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1.
J Pharmacol Sci ; 140(1): 1-7, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-31178329

RESUMEN

This study investigated whether NGF prevents tumor growth by promoting neuronal regulation of tumor blood flow. HT1080 fibrosarcoma cells or HepG2 hepatitis cells were subcutaneously implanted into nude mice. On Day 21 after the implantation of tumor cells, human NGF (40 or 80 ng/h for 14 days) was administered using a micro-osmotic pump. Growth rates of both tumors were significantly inhibited by the treatment of NGF, and the survival rate was also extended. Significant suppression of HT1080 tumor growth lasted after withdrawing NGF. NGF markedly increased the density of α-smooth muscle actin (α-SMA)-immunoreactive (ir) cells without changing neovessel density in HT1080 tumor tissues. Double immunostaining demonstrated protein gene product (PGP) 9.5-ir nerves around α-SMA-ir cells were found in HT1080 tumor tissue treated with NGF. The blood flow in HepG2 tumors treated with saline was significantly higher than in the non-tumor control area, but the tumor blood flow was markedly reduced by NGF treatment. In in vitro studies, NGF significantly accelerated migration of aortic smooth muscle cells but not endothelial cells, whereas NGF had no cytotoxic action on both cells. NGF inhibits tumor growth via indirect action, probably through innervation and maturation of tumor neovasculature, which regulates blood flow into tumor tissues.


Asunto(s)
Antineoplásicos , Vasos Sanguíneos/inervación , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/patología , Neovascularización Patológica , Factor de Crecimiento Nervioso/farmacología , Actinas/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Fibrosarcoma/metabolismo , Células Hep G2 , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Miocitos del Músculo Liso/patología , Trasplante de Neoplasias , Flujo Sanguíneo Regional
2.
Phys Med Biol ; 64(11): 115022, 2019 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-30995615

RESUMEN

Most solid tumors are characterized by highly dense, isotropic vessel networks. Characterization of such features has shown promise for early cancer diagnosis. Ultrasound diffusion has been used to characterize the micro-architecture of complex media, such as bone and the lungs. In this work, we examine a non-invasive diffusion-based ultrasound technique to assess neo-vascularization. Because the diffusion constant reflects the density of scatterers in heterogeneous media, we hypothesize that by injecting microbubbles into the vasculature, ultrasound diffusivity can reflect vascular density (VD), thus differentiating the microvascular patterns between tumors and healthy tissue. The diffusion constant and its anisotropy are shown to be significantly different between fibrosarcoma tumors (n = 16) and control tissue (n = 18) in a rat animal model in vivo. The diffusion constant values for control and tumor were found to be 1.38 ± 0.51 mm2 µs-1 and 0.65 ± 0.27 mm2 µs-1, respectively. These results are corroborated with VD from acoustic angiography (AA) data, confirming increased vessel density in tumors compared to controls. The diffusion constant offers a promising way to quantitatively assess vascular networks when combined with contrast agents, which may allow early tumor detection and characterization.


Asunto(s)
Fibrosarcoma/diagnóstico por imagen , Fibrosarcoma/patología , Microburbujas , Animales , Modelos Animales de Enfermedad , Fibrosarcoma/irrigación sanguínea , Neovascularización Patológica , Ratas , Ultrasonografía
3.
Ultrasound Med Biol ; 45(2): 539-548, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30509785

RESUMEN

Dynamic contrast-enhanced ultrasound (DCE-US) has been proposed as a powerful tool for cancer diagnosis by estimation of perfusion and dispersion parameters reflecting angiogenic vascular changes. This work was aimed at identifying which vascular features are reflected by the estimated perfusion and dispersion parameters through comparison with acoustic angiography (AA). AA is a high-resolution technique that allows quantification of vascular morphology. Three-dimensional AA and 2-D DCE-US bolus acquisitions were used to monitor the growth of fibrosarcoma tumors in nine rats. AA-derived vascular properties were analyzed along with DCE-US perfusion and dispersion to investigate the differences between tumor and control and their evolution in time. AA-derived microvascular density and DCE-US perfusion exhibited good agreement, confirmed by their spatial distributions. No vascular feature was correlated with dispersion. Yet, dispersion provided better cancer classification than perfusion. We therefore hypothesize that dispersion characterizes vessels that are smaller than those visible with AA.


