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1.
Mol Aspects Med ; 94: 101225, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38000334

RESUMO

In the last years, neuroprotective therapies have attracted the researcher interests as modern and challenging approach for the treatment of neurodegenerative diseases, aimed at protecting the nervous system from injuries. Glaucoma is a neurodegenerative disease characterized by progressive excavation of the optic nerve head, retinal axonal injury and corresponding vision loss that affects millions of people on a global scale. The molecular basis of the pathology is largely uncharacterized yet, and the therapeutic approaches available do not change the natural course of the disease. Therefore, in accordance with the therapeutic regimens proposed for other neurodegenerative diseases, a modern strategy to treat glaucoma includes prescription of drugs with neuroprotective activities. With respect to this, several preclinical and clinical investigations on a plethora of different drugs are currently ongoing. In this review, first, the conceptualization of the rationale for the adoption of neuroprotective strategies for retina is summarized. Second, the molecular aspects highlighting glaucoma as a neurodegenerative disease are reported. In conclusion, the molecular and pharmacological properties of most promising direct neuroprotective drugs used to delay glaucoma progression are examined, including: neurotrophic factors, NMDA receptor antagonists, the α2-adrenergic agonist, brimonidine, calcium channel blockers, antioxidant agents, nicotinamide and statins.


Assuntos
Glaucoma , Doenças Neurodegenerativas , Doenças Retinianas , Humanos , Doenças Neurodegenerativas/patologia , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/fisiologia , Glaucoma/tratamento farmacológico , Glaucoma/patologia , Tartarato de Brimonidina/uso terapêutico , Retina
2.
Cancers (Basel) ; 13(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638337

RESUMO

Immunoproteasome is a noncanonical form of proteasome with enzymological properties optimized for the generation of antigenic peptides presented in complex with class I MHC molecules. This enzymatic property makes the modulation of its activity a promising area of research. Nevertheless, immunotherapy has emerged as a front-line treatment of advanced/metastatic tumors providing outstanding improvement of life expectancy, even though not all patients achieve a long-lasting clinical benefit. To enhance the efficacy of the currently available immunotherapies and enable the development of new strategies, a broader knowledge of the dynamics of antigen repertoire processing by cancer cells is needed. Therefore, a better understanding of the role of immunoproteasome in antigen processing and of the therapeutic implication of its modulation is mandatory. Studies on the potential crosstalk between proteasome modulators and immune checkpoint inhibitors could provide novel perspectives and an unexplored treatment option for a variety of cancers.

3.
Oncol Rep ; 43(6): 2083-2092, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32236632

RESUMO

The anti­vascular endothelial growth factor­A (VEGF­A) monoclonal antibody (mAb) bevacizumab is an FDA­approved monotherapy for the treatment of recurrent glioblastoma (GB), a highly angiogenic and infiltrative tumour. However, bevacizumab does not increase overall survival and blockade of VEGF­A/VEGF receptor (VEGFR)­2 signal transduction is associated with severe adverse effects due to inhibition of physiological angiogenesis. Conversely, VEGFR­1 does not play a relevant role in physiological angiogenesis in the adult. VEGFR­1 is activated by both VEGF­A and placenta growth factor (PlGF), a protein involved in tumour growth and progression. In previous studies, it was demonstrated that inhibition of VEGFR­1 using a specific mAb developed in our laboratories reduced angiogenesis and GB cell chemotaxis and increased the survival of tumour­bearing mice. Failure of treatments directed toward the VEGF­A/VEGFR­2 axis could in part be due to inefficient targeting of the tumour microenvironment. In the present study, VEGFR­1 expression was investigated in GB­associated microglia/macrophages (GAMs) by analysing surgical specimens collected from 42 patients with GB. Data obtained from The Cancer Genome Atlas (TCGA) database revealed that upregulation of the VEGFR­1 ligands VEGF­A and PlGF was associated with a significant reduction in overall survival for patients with GB, highlighting the potential relevance of this receptor in the aggressiveness of GB. Immunohistochemical analysis indicated that VEGFR­1 is expressed not only in GB tissue but also in GAMs. Furthermore, the percentage of VEGFR­1­positive GAMs was significantly higher in the tumour region compared with that noted in the surrounding parenchyma. Thus, VEGFR­1 represents a potential therapeutic target for the treatment of GB, being present not only in GB and endothelial cells, but also in GAMs that are involved in tumour progression.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Macrófagos/metabolismo , Microglia/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Linhagem Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Análise de Sobrevida , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
4.
Expert Opin Drug Metab Toxicol ; 16(3): 195-207, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32067518

