , Camundongos , Ratos , Pressão Sanguínea , Endotélio Vascular/metabolismo , Hipertensão/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Endogâmicos SHR , Acidente Vascular Cerebral/genética , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , VasodilataçãoRESUMO
It has been recently reported that treatment with an anti-placenta growth factor (PlGF) antibody inhibits metastasis and primary tumor growth. Here we show that, although anti-PlGF treatment inhibited wound healing, extravasation of B16F10 cells, and growth of a tumor engineered to overexpress the PlGF receptor (VEGFR-1), neutralization of PlGF using four novel blocking antibodies had no significant effect on tumor angiogenesis in 15 models. Also, genetic ablation of the tyrosine kinase domain of VEGFR-1 in the host did not result in growth inhibition of the anti-VEGF-A sensitive or resistant tumors tested. Furthermore, combination of anti-PlGF with anti-VEGF-A antibodies did not result in greater antitumor efficacy than anti-VEGF-A monotherapy. In conclusion, our data argue against an important role of PlGF during primary tumor growth in most models and suggest that clinical evaluation of anti-PlGF antibodies may be challenging.
Assuntos
Neoplasias/irrigação sanguínea , Neovascularização Patológica , Proteínas da Gravidez/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fator de Crescimento Placentário , Proteínas da Gravidez/antagonistas & inibidores , Fatores de Crescimento do Endotélio VascularRESUMO
Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.
Assuntos
Fator 2 de Crescimento de Fibroblastos , Neoplasias Mamárias Experimentais , Menopausa , Obesidade , Fator A de Crescimento do Endotélio Vascular , Animais , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Lipocalina-2 , Neoplasias Mamárias Experimentais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neovascularização Patológica/patologia , Obesidade/genética , Inibidores de Proteínas Quinases , Sunitinibe , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
During neurovascular development, brain endothelial cells (BECs) respond to secreted signals from the neuroectoderm that regulate CNS angiogenesis, the formation of new blood vessels in the brain, and barriergenesis, the acquisition of blood-brain barrier (BBB) properties. Wnt/ß-catenin signaling and Vegf signaling are both required for CNS angiogenesis; however, the relationship between these pathways is not understood. Furthermore, while Wnt/ß-catenin signaling is essential for barriergenesis, the role of Vegf signaling in this vital process remains unknown. Here, we provide the first direct evidence, to our knowledge, that Vegf signaling is not required for barriergenesis and that activation of Wnt/ß-catenin in BECs is independent of Vegf signaling during neurovascular development. Using double transgenic glut1b:mCherry and plvap:EGFP zebrafish (Danio rerio) to visualize the developing brain vasculature, we performed a forward genetic screen and identified a new mutant allele of kdrl, an ortholog of mammalian Vegfr2. The kdrl mutant lacks CNS angiogenesis but, unlike the Wnt/ß-catenin pathway mutant gpr124, acquires BBB properties in BECs. To examine Wnt/ß-catenin pathway activation in BECs, we chemically inhibited Vegf signaling and found robust expression of the Wnt/ß-catenin transcriptional reporter line 7xtcf-Xla.Siam:EGFP. Taken together, our results establish that Vegf signaling is essential for CNS angiogenesis but is not required for Wnt/ß-catenin-dependent barriergenesis. Given the clinical significance of either inhibiting pathological angiogenesis or stimulating neovascularization, our study provides valuable new insights that are critical for the development of effective therapies that target the vasculature in neurological disorders.
Assuntos
Barreira Hematoencefálica , beta Catenina , Animais , beta Catenina/metabolismo , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Mamíferos/metabolismo , Neovascularização Patológica , Fatores de Crescimento do Endotélio Vascular/metabolismo , Via de Sinalização Wnt/fisiologia , Peixe-Zebra/metabolismoRESUMO
Adenovirus-mediated gene therapy holds promise for the treatment of cardiovascular diseases such as refractory angina. However, potential concerns around immunogenicity and vector dissemination from the target injected tissue require evaluation. This study was undertaken to evaluate the safety and biodistribution of XC001, a replication-deficient adenovirus serotype 5 vector expressing multiple isoforms of human vascular endothelial growth factor (VEGF), following direct administration into normal rat myocardium. Animals received the buffer formulation or increasing doses of XC001 (1 × 107, 2.5 × 108 or 2.5 × 109 viral particles). Based on in-life parameters (general health, body weights, clinical pathology, serum cardiac troponin I, plasma VEGF, and gross necropsy), there were no findings of clinical concern. On Day 8, intramyocardial administration of XC001 was associated with dose-related, left ventricular myocardial inflammation at injection sites, resolving by Day 30. XC001 DNA was not detected in blood at any time but was present at Day 8 around the site of injection and to a much lesser extent in the spleen, liver, and lungs, persisting at low levels in the heart and spleen until at least Day 91. These findings demonstrate that intramyocardial injection of XC001 is supported for use in human studies.