Asunto(s)
Medios de Contraste , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/diagnóstico por imagen , Aumento de la Imagen/métodos , Ultrasonografía/métodos , Acústica , Angiografía/métodos , Animales , Modelos Animales de Enfermedad , Imagen Tridimensional/métodos , Ratas , Ratas Endogámicas F344
4.
J Pathol ; 246(3): 311-322, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30027561

RESUMEN

Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Asunto(s)
Carcinoma Ductal Pancreático/irrigación sanguínea , Carcinoma Ductal Pancreático/metabolismo , Células Endoteliales/metabolismo , Neovascularización Patológica , Neuropilina-1/metabolismo , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Anciano , Animales , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular , Células Endoteliales/patología , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/metabolismo , Fibrosarcoma/patología , Humanos , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neuropilina-1/genética , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Unión Proteica , Factores de Riesgo , Transducción de Señal , Neoplasias Gástricas/irrigación sanguínea , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Sus scrofa , Carga Tumoral , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética
5.
Ultrasound Med Biol ; 43(10): 2488-2493, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28668636

RESUMEN

Ultrasound contrast-enhanced super-resolution imaging has recently attracted attention because of its extraordinary ability to image vascular features much smaller than the ultrasound diffraction limit. This method requires sensitive detection of separable microbubble events despite a noisy tissue background to indicate the microvasculature, and any approach that could improve the sensitivity of the ultrasound system to individual microbubbles would be highly beneficial. In this study, we evaluated the effect of varying microbubble size on super-resolution imaging sensitivity. Microbubble preparations were size sorted into different mean diameters and then were imaged at equal concentrations. Commercially manufactured Definity and Optison were also imaged for comparison. Both in vitro experiments in phantom vessels and in vivo experiments imaging rat tumors revealed that the sensitivity of contrast-enhanced super-resolution imaging can be improved by using microbubbles with a larger diameter.


Asunto(s)
Medios de Contraste , Fibrosarcoma/diagnóstico por imagen , Aumento de la Imagen/métodos , Microburbujas , Microvasos/diagnóstico por imagen , Ultrasonografía/métodos , Animales , Modelos Animales de Enfermedad , Femenino , Fibrosarcoma/irrigación sanguínea , Tamaño de la Partícula , Fantasmas de Imagen , Ratas , Ratas Endogámicas F344
6.
Genes Cells ; 21(6): 624-38, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27169545

RESUMEN

We previously demonstrated that IL-18 and CCL11 were highly expressed in an NFSA tumor cell line that showed limited angiogenesis and severe necrosis. However, IL-18 was not responsible for the immune cell accumulation and necrosis. Here, we attempted to clarify the relevance of CCL11 in angiogenesis and tumor formation. We established CCL11-overexpressing MS-K cell clones (MS-K-CCL11) to assess the role of CCL11 in immune cell accumulation and angiogenesis. The MS-K-CCL11 cells did not form tumors in mice. MS-K-CCL11-conditioned medium (CM) and recombinant CCL11 induced macrophage and eosinophil differentiation from bone marrow cells. The MS-K-CCL11-CM effectively recruited the differentiated eosinophils. Furthermore, the eosinophils damaged the MS-K, NFSA and endothelial cells in a dose-dependent manner. Administration of an antagonist of CCR3, a CCL11 receptor, to NFSA tumor-bearing mice restored the blood vessel formation and blocked the eosinophil infiltration into the NFSA tumors. Furthermore, other CCL11-overexpressing LM8 clones were established, and their tumor formation ability was reduced compared to the parental LM8 cells, accompanied by increased eosinophil infiltration, blockade of angiogenesis and necrosis. These results indicate that CCL11 was responsible for the limited angiogenesis and necrosis by inducing and attracting eosinophils in the tumors.


