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1.
Eur J Endocrinol ; 182(3): 293-302, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31917679

RESUMEN

Objective: Excess of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), as in acromegaly, is associated with increased risk of diabetes, but whether retinal vessels are altered is unknown. The aim of this study was to evaluate retinal vessel morphology in patients with acromegaly at diagnosis and after treatment and to describe the prevalence of diabetic retinopathy in patients with long-standing acromegaly and diabetes. Design: Two independent observational studies, one being prospective and the other retrospective and cross-sectional. Methods: Retinal vessel morphology of 26 patients with acromegaly was examined at diagnosis and 1 year after treatment and compared to 13 healthy controls. Cross-sectional evaluation of 39 patients with long-standing acromegaly and diabetes was performed. Fundus photographs were digitally analyzed for vessel morphology. Results: Patients with acromegaly had a median (interquartile range) of 34.3 (30.0-39.0) vessel branching points compared to 27.0 (24.0-29.0) for healthy controls (P < 0.001). Tortuosity of arterioles and venules remained unchanged. Vessel morphology did not change significantly after treatment. Patients with acromegaly and diabetes for a median of 14 years also had a high number of branching points (34.2 (32.5-35.6)), but the prevalence of diabetic retinopathy was not higher than expected in diabetic patients without acromegaly. Conclusions: Patients with acromegaly have an increased number of vascular branching points in the retina without an alteration of macroscopic vessel morphology. This is consistent with an angiogenic effect of GH/IGF-1 in humans. The prevalence of diabetic retinopathy was not increased in patients with acromegaly and diabetes.


Asunto(s)
Acromegalia/patología , Vasos Retinianos/patología , Acromegalia/complicaciones , Acromegalia/terapia , Adolescente , Adulto , Anciano , Arteriolas/patología , Estudios de Casos y Controles , Estudios Transversales , Complicaciones de la Diabetes/patología , Retinopatía Diabética/epidemiología , Retinopatía Diabética/etiología , Retinopatía Diabética/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/etiología , Neovascularización Patológica/patología , Prevalencia , Estudios Retrospectivos , Vénulas/patología , Adulto Joven
2.
Life Sci ; 244: 117342, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31978450

RESUMEN

AIMS: Microvascular endothelial cell dysfunction is a leading cause of radiation-induced heart disease (RIHD). BRCA1 plays an important role in DNA damage repair. The study aims to explore the effect of BRCA1 in endothelial cells involved in RIHD. MATERIALS AND METHODS: BRCA1 and p21 expression were detected in human umbilical vein endothelial cells (HUVECs) and in mouse heart tissue after irradiation exposure. The effects of BRCA1 on cell proliferation, cell cycle and radiosensitivity were determined in HUVECs with overexpression and knockdown of BRCA1. A mouse model of RIHD was established. Heart damage was detected in C57BL/6J mice and endothelial cell specific knockout BRCA1 mice (EC-BRCA1-/-). KEY FINDINGS: BRCA1 and p21 expression was significantly increased both in vitro and vivo response to irradiation. BRCA1 overexpression in endothelial cells enhanced cell growth and G1/S phase arrest, and the opposite results were observed in BRCA1 knockdown endothelial cells. BRCA1 downregulated endothelial cell cycle-related genes cyclin A, cyclin D1, cyclin E and p-Rb through increasing p21 expression, and HUVECs with BRCA1 gene knockdown were more sensitive to radiation. In vivo, a decrease in cardiac microvascular density, as well as cardiomyocyte hypoxia and apoptosis were observed in a time-dependent manner. EC-BRCA1-/- mice were more prone to severe RIHD than EC-BRCA1+/- mice after 16Gy radiation exposure due to endothelial dysfunction caused by loss of BRCA1, and p21 was declined in EC-BRCA1-/- mice heart. SIGNIFICANCE: These findings indicate that BRCA1 plays a protective role in RIHD by regulating endothelial cell cycle arrest mediated by p21 signal.


Asunto(s)
Proteína BRCA1/metabolismo , Puntos de Control del Ciclo Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Células Endoteliales de la Vena Umbilical Humana/citología , Neovascularización Patológica/prevención & control , Sustancias Protectoras/administración & dosificación , Tolerancia a Radiación , Animales , Proteína BRCA1/genética , Proteína BRCA1/fisiología , Proliferación Celular , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de la radiación , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Patológica/etiología , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Radiación Ionizante
3.
J Cancer Res Clin Oncol ; 146(1): 245-259, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31617074