RESUMO

Introduction: The worldwide incidence of central nervous system (CNS) primary tumors is increasing. Most of the chemotherapeutic agents used for treating these cancer types induce DNA damage, and their activity is affected by the functional status of repair systems involved in the detection or correction of DNA lesions. Unfortunately, treatment of malignant high-grade tumors is still an unmet medical need.Areas covered: We summarize the action mechanisms of the main DNA inhibitors used for the treatment of brain tumors. In addition, studies on new agents or drug combinations investigated for this indication are reviewed, focusing our attention on clinical trials that in the last 3 years have been completed, terminated or are still recruiting patients.Expert opinion: Much still needs to be done to render aggressive CNS tumors curable or at least to transform them from lethal to chronic diseases, as it is possible for other cancer types. Drugs with improved penetration in the CNS, toxicity profile, and activity against primary and recurrent tumors are eagerly needed. Targeted agents with innovative mechanisms of action and ability to harness the cells of the tumor microenvironment against cancer cells represent a promising approach for improving the clinical outcome of CNS tumors.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Inibidores da Topoisomerase/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/metabolismo , Antineoplásicos/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , DNA/antagonistas & inibidores , DNA/metabolismo , Dano ao DNA/fisiologia , Humanos , Inibidores da Topoisomerase/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
5.
Chemotherapy ; 64(2): 62-80, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31387102

RESUMO

BACKGROUND: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. SUMMARY: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Ensaios Clínicos como Assunto , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Microambiente Tumoral , Proteína do Gene 3 de Ativação de Linfócitos
6.
Nutrients ; 10(11)2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30441769

RESUMO

Ellagic acid (EA) is a naturally occurring polyphenolic compound endowed with strong antioxidant and anticancer properties that is present in high quantity in a variety of berries, pomegranates, and dried fruits. The antitumor activity of EA has been mostly attributed to direct antiproliferative and apoptotic effects. Moreover, EA can inhibit tumour cell migration, extra-cellular matrix invasion and angiogenesis, all processes that are crucial for tumour infiltrative behaviour and the metastatic process. In addition, EA may increase tumour sensitivity to chemotherapy and radiotherapy. The aim of this review is to summarize the in vitro and in vivo experimental evidence supporting the anticancer activity of pure EA, its metabolites, and EA-containing fruit juice or extracts in a variety of solid tumour models. The EA oral administration as supportive therapy to standard chemotherapy has been recently evaluated in small clinical studies with colorectal or prostate cancer patients. Novel formulations with improved solubility and bioavailability are expected to fully develop the therapeutic potential of EA derivatives in the near future.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ácido Elágico/farmacologia , Inibidores da Angiogênese/química , Animais , Antineoplásicos Fitogênicos/química , Ácido Elágico/química
7.
Br J Cancer ; 118(12): 1596-1608, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29795310

RESUMO

BACKGROUND: While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain. sVEGFR1-i13 is mainly viewed as an anti-angiogenic factor which counteracts VEGF-A/VEGFR signalling in endothelial cells. However, its role in tumour cells is poorly known. METHODS: mRNA and protein status were analysed by Real-Time qPCR, western blotting, ELISA assay, proximity ligation assay or immunohistochemistry in human tumour cell lines, murine tumourgrafts and non small cell lung carcinoma patients samples. RESULTS: We show that anti-angiogenic therapies specifically increase the levels of sVEGFR1-i13 in SQLC cell lines and chemically induced SQLC murine tumourgrafts. At the molecular level, we characterise a sVEGFR1-i13/ß1 integrin/VEGFR autocrine loop which determines whether SQLC cells proliferate or go into apoptosis, in response to anti-angiogenic therapies. Furthermore, we show that high levels of both sVEGFR1-i13 and ß1 integrin mRNAs and proteins are associated with advanced stages in SQLC patients and with a poor clinical outcome in patients with early stage SQLC. CONCLUSIONS: Overall, these results reveal an unexpected pro-tumoural function of sVEGFR1-i13 in SQLC tumour cells, which contributes to their progression and escape from anti-angiogenic therapies. These data might help to understand why some SQLC patients do not respond to anti-angiogenic therapies.