Asunto(s)
Quimiocina CCL11/inmunología , Fibrosarcoma/patología , Granulocitos/inmunología , Neovascularización Patológica , Animales , Línea Celular Tumoral , Células Endoteliales/metabolismo , Eosinófilos/metabolismo , Fibrosarcoma/irrigación sanguínea , Ratones , Naftalenos , Fenilalanina/análogos & derivados , Receptores CCR3/antagonistas & inhibidores
7.
Oncotarget ; 7(2): 2022-37, 2016 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-26655500

RESUMEN

Angiogenesis is a key process occurring under both physiological and pathological conditions and is a hallmark of cancer. We have recently demonstrated that the extracellular matrix (ECM) molecule MULTIMERIN2 exerts an angiostatic function through the binding to VEGF-A. In this study we identify the region of the molecule responsible for the binding and demonstrate that the interaction involves the carbohydrate chains. MULTIMERIN2 interacts with other VEGF-A isoforms and VEGF family members such as VEGF-B, -C, -D and PlGF-1 suggesting that the molecule may function as a reservoir for different cytokines. In response to VEGF-A165, we show that MULTIMERIN2 impairs the phosphorylation of VEGFR2 at both Y1175 and Y1214 residues, halts SAPK2/p38 activation and negatively affects endothelial cell motility. In addition, MULTIMERIN2 and its active deletion mutant decrease the availability of the VEGFR2 receptor at the EC plasma membrane. The ectopic expression of MULTIMERIN2 or its active deletion mutant led to a striking reduction of tumor-associated angiogenesis and tumor growth. In conclusion, these data pinpoint MULTIMERIN2 as a key angiostatic molecule and disclose the possibility to develop new prognostic tools and improve the management of cancer patients.


Asunto(s)
Antígenos de Superficie/metabolismo , Carbohidratos/química , Fibrosarcoma/prevención & control , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Glicoproteínas de Membrana/metabolismo , Neovascularización Patológica/prevención & control , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Apoptosis , Movimiento Celular , Proliferación Celular , Femenino , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/patología , Técnica del Anticuerpo Fluorescente , Glicosilación , Humanos , Técnicas para Inmunoenzimas , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resonancia por Plasmón de Superficie , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Int J Radiat Oncol Biol Phys ; 93(1): 166-72, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26279032

RESUMEN

PURPOSE: The purpose of this study was to reveal the biological mechanisms underlying stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). METHODS AND MATERIALS: FSaII fibrosarcomas grown subcutaneously in the hind limbs of C3H mice were irradiated with 10 to 30 Gy of X rays in a single fraction, and the clonogenic cell survival was determined with in vivo--in vitro excision assay immediately or 2 to 5 days after irradiation. The effects of radiation on the intratumor microenvironment were studied using immunohistochemical methods. RESULTS: After cells were irradiated with 15 or 20 Gy, cell survival in FSaII tumors declined for 2 to 3 days and began to recover thereafter in some but not all tumors. After irradiation with 30 Gy, cell survival declined continuously for 5 days. Cell survival in some tumors 5 days after 20 to 30 Gy irradiation was 2 to 3 logs less than that immediately after irradiation. Irradiation with 20 Gy markedly reduced blood perfusion, upregulated HIF-1α, and increased carbonic anhydrase-9 expression, indicating that irradiation increased tumor hypoxia. In addition, expression of VEGF also increased in the tumor tissue after 20 Gy irradiation, probably due to the increase in HIF-1α activity. CONCLUSIONS: Irradiation of FSaII tumors with 15 to 30 Gy in a single dose caused dose-dependent secondary cell death, most likely by causing vascular damage accompanied by deterioration of intratumor microenvironment. Such indirect tumor cell death may play a crucial role in the control of human tumors with SBRT and SRS.


Asunto(s)
Muerte Celular , Supervivencia Celular/efectos de la radiación , Fibrosarcoma/radioterapia , Radiocirugia/métodos , Microambiente Tumoral/efectos de la radiación , Animales , Anhidrasas Carbónicas/metabolismo , Hipoxia de la Célula , Supervivencia Celular/fisiología , Fraccionamiento de la Dosis de Radiación , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/metabolismo , Fibrosarcoma/patología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Ratones Endogámicos C3H , Factores de Tiempo , Microambiente Tumoral/fisiología
9.
Oncotarget ; 6(23): 19469-82, 2015 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-26254223