RESUMEN

PURPOSE: In the present study, we have systematically examined the clinical significance of Nectin-4 (encoded by the PVRL-4 gene), a marker for breast cancer stem cells (CSCs), in cancer metastasis and angiogenesis using a variety of human specimens, including invasive duct carcinoma (IDC) with multiple grades, several types of primary tumors to local and distant relapses, lymph node metastases and circulating tumor cells (CTCs). METHODS: Nectin-4 was overexpressed in more than 92% of samples with 65.2% Nectin-4-positive cells. The level of expression was increased with increasing tumor grade (GI-III) and size (T1-4) of IDC specimens. RESULTS: More induction of Nectin-4 was noted in relapsed samples from a variety of tumors (colon, tongue, liver, kidney, ovary, buccal mucosa) in comparison to primary tumors, while paired adjacent normal tissues do not express any Nectin-4. A high expression of Nectin-4 along with other representative markers in CTCs and lymph node metastasis was also observed in cancer specimens. An increased level of Nectin-4 along with representative metastatic (CD-44, Sca1, ALDH1, Nanog) and angiogenic (Ang-I, Ang-II, VEGF) markers were noted in metastatic tumors (local and distant) in comparison to primary tumors that were correlated with different grades of tumor progression. In addition, greater expression of Nectin-4 was observed in secondary tumors (distant metastasis, e.g., breast to liver or stomach to gall bladder) in comparison to primary tumors. CONCLUSION: Our study demonstrated a significant correlation between Nectin-4 expression and tumor grade as well as stages (p < 0.001), suggesting its association with tumor progression. Nectin-4 was overexpressed at all stages of metastasis and angiogenesis, thus appearing to play a major role in tumor relapse through the PI3K-Akt-NFκß pathway.


Asunto(s)
Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/irrigación sanguínea , Carcinoma Ductal de Mama/genética , Moléculas de Adhesión Celular/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/metabolismo , Femenino , Humanos , Persona de Mediana Edad , FN-kappa B/metabolismo , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal
4.
Gene ; 726: 144132, 2020 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-31669643

RESUMEN

The NF-κB signaling pathway is a key regulator of CRC cell proliferation, apoptosis, angiogenesis, inflammation, metastasis, and drug resistance. Over-activation of the NF-κB pathway is a feature of colorectal cancer (CRC). While new combinatorial treatments have improved overall patient outcome; quality of life, cost of care, and patient survival rate have seen little improvement. Suppression of the NF-κB signaling pathway using biological or specific pharmacological inhibitors is a potential therapeutic approach in the treatment of colon cancer. This review summarizes the regulatory role of NF-κB signaling pathway in the pathogenesis of CRC for a better understanding and hence a better management of the disease.


Asunto(s)
Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , FN-kappa B/metabolismo , Transducción de Señal/fisiología , Animales , Apoptosis/fisiología , Proliferación Celular/fisiología , Humanos , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Calidad de Vida , Tasa de Supervivencia
5.
Int J Cancer ; 146(2): 553-565, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31173338

RESUMEN

Tumors are complex networks of constantly interacting elements: tumor cells, stromal cells, immune and stem cells, blood/lympathic vessels, nerve fibers and extracellular matrix components. These elements can influence their microenvironment through mechanical and physical signals to promote tumor cell growth. To get a better understanding of tumor biology, cooperation between multidisciplinary fields is needed. Diverse mathematic computations and algorithms have been designed to find prognostic targets and enhance diagnostic assessment. In this work, we use computational digital tools to study the topology of vitronectin, a glycoprotein of the extracellular matrix. Vitronectin is linked to angiogenesis and migration, two processes closely related to tumor cell spread. Here, we investigate whether the distribution of this molecule in the tumor stroma may confer mechanical properties affecting neuroblastoma aggressiveness. Combining image analysis and graph theory, we analyze different topological features that capture the organizational cues of vitronectin in histopathological images taken from human samples. We find that the Euler number and the branching of territorial vitronectin, two topological features, could allow for a more precise pretreatment risk stratification to guide treatment strategies in neuroblastoma patients. A large amount of recently synthesized VN would create migration tracks, pinpointed by both topological features, for malignant neuroblasts, so that dramatic change in the extracellular matrix would increase tumor aggressiveness and worsen patient outcomes.


Asunto(s)
Neuroblastoma/etiología , Neuroblastoma/genética , Vitronectina/genética , Algoritmos , Proliferación Celular/genética , Matriz Extracelular/genética , Matriz Extracelular/patología , Humanos , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Neuroblastoma/patología , Pronóstico , Riesgo , Células del Estroma/patología , Microambiente Tumoral/genética
6.
Cell Physiol Biochem ; 53(S1): 63-78, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31860207

RESUMEN

Mitochondria play a central role in cancer development, by contributing to most of the classical hallmarks of cancer, including sustained proliferation, metabolic re-programming, apoptosis resistance, invasion and induction of angiogenesis [1]. In addition, mitochondria affect also the function of anti- and pro-tumoral immune cells in the tumor microenvironment. Mitochondria harbor a plethora of regulated ion channels whose function is related to ion/ metabolite transport and to fine-tuning of mitochondrial membrane potential as well as of reactive oxygen species release. As a consequence, growing evidence link ion channels located both in the outer and inner mitochondrial membranes to several cancer hallmarks. The present review summarizes our recent knowledge about the participation and role of mitochondrial channels leading to acquisition of cancer hallmarks and thus to cancer progression.