Assuntos
Inibidores da Angiogênese/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Integrina beta1/metabolismo , Neoplasias Pulmonares/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Comunicação Autócrina/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Progressão da Doença , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Isoformas de Proteínas , Receptor Cross-Talk/efeitos dos fármacos , Células Tumorais Cultivadas , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Oncotarget ; 8(40): 66833-66848, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28977999

RESUMO

Despite recent progress in advanced melanoma therapy, identification of signalling pathways involved in melanoma switch from proliferative to invasive states is still crucial to uncover new therapeutic targets for improving the outcome of metastatic disease. Neuropilin-1 (NRP-1), a co-receptor for vascular endothelial growth factor-A (VEGF-A) tyrosine kinase receptors (VEGFRs), has been suggested to play a relevant role in melanoma progression. NRP-1 can be activated by VEGF-A also in the absence of VEGFRs, triggering specific signal transduction pathways (e.g. p130Cas phosphorylation). Since melanoma cells co-expressing high levels of NRP-1 and platelet derived growth factor-C (PDGF-C) show a highly invasive behaviour and PDGF-C shares homology with VEGF-A, in this study we have investigated whether PDGF-C directly interacts with NRP-1 and promotes melanoma aggressiveness. Results demonstrate that PDGF-C specifically binds in vitro to NRP-1. In melanoma cells expressing NRP-1 but lacking PDGFRα, PDGF-C stimulates extra-cellular matrix (ECM) invasion and induces p130Cas phosphorylation. Blockade of PDGF-C function by neutralizing antibodies or reduction of its secretion by specific siRNA inhibit ECM invasion and vasculogenic mimicry. Moreover, PDGF-C silencing significantly down-modulates the expression of Snail, a transcription factor involved in tumour invasiveness that is highly expressed in NRP-1 positive melanoma cells. In conclusion, our results demonstrate for the first time a direct activation of NRP-1 by PDGF-C and strongly suggest that autocrine and/or paracrine stimulation of NRP-1 by PDGF-C might contribute to the acquisition of a metastatic phenotype by melanoma cells.

9.
Nutrients ; 8(11)2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27879653

RESUMO

Ellagic acid (EA) is a polyphenolic compound that can be found as a naturally occurring hydrolysis product of ellagitannins in pomegranates, berries, grapes, green tea and nuts. Previous studies have reported the antitumor properties of EA mainly using in vitro models. No data are available about EA influence on bladder cancer cell invasion of the extracellular matrix triggered by vascular endothelial growth factor-A (VEGF-A), an angiogenic factor associated with disease progression and recurrence, and tumor growth in vivo. In this study, we have investigated EA activity against four different human bladder cancer cell lines (i.e., T24, UM-UC-3, 5637 and HT-1376) by in vitro proliferation tests (measuring metabolic and foci forming activity), invasion and chemotactic assays in response to VEGF-A and in vivo preclinical models in nude mice. Results indicate that EA exerts anti-proliferative effects as a single agent and enhances the antitumor activity of mitomycin C, which is commonly used for the treatment of bladder cancer. EA also inhibits tumor invasion and chemotaxis, specifically induced by VEGF-A, and reduces VEGFR-2 expression. Moreover, EA down-regulates the expression of programmed cell death ligand 1 (PD-L1), an immune checkpoint involved in immune escape. EA in vitro activity was confirmed by the results of in vivo studies showing a significant reduction of the growth rate, infiltrative behavior and tumor-associated angiogenesis of human bladder cancer xenografts. In conclusion, these results suggest that EA may have a potential role as an adjunct therapy for bladder cancer.