RESUMEN

Curcumin, a natural polyphenol compound from the perennial herb Curcuma longa, has been proved to be beneficial for tumor-bearing animals through inhibiting tumor neovasculature formation, but the underlying mechanisms are unclear. Here, we aim to test whether curcumin affects VEGF-VEGFR2 signaling pathway and attenuates defective hematopoiesis induced by VEGF in tumor model. We demonstrated that curcumin inhibited proliferation, migration of HUVEC under VEGF stimulation and caused HUVEC apoptosis, and blocked VEGFR2 activation and its downstream signaling pathways in vitro. Furthermore, in VEGF over-expressing tumor model, curcumin significantly inhibited the tumor growth accelerated by VEGF in a dose-dependent manner and improved anemia and extramedullary hematopoiesis in livers and spleens of tumor-bearing mice induced by tumor-derived VEGF. Immunohistochemical analysis showed that curcumin normalized vasculature structures of livers and reduced tumor microvessel density. ELISA revealed that curcumin suppressed VEGF secretion from tumor cells both in vitro and in vivo. Survival analysis showed that curcumin significantly improved survival ability of VEGF tumor-bearing mice. Taken together, these findings establish curcumin as a modulator of VEGF and VEGF-VEGFR2 signaling pathway, with potential implication for improving the quality of life of cancer patients.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos Fitogénicos/farmacología , Curcumina/farmacología , Fibrosarcoma/tratamiento farmacológico , Hematopoyesis/efectos de los fármacos , Neovascularización Patológica , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/genética , Fibrosarcoma/metabolismo , Fibrosarcoma/patología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Porcinos , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
10.
J Ultrasound Med ; 34(7): 1227-36, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26112625

RESUMEN

OBJECTIVES: To enhance the regional antitumor activity of the vascular-targeting agent truncated tissue factor (tTF)-NGR by combining the therapy with low-energy ultrasound (US) treatment. METHODS: For the in vitro US exposure of human umbilical vein endothelial cells (HUVECs), cells were put in the focus of a US transducer. For analysis of the US-induced phosphatidylserine (PS) surface concentration on HUVECs, flow cytometry was used. To demonstrate the differences in the procoagulatory efficacy of TF-derivative tTF-NGR on binding to HUVECs with a low versus high surface concentration of PS, we performed factor X activation assays. For low-energy US pretreatment, HT1080 fibrosarcoma xenotransplant-bearing nude mice were treated by tumor-regional US-mediated stimulation (ie, destruction) of microbubbles. The therapy cohorts received the tumor vessel-infarcting tTF-NGR protein with or without US pretreatment (5 minutes after US stimulation via intraperitoneal injection on 3 consecutive days). RESULTS: Combination therapy experiments with xenotransplant-bearing nude mice significantly increased the antitumor activity of tTF-NGR by regional low-energy US destruction of vascular microbubbles in tumor vessels shortly before application of tTF-NGR (P < .05). Mechanistic studies proved the upregulation of anionic PS on the outer leaflet of the lipid bilayer of endothelial cell membranes by low-energy US and a consecutive higher potential of these preapoptotic endothelial cells to activate coagulation via tTF-NGR and coagulation factor X as being a basis for this synergistic activity. CONCLUSIONS: Combining retargeted tTF to tumor vessels with proapoptotic stimuli for the tumor vascular endothelium increases the antitumor effects of tumor vascular infarction. Ultrasound treatment may thus be useful in this respect for regional tumor therapy.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Fibrosarcoma/terapia , Infarto/etiología , Tromboplastina/farmacología , Terapia por Ultrasonido , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Endotelio Vascular , Femenino , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/tratamiento farmacológico , Citometría de Flujo , Humanos , Ratones , Ratones Desnudos , Microburbujas , Neovascularización Patológica/prevención & control
12.
Oncotarget ; 6(22): 19027-42, 2015 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-25848918