Assuntos
Doenças Cardiovasculares , Fator A de Crescimento do Endotélio Vascular , Humanos , Ratos , Animais , Fator A de Crescimento do Endotélio Vascular/genética , Distribuição Tecidual , Terapia Genética , Fatores de Crescimento do Endotélio Vascular/genética , Vetores Genéticos/genéticaRESUMO
Placental angiogenesis is critical for normal development. Angiogenic factors and their receptors are key regulators of this process. Dysregulated placental vascular development is associated with pregnancy complications. Despite their importance, vascular growth factor expression has not been thoroughly correlated with placental morphologic development across gestation in cats. We postulate that changes in placental vessel morphology can be appreciated as consequences of dynamic expression of angiogenic signaling agents. Here, we characterized changes in placental morphology alongside expression analysis of angiogenic factor splice variants and receptors throughout pregnancy in domestic shorthair cats. We observed increased vascular and lamellar density in the lamellar zone during mid-pregnancy. Immunohistochemical analysis localized the vascular endothelial growth factor A (VEGF-A) receptor KDR to endothelial cells of the maternal and fetal microvasculatures. PlGF and its principal receptor Flt-1 were localized to the trophoblasts and fetal vasculature. VEGF-A was found in trophoblast cells and associated with endothelial cells. We detected expression of two Plgf splice variants and four Vegf-a variants. Quantitative real-time polymerase chain reaction analysis showed upregulation of mRNAs encoding pan Vegf-a and all Vegf-a splice forms at gestational days 30-35. Vegf-A showed a marked relative increase in expression during mid-pregnancy, consistent with the pro-angiogenic changes seen in the lamellar zone at days 30-35. Flt-1 was upregulated during late pregnancy. Plgf variants showed stable expression during the first two-thirds of pregnancy, followed by a marked increase toward term. These findings revealed specific spatiotemporal expression patterns of VEGF-A family members consistent with pivotal roles during normal placental development.
Assuntos
Placenta , Fator A de Crescimento do Endotélio Vascular , Gatos , Gravidez , Animais , Feminino , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Placenta/metabolismo , Fatores de Crescimento do Endotélio Vascular/análise , Fatores de Crescimento do Endotélio Vascular/genética , Fatores de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais , Fator de Crescimento Placentário/genética , Fator de Crescimento Placentário/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Expressão GênicaRESUMO
BACKGROUND: Diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. This study aimed to develop and evaluate an OCT-omics prediction model for assessing anti-vascular endothelial growth factor (VEGF) treatment response in patients with DME. METHODS: A retrospective analysis of 113 eyes from 82 patients with DME was conducted. Comprehensive feature engineering was applied to clinical and optical coherence tomography (OCT) data. Logistic regression, support vector machine (SVM), and backpropagation neural network (BPNN) classifiers were trained using a training set of 79 eyes, and evaluated on a test set of 34 eyes. Clinical implications of the OCT-omics prediction model were assessed by decision curve analysis. Performance metrics (sensitivity, specificity, F1 score, and AUC) were calculated. RESULTS: The logistic, SVM, and BPNN classifiers demonstrated robust discriminative abilities in both the training and test sets. In the training set, the logistic classifier achieved a sensitivity of 0.904, specificity of 0.741, F1 score of 0.887, and AUC of 0.910. The SVM classifier showed a sensitivity of 0.923, specificity of 0.667, F1 score of 0.881, and AUC of 0.897. The BPNN classifier exhibited a sensitivity of 0.962, specificity of 0.926, F1 score of 0.962, and AUC of 0.982. Similar discriminative capabilities were maintained in the test set. The OCT-omics scores were significantly higher in the non-persistent DME group than in the persistent DME group (p < 0.001). OCT-omics scores were also positively correlated with the rate of decline in central subfield thickness after treatment (Pearson's R = 0.44, p < 0.001). CONCLUSION: The developed OCT-omics model accurately assesses anti-VEGF treatment response in DME patients. The model's robust performance and clinical implications highlight its utility as a non-invasive tool for personalized treatment prediction and retinal pathology assessment.