Assuntos
Inibidores da Angiogênese/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácido Elágico/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Masculino , Camundongos Nus , Mitomicina/farmacologia , Invasividade Neoplásica , Neovascularização Patológica , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Oncotarget ; 7(45): 72868-72885, 2016 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-27655684

RESUMO

Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase transmembrane receptor that has also a soluble isoform containing most of the extracellular ligand binding domain (sVEGFR-1). VEGF-A binds to both VEGFR-2 and VEGFR-1, whereas placenta growth factor (PlGF) interacts exclusively with VEGFR-1. In this study we generated an anti-VEGFR-1 mAb (D16F7) by immunizing BALB/C mice with a peptide that we had previously reported to inhibit angiogenesis and endothelial cell migration induced by PlGF. D16F7 did not affect binding of VEGF-A or PlGF to VEGFR-1, thus allowing sVEGFR-1 to act as decoy receptor for these growth factors, but it hampered receptor homodimerization and activation. D16F7 inhibited both the chemotactic response of human endothelial, myelomonocytic and melanoma cells to VEGFR-1 ligands and vasculogenic mimicry by tumor cells. Moreover, D16F7 exerted in vivo antiangiogenic effects in a matrigel plug assay. Importantly, D16F7 inhibited tumor growth and was well tolerated by B6D2F1 mice injected with syngeneic B16F10 melanoma cells. The antitumor effect was associated with melanoma cell apoptosis, vascular abnormalities and decrease of both monocyte/macrophage infiltration and myeloid progenitor mobilization. For all the above, D16F7 may be exploited in the therapy of metastatic melanoma and other tumors or pathological conditions involving VEGFR-1 activation.


Assuntos
Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacologia , Antineoplásicos Imunológicos/metabolismo , Antineoplásicos Imunológicos/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Ligantes , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Melanoma Experimental , Proteínas de Membrana/farmacologia , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Fosforilação , Ligação Proteica , Multimerização Proteica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/química
11.
Front Oncol ; 5: 125, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26090340

RESUMO

Neuropilin-1 (NRP-1) is a transmembrane glycoprotein that acts as a co-receptor for various members of the vascular endothelial growth factor (VEGF) family. Its ability to bind or modulate the activity of a number of other extracellular ligands, such as class 3 semaphorins, TGF-ß, HGF, FGF, and PDGF, has suggested the involvement of NRP-1 in a variety of physiological and pathological processes. Actually, this co-receptor has been implicated in axon guidance, angiogenesis, and immune responses. NRP-1 is also expressed in a variety of cancers (prostate, lung, pancreatic, or colon carcinoma, melanoma, astrocytoma, glioblastoma, and neuroblastoma), suggesting a critical role in tumor progression. Moreover, a growing amount of evidence indicates that NRP-1 might display important functions independently of other VEGF receptors. In particular, in the absence of VEGFR-1/2, NRP-1 promotes melanoma invasiveness, through the activation of selected integrins, by stimulating VEGF-A and metalloproteinases secretion and modulating specific signal transduction pathways. This review is focused on the role of NRP-1 in melanoma aggressiveness and on the evidence supporting its use as target of therapies for metastatic melanoma.

12.
Int J Cancer ; 136(6): E545-58, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25284767

RESUMO

During melanoma progression, tumour cells show increased adhesiveness to the vascular wall, invade the extracellular matrix (ECM) and frequently form functional channels similar to vascular vessels (vasculogenic mimicry). These properties are mainly mediated by the interaction of integrins with ECM components. Since we had previously identified neuropilin 1 (NRP-1), a coreceptor of vascular endothelial growth factor A (VEGF-A), as an important determinant of melanoma aggressiveness, aims of this study were to identify the specific integrins involved in the highly invasive phenotype of NRP-1 expressing cells and to investigate their role as targets to counteract melanoma progression. Melanoma aggressiveness was evaluated in vitro as cell ability to migrate through an ECM layer and to form tubule-like structures using transfected cells. Integrins relevant to these processes were identified using specific blocking antibodies. The αvß5 integrin was found to be responsible for about 80% of the capability of NRP-1 expressing cells to adhere on vitronectin. In these cells αvß5 expression level was twice higher than in low-invasive control cells and contributed to the ability of melanoma cells to form tubule-like structures on matrigel. Cilengitide, a potent inhibitor of αν integrins activation, reduced ECM invasion, vasculogenic mimicry and secretion of VEGF-A and metalloproteinase 9 by melanoma cells. In conclusion, we demonstrated that ανß5 integrin is involved in the highly aggressive phenotype of melanoma cells expressing NRP-1. Moreover, we identified a novel mechanism that contributes to the antimelanoma activity of the αv integrin inhibitor cilengitide based on the inhibition of vasculogenic mimicry.