RESUMEN

Cathepsin B is a ubiquitously expressed lysosomal cysteine protease that participates in protein turnover within lysosomes. However, its protein and activity levels have been shown to be increased in cancer. Cathepsin B endopeptidase activity is involved in the degradation of extracellular matrix, a process that promotes tumor invasion, metastasis and angiogenesis. Previously, we reported an established antibiotic nitroxoline as a potent and selective inhibitor of cathepsin B. In the present study, we elucidated its anti-tumor properties in in vitro and in vivo tumor models. Tumor and endothelial cell lines with high levels of active cathepsin B were selected for functional analysis of nitroxoline in vitro. Nitroxoline significantly reduced extracellular DQ-collagen IV degradation by all evaluated cancer cell lines using spectrofluorimetry. Nitroxoline also markedly decreased tumor cell invasion monitored in real time and reduced the invasive growth of multicellular tumor spheroids, used as a 3D in vitro model of tumor invasion. Additionally, endothelial tube formation was significantly reduced by nitroxoline in an in vitro angiogenesis assay. Finally, nitroxoline significantly abrogated tumor growth, angiogenesis and metastasis in vivo in LPB fibrosarcoma and MMTV-PyMT breast cancer mouse models. Overall, our results designate nitroxoline as a promising drug candidate for anti-cancer treatment.


Asunto(s)
Inductores de la Angiogénesis/farmacología , Catepsina B/antagonistas & inhibidores , Nitroquinolinas/farmacología , Animales , Estudios de Casos y Controles , Catepsina B/metabolismo , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Progresión de la Enfermedad , Células Endoteliales/efectos de los fármacos , Femenino , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/enzimología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Metástasis de la Neoplasia , Distribución Aleatoria , Sarcoma Experimental/irrigación sanguínea , Sarcoma Experimental/tratamiento farmacológico , Sarcoma Experimental/enzimología , Esferoides Celulares
13.
Oncotarget ; 5(22): 11428-41, 2014 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-25426549

RESUMEN

Myxofibrosarcomas are genetically complex and involve recurrently deleted chromosome 9p, for which we characterized the pathogenically relevant target(s) using genomic profiling. In 12 of the 15 samples, we detected complete or partial losses of 9p. The only aggressiveness-associated, differentially lost region was 9p21.3, spanning the potential inactivated methylthioadenosine phosphorylase (MTAP) that exhibited homozygous (4/15) or hemizygous (3/15) deletions. In independent samples, MTAP gene status was assessed using quantitative- and methylation-specific PCR assays, and immunoexpression was evaluated. We applied MTAP reexpression or knockdown to elucidate the functional roles of MTAP and the therapeutic potential of L-alanosine in MTAP-preserved and MTAP-deficient myxofibrosarcoma cell lines and xenografts. MTAP protein deficiency (37%) was associated with MTAP gene inactivation (P < 0.001) by homozygous deletion or promoter methylation, and independently portended unfavorable metastasis-free survival (P = 0.0318) and disease-specific survival (P = 0.014). Among the MTAP-deficient cases, the homozygous deletion of MTAP predicted adverse outcome. In MTAP-deficient cells, MTAP reexpression inhibited cell migration and invasion, proliferation, and anchorage-independent colony formation and downregulated cyclin D1. This approach also attenuated the tube-forming abilities of human umbilical venous endothelial cells, attributable to the transcriptional repression of MMP-9, and abrogated the susceptibility to L-alanosine. The inhibiting effects of MTAP expression on tumor growth, angiogenesis, and the induction of apoptosis by L-alanosine were validated using MTAP-reexpressing xenografts and reverted using RNA interference in MTAP-preserved cells. In conclusion, homozygous deletion primarily accounts for the adverse prognostic impact of MTAP deficiency and confers the biological aggressiveness and susceptibility to L-alanosine in myxofibrosarcomas.


Asunto(s)
Fibrosarcoma/metabolismo , Purina-Nucleósido Fosforilasa/metabolismo , Alanina/análogos & derivados , Alanina/farmacología , Animales , Apoptosis/efectos de los fármacos , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Ciclina D1/metabolismo , Regulación hacia Abajo , Femenino , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/patología , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Terapia Molecular Dirigida , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Análisis de Supervivencia
14.
Amino Acids ; 46(10): 2355-64, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24990522