Assuntos
Diabetes Mellitus , Retinopatia Diabética , Edema Macular , Humanos , Inibidores da Angiogênese/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Retinopatia Diabética/diagnóstico por imagem , Retinopatia Diabética/tratamento farmacológico , Injeções Intravítreas , Aprendizado de Máquina , Edema Macular/complicações , Edema Macular/diagnóstico por imagem , Edema Macular/tratamento farmacológico , Radiômica , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Fatores de Crescimento do Endotélio VascularRESUMO
Pedunculagin (PD) and tellimagrandin-I (TL), isolated from Myrciaria cauliflora seeds and Eucaliptus microcorys leaves, respectively, have attracted great attention owing to their relevant biological activities, such as antitumor, antioxidant, and hepatoprotective activities. This study investigated the angiogenic potential of PD and TL using a chick embryo chorioallantoic membrane (CAM) assay. Using the CAM assay, our results showed that both PD and TL promoted a significant increase in the number and caliber of blood vessels, the thickness of the CAM, and the presence of fibroblasts and inflammatory cells. Moreover, an increase of tumor necrosis factor-α and vascular endothelial growth factor was observed in the CAM treated with PD and TL, indicating the induction of angiogenic factors. Thus, the remarkable profile of PD and TL in inducing angiogenesis opens up new perspectives for their potential utilization in different therapeutic approaches involving neovascularization.
Assuntos
Fator de Necrose Tumoral alfa , Fator A de Crescimento do Endotélio Vascular , Animais , Embrião de Galinha , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Angiogênese , Neovascularização Fisiológica , Fatores de Crescimento do Endotélio Vascular , Membrana Corioalantoide/irrigação sanguínea , InflamaçãoRESUMO
BACKGROUND: Angiogenesis is crucial for tumor development, progression, and metastasizing. The most important regulator of angiogenesis is the vascular endothelial growth factor (VEGF) family, which is involved in multiple pathways in tumor microenvironment. The objective of this study was to investigate the prognostic value of the VEGF family in patients treated for metastatic breast cancer. The emphasis was on neuropilin-1 (NRP-1) and placental growth factor (PlGF). MATERIALS AND METHODS: An analysis of eight members of the VEGF family was performed using baseline plasma samples of 65 patients treated for metastatic HER2 negative breast cancer in a phase II first-line bevacizumab plus chemotherapy trial. The patients were divided into two groups, high or low, according to the median for each VEGF family member. Progression-free survival (PFS) and overall survival (OS) were determined for each VEGF family member. RESULTS: The patients with low plasma levels of NRP-1 and PlGF had a longer OS than those with high plasma levels [multivariable adjusted hazard ratios (HRs) 2.54 (95% confidence interval (CI) 1.11-5.82, p = 0.02) and 3.11 (95% CI 1.30-7.47, p = 0.01), respectively]. The patients with low levels of both NRP-1 and PlGF had a remarkably long OS with HR of 6.24, (95% CI 1.97-19.76, p = 0.002). In addition, high baseline NRP-1 level was associated with a significantly shorter PFS [multivariable adjusted HR 2.90 (95% CI 1.02-8.28, p = 0.04)] than that in the low-level group, and a high baseline vascular endothelial growth factor receptor-2 level was associated with a longer PFS [multivariable adjusted HR 0.43 (95% CI 0.19-0.98, p = 0.04)]. CONCLUSION: Especially NRP-1 and PlGF have prognostic potential in metastatic breast cancer patients treated with a bevacizumab-taxane combination. Patients with low plasma levels of NRP-1 or PlGF have longer OS than patients with high levels. Patients with both low NRP-1 and PlGF levels appear to have excellent long-term survival. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00979641, registration date 18/09/2009. The regional Ethics Committee: R08142M, registration date 18/11/2008.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Bevacizumab/uso terapêutico , Fator de Crescimento Placentário , Fator A de Crescimento do Endotélio Vascular , Neuropilina-1 , Prognóstico , Fatores de Crescimento do Endotélio Vascular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Microambiente TumoralRESUMO
CONTEXT: Echinacoside (ECH) is a natural anti-cancer compound and is of great value in cancer treatment. However, the mechanism underlying this effect on breast cancer (BC) was unclear. OBJECTIVE: To explore the mechanism of ECH treating BC by network pharmacology and experimental validation. MATERIALS & METHODS: Several databases were searched to screen potential targets of ECH and obtain information on targets related to BC. STRING was applied to construct a Protein-protein interaction (PPI) network. DAVID was applied for Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Gene Expression Profiling Interactive Analysis (GEPIA) was searched for the relationship between the expression profile and overall survival of major targets in normal breast and BC tissues. Finally, the results of network pharmacology