Assuntos
Melanoma/tratamento farmacológico , Neuropilina-1/fisiologia , Receptores de Vitronectina/antagonistas & inibidores , Venenos de Serpentes/farmacologia , Linhagem Celular Tumoral , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Melanoma/química , Melanoma/patologia , Invasividade Neoplásica , Neuropilina-1/análise , Receptores de Vitronectina/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análise
13.
Pigment Cell Melanoma Res ; 28(1): 73-81, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25256553

RESUMO

Differently from most transformed cells, cutaneous melanoma expresses the pleiotropic factor thrombospondin-1 (TSP-1). Herein, we show that TSP-1 (RNA and protein), undetectable in four cultures of melanocytes and a RGP melanoma, was variously present in 13 cell lines from advanced melanomas or metastases. Moreover, microarray analysis of 55 human lesions showed higher TSP-1 expression in primary melanomas and metastases than in common and dysplastic nevi. In a functional enrichment analysis, the expression of TSP-1 correlated with motility-related genes. Accordingly, TSP-1 production was associated with melanoma cell motility in vitro and lung colonization potential in vivo. VEGF/VEGFR-1 and FGF-2, involved in melanoma progression, regulated TSP-1 production. These factors were coexpressed with TSP-1 and correlated negatively with Slug (SNAI2), a cell migration master gene implicated in melanoma metastasis. We conclude that TSP-1 cooperates with FGF-2 and VEGF/VEGFR-1 in determining melanoma invasion and metastasis, as part of a Slug-independent motility program.


Assuntos
Movimento Celular , Fator 2 de Crescimento de Fibroblastos/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/patologia , Trombospondina 1/metabolismo , Fatores de Transcrição/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Linhagem Celular Tumoral , Redes Reguladoras de Genes , Humanos , Pulmão/patologia , Melanoma/metabolismo , Camundongos , Células NIH 3T3 , Metástase Neoplásica , Fenótipo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Fatores de Transcrição da Família Snail
14.
Elife ; 2: e00324, 2013 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-23795287

RESUMO

Optimal phototransduction requires separation of the avascular photoreceptor layer from the adjacent vascularized inner retina and choroid. Breakdown of peri-photoreceptor vascular demarcation leads to retinal angiomatous proliferation or choroidal neovascularization, two variants of vascular invasion of the photoreceptor layer in age-related macular degeneration (AMD), the leading cause of irreversible blindness in industrialized nations. Here we show that sFLT-1, an endogenous inhibitor of vascular endothelial growth factor A (VEGF-A), is synthesized by photoreceptors and retinal pigment epithelium (RPE), and is decreased in human AMD. Suppression of sFLT-1 by antibodies, adeno-associated virus-mediated RNA interference, or Cre/lox-mediated gene ablation either in the photoreceptor layer or RPE frees VEGF-A and abolishes photoreceptor avascularity. These findings help explain the vascular zoning of the retina, which is critical for vision, and advance two transgenic murine models of AMD with spontaneous vascular invasion early in life. DOI:http://dx.doi.org/10.7554/eLife.00324.001.


Assuntos
Neovascularização de Coroide/metabolismo , Degeneração Macular/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Neovascularização Retiniana/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Visão Ocular , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos/farmacologia , Estudos de Casos e Controles , Neovascularização de Coroide/genética , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Degeneração Macular/genética , Degeneração Macular/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Fotorreceptoras de Vertebrados/patologia , Interferência de RNA , Neovascularização Retiniana/genética , Neovascularização Retiniana/patologia , Epitélio Pigmentado da Retina/patologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
15.
Int J Oncol ; 43(1): 297-306, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23685409