RESUMEN

Peptides containing asparagine-glycine-arginine (NGR) and arginine-glycine-aspartic acid (RGD) sequence are being developed for tumor angiogenesis-targeted imaging and therapy. The aim of this study was to compare the efficacy of NGR- and RGD-based probes for imaging tumor angiogenesis in HT-1080 tumor xenografts. Two PET probes, (68)Ga-NOTA-G3-NGR2 and 68Ga-NOTA-G3-RGD2, were successfully prepared. In vitro stability, partition coefficient, tumor cell binding, as well as in vivo biodistribution properties were also analyzed for both PET probes. The results revealed that the two probes were both hydrophilic and stable in vitro and in vivo, and they were excreted predominately and rapidly through the kidneys. For both probes, the higher tumor uptake and lower accumulation in vital organs were determined. No significant difference between two probes was observed in terms of tumor uptake and the in vivo biodistribution properties. We concluded that these two probes are promising in tumor angiogenesis imaging. 68Ga-NOTA-G3-NGR2 has the potential as an alternative for PET imaging in patients with fibrosarcoma, and it may offer an opportunity to noninvasively monitor CD13-targeted therapy.


Asunto(s)
Fibrosarcoma/irrigación sanguínea , Imagen Molecular , Neovascularización Patológica/diagnóstico por imagen , Oligopéptidos , Radiofármacos , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/diagnóstico por imagen , Animales , Transporte Biológico , Línea Celular Tumoral , Estabilidad de Medicamentos , Femenino , Fibrosarcoma/diagnóstico por imagen , Radioisótopos de Galio , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones Desnudos , Oligopéptidos/química , Oligopéptidos/farmacocinética , Tomografía de Emisión de Positrones , Radiofármacos/química , Radiofármacos/farmacocinética , Eliminación Renal , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Dev Cell ; 28(6): 633-46, 2014 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-24656741

RESUMEN

Neuropilin 1 (NRP1) modulates angiogenesis by binding vascular endothelial growth factor (VEGF) and its receptor, VEGFR2. We examined the consequences when VEGFR2 and NRP1 were expressed on the same cell (cis) or on different cells (trans). In cis, VEGF induced rapid VEGFR2/NRP1 complex formation and internalization. In trans, complex formation was delayed and phosphorylation of phospholipase Cγ (PLCγ) and extracellular regulated kinase 2 (ERK2) was prolonged, whereas ERK1 phosphorylation was reduced. Trans complex formation suppressed initiation and vascularization of NRP1-expressing mouse fibrosarcoma and melanoma. Suppression in trans required high-affinity, steady-state binding of VEGF to NRP1, which was dependent on the NRP1 C-terminal domain. Compatible with a trans effect of NRP1, quiescent vasculature in the developing retina showed continuous high NRP1 expression, whereas angiogenic sprouting occurred where NRP1 levels fluctuated between adjacent endothelial cells. Therefore, through communication in trans, NRP1 can modulate VEGFR2 signaling and suppress angiogenesis.


Asunto(s)
Endocitosis/fisiología , Endotelio Vascular/patología , Fibrosarcoma/irrigación sanguínea , Melanoma Experimental/irrigación sanguínea , Neovascularización Patológica/prevención & control , Neuropilina-1/fisiología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Comunicación Celular , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Endotelio Vascular/metabolismo , Fibrosarcoma/metabolismo , Fibrosarcoma/prevención & control , Técnica del Anticuerpo Fluorescente , Humanos , Melanoma Experimental/metabolismo , Melanoma Experimental/prevención & control , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Fosfolipasa C gamma/metabolismo , Fosforilación , Estereoisomerismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
18.
Mol Cancer Ther ; 13(4): 986-95, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24552776

RESUMEN

The heterogeneous delivery of drugs in tumors is an established process contributing to variability in treatment outcome. Despite the general acceptance of variable delivery, the study of the underlying causes is challenging, given the complex tumor microenvironment including intra- and intertumor heterogeneity. The difficulty in studying this distribution is even more significant for small-molecule drugs where radiolabeled compounds or mass spectrometry detection lack the spatial and temporal resolution required to quantify the kinetics of drug distribution in vivo. In this work, we take advantage of the synthesis of fluorescent drug conjugates that retain their target binding but are designed with different physiochemical and thus pharmacokinetic properties. Using these probes, we followed the drug distribution in cell culture and tumor xenografts with temporal resolution of seconds and subcellular spatial resolution. These measurements, including in vivo permeability of small-molecule drugs, can be used directly in predictive pharmacokinetic models for the design of therapeutics and companion imaging agents as demonstrated by a finite element model.


Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Ftalazinas/química , Ftalazinas/farmacocinética , Piperazinas/química , Piperazinas/farmacocinética , Análisis de la Célula Individual/métodos , Animales , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/patología , Análisis de Elementos Finitos , Humanos , Ratones , Ratones Desnudos , Neoplasias Experimentales , Ftalazinas/farmacología , Piperazinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Fracciones Subcelulares/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Int J Cancer ; 134(2): 467-77, 2014 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23818211

RESUMEN

Preclinical studies with recombinant murine interleukin 4 (IL4) in models of cancer have shown potent tumor growth inhibition. However, systemic administration of human IL4 to cancer patients exhibited modest antitumor activity and considerable toxicities. To improve the therapeutic index and reduce side effects of this cytokine, we developed of a novel "immunocytokine" based on sequential fusion of murine IL4 with the antibody fragment F8 (specific to the alternatively spliced extra-domain A of fibronectin, a marker for tumor-angiogenesis) in diabody format. The resulting fusion protein, termed F8-IL4, retained full antigen-binding activity and cytokine bioactivity and was able to selectively localize on solid tumors in vivo. When used as single agent, F8-IL4 inhibited tumor growth in three different immunocompetent murine cancer models (F9 teratocarcinoma, CT26 colon carcinoma and A20 lymphoma). Furthermore, F8-IL4 showed synergistic effects when coadministered with immunocytokines based on IL2 and IL12. Indeed, combination therapy with an IL12-based immunocytokine yielded complete tumor eradication, in spite of the fact that IL4 and IL12 display opposite immunological mechanisms of action in terms of their polarization of T-cell based responses. No weight loss or any signs of toxicity were observed in treated mice, both in monotherapy and in combination, indicating a good tolerability of the immunocytokine treatment. Interestingly, mice cured from CT26 tumors acquired a durable protective antitumor immunity. Depletion experiments indicated that the antitumor activity was mediated by CD8+ T cells and by NK cells.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Neoplasias del Colon/prevención & control , Modelos Animales de Enfermedad , Fibrosarcoma/prevención & control , Interleucina-12/inmunología , Interleucina-4/inmunología , Linfoma/prevención & control , Neovascularización Patológica/prevención & control , Teratocarcinoma/prevención & control , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Neoplasias del Colon/irrigación sanguínea , Neoplasias del Colon/inmunología , Femenino , Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/inmunología , Técnica del Anticuerpo Fluorescente , Humanos , Inmunoconjugados , Interleucina-12/administración & dosificación , Interleucina-4/administración & dosificación , Linfoma/inmunología , Linfoma/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Anticuerpos de Cadena Única/administración & dosificación , Teratocarcinoma/irrigación sanguínea , Teratocarcinoma/inmunología , Neoplasias Testiculares/irrigación sanguínea , Neoplasias Testiculares/inmunología , Neoplasias Testiculares/prevención & control , Distribución Tisular
20.
Conf Proc IEEE Eng Med Biol Soc ; 2014: 4283-5, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25570939

RESUMEN

Recently, it has been demonstrated that through the use of contrast agents and multi-frequency transducer technology, high resolution and high signal to noise ultrasound images can be obtained which illustrate microvascular structure in unprecedented detail for an ultrasound modality. The enabling technology is ultrasound transducers which are fabricated with elements which can excite microbubble contrast agents near resonance and detect their broadband harmonics at a much higher bandwidth (several times the fundamental frequency). The resulting images contain very little background from tissue scattering and thus provide high contrast, and can have a resolution on the order of 130 microns with an appropriate high frequency receiving element. Because microbubbles are strictly an intravascular agent, this approach enables visualization of microvascular morphology with unique clarity, providing insight into angiogenesis associated with tumor development.


Asunto(s)
Fibrosarcoma/diagnóstico por imagen , Microvasos/diagnóstico por imagen , Neovascularización Patológica/diagnóstico por imagen , Angiografía/métodos , Animales , Medios de Contraste , Fibrosarcoma/irrigación sanguínea , Humanos , Ratones , Microburbujas , Ratas , Relación Señal-Ruido , Transductores , Ultrasonografía
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