analysis were validated by experiments. RESULTS: Seventeen targets of ECH overlapped with targets in BC. Ten hub targets were determined through PPI. By GO and KEGG analysis 15 entries and 25 pathways were obtained, in which phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) played greater roles. Validation of key targets in the GEPIA database showed that PIK3R1 and PIK3CD remained consistent with the results of the study. Experiments in vitro showed ECH inhibited proliferation, induced apoptosis and reduced mRNA levels and protein expression of PI3K, AKT, hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA) in MCF-7 cells. Furthermore, experiments in vivo revealed that ECH significantly reduced tumor growth, promoted apoptosis and decreased the related mRNA levels and protein expression, suggesting ECH works on BC by regulating PI3K/AKT/HIF-1α/VEGF signaling pathway. DISCUSSION & CONCLUSION: In summary, ECH played an important role in anti-BC by regulating PI3K/AKT/HIF-1α/VEGF signaling pathway. Furthermore, ECH had multi-target and multi-pathway effects, which may be a promising natural compound for treating BC.
Assuntos
Neoplasias da Mama , Proteínas Proto-Oncogênicas c-akt , Feminino , Humanos , Neoplasias da Mama/metabolismo , Proliferação de Células , Hipóxia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fatores de Crescimento do Endotélio VascularRESUMO
Diabetic retinopathy (DR) is caused by retinal vascular dysfunction and neurodegeneration. Intraocular delivery of C-peptide has been shown to be beneficial against hyperglycemia-induced microvascular leakage in the retina of diabetes; however, the effect of C-peptide on diabetes-induced retinal neurodegeneration remains unknown. Moreover, extraocular C-peptide replacement therapy against DR to avoid various adverse effects caused by intravitreal injections has not been studied. Here, we demonstrate that systemic C-peptide supplementation using osmotic pumps or biopolymer-conjugated C-peptide hydrogels ameliorates neurodegeneration by inhibiting vascular endothelial growth factor-induced pathological events, but not hyperglycemia-induced vascular endothelial growth factor expression, in the retinas of diabetic mice. C-peptide inhibited hyperglycemia-induced activation of macroglial and microglial cells, downregulation of glutamate aspartate transporter 1 expression, neuronal apoptosis, and histopathological changes by a mechanism involving reactive oxygen species generation in the retinas of diabetic mice, but transglutaminase 2, which is involved in retinal vascular leakage, is not associated with these pathological events. Overall, our findings suggest that systemic C-peptide supplementation alleviates hyperglycemia-induced retinal neurodegeneration by inhibiting a pathological mechanism, involving reactive oxygen species, but not transglutaminase 2, in diabetes.
Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Hiperglicemia , Animais , Camundongos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Peptídeo C/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Retina/metabolismo , Fatores de Crescimento do Endotélio Vascular , Retinopatia Diabética/metabolismo , Hiperglicemia/metabolismo , Suplementos NutricionaisRESUMO
In order to investigate the mechanism of gemcitabine combined with lobaplatin in the interventional treatment of locally advanced cervical cancer (LACC), 90 patients with LACC were divided into control group (oxaliplatin + gemcitabine) and experimental group (lobaplatin + gemcitabine) according to different perfusion drugs and embolization drugs, 45 cases in each group. They were treated with arterial chemotherapy and arterial embolization. Postoperative recurrence, metastasis, and survival, as well as changes in serum vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) levels before and after treatment were observed in both groups. The results showed that the recurrence rate of cervical cancer at 0.5, 1, 2, 3, 4, and 5 years after operation in the experimental group was significantly lower than that in the control group, P â <â 0.05; there was no significant difference in the postoperative cervical cancer metastasis rate, P â >â 0.05. Before treatment, the serum VEGF in the experimental group and the control group were (642.76â ±â 216.67) ng/L and (626.30â ±â 275.43) ng/L, respectively, and MMP-9 were (580.61â ±â 194.12) ng/L and (575.28â ±â 202.55) ng/L, respectively. After treatment, the serum VEGF levels in the experimental group and the control group were (429.24â ±â 132.69) ng/L and (554.63â ±â 178.11) ng/L, respectively, and MMP-9 levels were (357.60â ±â 123.11) ng/L and (461.83â ±â 144.45) ng/L, respectively. There was no significant difference in the serum VEGF and MMP-9 levels between the two groups before treatment ( P â >â 0.05); after treatment, the serum VEGF and MMP-9 levels in the experimental group were significantly lower than those in the control group, P â <â 0.05. Therefore, gemcitabine combined with lobaplatin interventional therapy can improve the cure rate of LACC by reducing VEGF and MMP-9 levels in the serum of patients.