RESUMO

The majority of human melanoma cell lines secretes vascular endothelial growth factor-A (VEGF-A) and expresses its receptors VEGFR-1, VEGFR-2 and neuropilin-1 (NRP­1), a co-receptor for VEGF-A that amplifies the signalling through VEGFR-2. Since it is known that the VEGF-A/VEGFR-2 autocrine loop promotes melanoma cell invasiveness, the aim of the present study was to investigate the involvement of NPR-1 in melanoma progression. Syngeneic human melanoma cell lines expressing either VEGFR-2 or NRP-1, both or none of them, were analyzed for their in vitro ability to migrate, invade the extracellular matrix (ECM) and secrete active metalloproteinase-2 (MMP-2). The results indicate that NRP-1 cooperates with VEGFR-2 in melanoma cell migration induced by VEGF-A. Moreover, NRP-1 expression is sufficient to promote MMP-2 secretion and melanoma cell invasiveness, as demonstrated by the ability of cells expressing solely NRP-1 to spontaneously invade the ECM. This ability is specifically downregulated by anti-NRP-1 antibodies or by interfering with NRP-1 expression using an shRNA construct. Investigation of the signal transduction pathways triggered by NRP-1 in melanoma cells, indicated that NRP-1-dependent promotion of cell invasiveness involves Akt activation through its phosphorylation on T308. Overall, the results demonstrate that NRP-1 is involved in melanoma progression through VEGFR-2-dependent and -independent mechanisms and suggest NRP-1 as a target for the treatment of the metastatic disease.


Assuntos
Melanoma/genética , Neuropilina-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Melanoma/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neuropilina-1/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
16.
Proc Natl Acad Sci U S A ; 109(6): 2015-20, 2012 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-22171010

RESUMO

Normal vision requires the precise control of vascular growth to maintain corneal transparency. Here we provide evidence for a unique mechanism by which the Forkhead box transcription factor FoxC1 regulates corneal vascular development. Murine Foxc1 is essential for development of the ocular anterior segment, and in humans, mutations have been identified in Axenfeld-Rieger syndrome, a disorder characterized by anterior segment dysgenesis. We show that FOXC1 mutations also lead to corneal angiogenesis, and that mice homozygous for either a global (Foxc1(-/-)) or neural crest (NC)-specific (NC-Foxc1(-/-)) null mutation display excessive growth of corneal blood and lymphatic vessels. This is associated with disorganization of the extracellular matrix and increased expression of multiple matrix metalloproteinases. Heterozygous mutants (Foxc1(+/-) and NC-Foxc1(+/-)) exhibit milder phenotypes, such as disrupted limbal vasculature. Moreover, environmental exposure to corneal injury significantly increases growth of both blood and lymphatic vessels in both Foxc1(+/-) and NC-Foxc1(+/-) mice compared with controls. Notably, this amplification of the angiogenic response is abolished by inhibition of VEGF receptor 2. Collectively, these findings identify a role for FoxC1 in inhibiting corneal angiogenesis, thereby maintaining corneal transparency by regulating VEGF signaling.


Assuntos
Vasos Sanguíneos/crescimento & desenvolvimento , Córnea/irrigação sanguínea , Fatores de Transcrição Forkhead/metabolismo , Álcalis , Animais , Segmento Anterior do Olho/anormalidades , Segmento Anterior do Olho/metabolismo , Segmento Anterior do Olho/patologia , Vasos Sanguíneos/patologia , Queimaduras/patologia , Córnea/patologia , Substância Própria/enzimologia , Substância Própria/patologia , Anormalidades do Olho/complicações , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Oftalmopatias Hereditárias , Haploinsuficiência/genética , Heterozigoto , Linfangiogênese , Metaloproteinases da Matriz/metabolismo , Camundongos , Mutação/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Crista Neural/metabolismo , Crista Neural/patologia , Fenótipo , Pupila , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Eur J Cancer ; 44(13): 1914-21, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18682321

RESUMO

Vascular endothelial growth factor receptor-1 (VEGFR-1) exists in two isoforms: a membrane-bound isoform (mVEGFR-1) and a soluble one (sVEGFR-1). mVEGFR-1 is involved in endothelial cell migration and survival supported by VEGF-A and placenta growth factor (PlGF), whereas the biologic function of sVEGFR-1 has not been fully elucidated. We previously reported that sVEGFR-1 induces endothelial cell motility and promotes endothelial cell adhesion. In this study, we tested a set of VEGFR-1-derived peptides for their ability to interfere with endothelial cell migration. Peptide B3 was found to specifically inhibit cell migration induced by sVEGFR-1 and by mVEGFR-1-specific ligands. Moreover, peptide B3 markedly hampered angiogenesis in vitro and in vivo and was found to interfere with VEGFR-1 homodimerisation. Altogether, these data demonstrate that peptide B3 might be a useful tool for the specific inhibition of VEGFR-1 function and might represent a basis for the development of new anti-angiogenic compounds.