Assuntos
Neoplasias do Colo do Útero , Fator A de Crescimento do Endotélio Vascular , Feminino , Humanos , Gencitabina , Metaloproteinase 9 da Matriz , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/cirurgia , Fatores de Crescimento do Endotélio VascularRESUMO
The goal of this study is to calibrate a multiscale model of tumor angiogenesis with time-resolved data to allow for systematic testing of mathematical predictions of vascular sprouting. The multi-scale model consists of an agent-based description of tumor and endothelial cell dynamics coupled to a continuum model of vascular endothelial growth factor concentration. First, we calibrate ordinary differential equation models to time-resolved protein concentration data to estimate the rates of secretion and consumption of vascular endothelial growth factor by endothelial and tumor cells, respectively. These parameters are then input into the multiscale tumor angiogenesis model, and the remaining model parameters are then calibrated to time resolved confocal microscopy images obtained within a 3D vascularized microfluidic platform. The microfluidic platform mimics a functional blood vessel with a surrounding collagen matrix seeded with inflammatory breast cancer cells, which induce tumor angiogenesis. Once the multi-scale model is fully parameterized, we forecast the spatiotemporal distribution of vascular sprouts at future time points and directly compare the predictions to experimentally measured data. We assess the ability of our model to globally recapitulate angiogenic vasculature density, resulting in an average relative calibration error of 17.7% ± 6.3% and an average prediction error of 20.2% ± 4% and 21.7% ± 3.6% using one and four calibrated parameters, respectively. We then assess the model's ability to predict local vessel morphology (individualized vessel structure as opposed to global vascular density), initialized with the first time point and calibrated with two intermediate time points. In this study, we have rigorously calibrated a mechanism-based, multiscale, mathematical model of angiogenic sprouting to multimodal experimental data to make specific, testable predictions.
Assuntos
Microfluídica , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neovascularização Fisiológica , Neovascularização Patológica/patologia , Fatores de Crescimento do Endotélio Vascular , Microscopia ConfocalRESUMO
INTRODUCTION: Angiogenesis is fundamental for tumor growth and metastasis across many solid malignancies. Considerable interest has focused on the molecular regulation of tumor angiogenesis as a means to predict disease outcomes and guide therapeutic decisions. METHODS: In the present study, we investigated the prognostic value of transforming growth factor beta (TGF-ß), epidermal growth factor (EGF), fibroblast growth factor (FGF), delta-like ligand 4 (DLL4), and vascular endothelial growth factor (VEGF) in the serum of 120 women diagnosed with breast cancer using ELISA as well as examined their associations with clinical parameters and the outcome of the disease. RESULTS: Our results demonstrated that the serum concentration of TGF-ß and EGF were remarkably higher in patients with higher tumor size, end stages of the disease, and positive lymph node involvement compared to patients with lower tumor size, early stages of the disease, and negative lymph node involvement. In addition, we found a significant correlation between the serum concentration of VEGF and the level of EGF, FGF, and DLL4 in patients with breast cancer. Furthermore, both univariate and multivariate analyses showed that TGF-ß and EGF can be used as end-stage predictors. DISCUSSION/CONCLUSION: Based on our findings, increasing the level of angiogenesis factors is significantly associated with higher tumor size and late stages of the disease in patients with breast cancer. Moreover, measuring the level of angiogenesis factors could lead to better prediction of disease outcomes and choosing the best treatments for patients.