Assuntos
Inibidores da Angiogênese/farmacologia , Movimento Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Veias Umbilicais/irrigação sanguínea , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/fisiologia , Humanos , Neovascularização Patológica/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Fator de Crescimento Placentário , Proteínas da Gravidez/metabolismo
18.
Eur J Cancer ; 44(9): 1302-14, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18440222

RESUMO

Poly(ADP-ribose) polymerase (PARP)-1, which plays a key role in DNA repair, inflammation and transcription, has recently been shown to be involved in angiogenesis. The aim of this study was to investigate PARP-1 role in melanoma aggressiveness and chemoresistance in vivo using clones stably silenced for PARP-1 expression. Whilst the growth characteristics of PARP-1-deficient melanoma cells were comparable to those of PARP-1-proficient cells in vitro, their tumourigenic potential in vivo was significantly compromised. In fact, mice challenged intra-muscle with PARP-1-deficient cells showed a delayed development of measurable tumour nodules, which were also significantly reduced in size with respect to those of mice inoculated with PARP-1-proficient cells. Moreover, animals challenged intra-cranially with PARP-1-deficient cells, a model that mimics CNS localisation of melanoma, showed an increased survival. Immunohistochemical analyses of PARP-1-depleted melanoma grafts indicated a reduced expression of the angiogenesis marker PECAM-1/CD31 and of the pro-inflammatory mediators TNF-alpha and GITR. Notably, PARP-1-silenced melanoma was extremely sensitive to temozolomide, an anticancer agent used for the treatment of metastatic melanoma. These results provide novel evidence for a direct role of PARP-1 in tumour aggressiveness and chemoresistance.


Assuntos
Melanoma/enzimologia , Poli(ADP-Ribose) Polimerases/deficiência , Animais , Proliferação de Células/efeitos dos fármacos , Células Clonais , Resistencia a Medicamentos Antineoplásicos , Citometria de Fluxo , Imuno-Histoquímica , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Camundongos Knockout , Microcirculação , Neovascularização Patológica/enzimologia , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/fisiologia , Interferência de RNA , Células Tumorais Cultivadas
19.
Cancer ; 98(4): 789-97, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12910524

RESUMO

BACKGROUND: Melanoma metastasizes by different mechanisms comprising direct invasion of the surrounding tissue and spreading via the lymphatic or vascular system. Despite their clinical relevance, the molecular mechanisms that guide the route of spreading and localization of the metastases in different tissues are not well known. Recent studies in different tumor types have shown that vascular endothelial growth factor-C (VEGF-C), which displays a high specificity for lymphatic endothelium, is involved in tumor-induced lymphangiogenesis and lymphatic metastatic spread. The authors studied the expression of VEGF-C in cultured human melanoma cells derived from cutaneous and lymph node metastases as well as in metastatic melanoma tissue specimens to assess a possible involvement of this growth factor in lymph node localization of melanoma metastases. METHODS: VEGF-C expression was evaluated in vitro on human melanoma cell lines established from cutaneous and lymph node metastasis specimens by reverse transcriptase-polymerase chain reaction, Northern blot analysis, and immunofluorescence analysis. Immunohistochemical analysis of 42 tissue specimens of melanoma metastases and 10 tissue specimens of primary skin melanomas was also performed. RESULTS: Preferential expression of VEGF-C was detected in lymph node-derived tumor cell lines at both the mRNA and protein levels. The association between VEGF-C production and lymph node localization of metastases was confirmed by the in vivo analysis. In addition, analysis of 10 patients, from whom specimens of both the primary skin melanoma and melanoma metastases were available, indicated a correlation between VEGF-C expression in the primary tumor and lymph node localization of metastases. CONCLUSIONS: The findings of the current study demonstrate that VEGF-C expression is correlated with localization of melanoma metastases in the lymph nodes and suggest that VEGF-C expression in primary skin melanoma may be predictive of lymph node metastatic dissemination.


Assuntos
Fatores de Crescimento Endotelial/metabolismo , Linfonodos/química , Melanoma/química , Melanoma/secundário , Neoplasias Cutâneas/patologia , Northern Blotting , Southern Blotting , Fatores de Crescimento Endotelial/genética , Humanos , Imuno-Histoquímica , Metástase Linfática , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/química , Neoplasias Cutâneas/química , Células Tumorais Cultivadas , Fator C de Crescimento do Endotélio Vascular
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