Asunto(s)
Canales Iónicos/metabolismo , Mitocondrias/patología , Neoplasias/patología , Animales , Apoptosis , Proliferación Celular , Progresión de la Enfermedad , Humanos , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Membranas Mitocondriales/patología , Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología
7.
Expert Opin Ther Pat ; 29(12): 987-1009, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31722579

RESUMEN

Introduction: The ubiquitously expressed 37 kDa/67 kDa high-affinity laminin receptor (laminin receptor precursor/laminin receptor, LRP/LR) is a protein found to play several roles within cells. The receptor is located in the nucleus, cytosol and the cell surface. LRP/LR mediates cell proliferation, cell adhesion and cell differentiation. As a result, it is seen to enhance tumor angiogenesis as well as invasion and adhesion, key steps in the metastatic cascade of cancer. Recent findings have shown that LRP/LR is involved in the maintenance of cell viability through apoptotic evasion, allowing for tumor progression. Thus, several patented therapeutic approaches targeting the receptor for the prevention and treatment of cancer have emerged.Areas covered: The several roles that LRP/LR plays in cancer progression as well as an overview of the current therapeutic patented strategies targeting LRP/LR and cancer to date.Expert opinion: Small molecule inhibitors, monoclonal antibodies and small interfering RNAs might act used as powerful tools in preventing tumor angiogenesis and metastasis through the induction of apoptosis and telomere erosion in several cancers. This review offers an overview of the roles played by LRP/LR in cancer progression, while providing novel patented approaches targeting the receptor as potential therapeutic routes for the treatment of cancer as well as various other diseases.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Receptores de Laminina/antagonistas & inhibidores , Proteínas Ribosómicas/antagonistas & inhibidores , Animales , Progresión de la Enfermedad , Diseño de Drogas , Humanos , Terapia Molecular Dirigida , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Patentes como Asunto , Receptores de Laminina/metabolismo , Proteínas Ribosómicas/metabolismo
8.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(9): 1065-1070, 2019 Sep 30.
Artículo en Chino | MEDLINE | ID: mdl-31640948

RESUMEN

OBJECTIVE: To isolate tumor stem-like cells from human epithelial ovarian cancer SKOV3 cells and explore their role in the formation of vascularization mimicry (VM). METHODS: SKOV3 cells were passaged to the 7th generation by suspension culture in serum-free medium, and the percentages of CD133- and CD117-positive cells in the 1st, 3rd, 5th and 7th generations were analyzed using flow cytometry. The proliferative activity of the cells sorted from the 7th generation SKOV3 cells was assessed with colony formation assay. A three-dimensional cell culture model was established to compare the ability of VM formation between the sorted cells and the parental SKOV3 cells. The expression levels of matrix metalloproteinases-2 (MMP-2) and MMP-9 in the two groups were detected using real-time PCR and Western blotting. RESULTS: Some SKOV3 cells formed typical cell spheres with suspension growth in serum-free medium and were passaged to the 7th generation. Flow cytometry revealed that the percentage of CD133-positive cells increased with cell passaging. The cloning efficiency of the sorted cells was significantly higher than that of the parental SKOV3 cells (50.33% vs 5.33%, P < 0.001). The VM formation ability of the sorted cells was stronger than that of the parental SKOV3 cells in the three-dimensional cell culture system. RT-PCR and Western blotting showed that the expression levels of MMP-2 and MMP-9 were significantly higher in the 7th passage cells than in the parental cells (P < 0.05). CONCLUSIONS: The sorted cells from SKOV3 cells cultured in serum-free medium exhibit biological properties of tumor stem cells with strong VM formation ability, suggesting their role in VM formation.


Asunto(s)
Carcinoma Epitelial de Ovario/patología , Células Madre Neoplásicas/citología , Neovascularización Patológica/patología , Neoplasias Ováricas/patología , Línea Celular Tumoral , Movimiento Celular , Femenino , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo
9.
Zhonghua Shao Shang Za Zhi ; 35(9): 676-682, 2019 Sep 20.
Artículo en Chino | MEDLINE | ID: mdl-31594186

RESUMEN

Objective: To investigate the expressions of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 alpha (HIF-1α), and epidermal growth factor receptor (EGFR) in different morphological regions of Marjolin ulcer and their clinical relationship with angiogenesis. Methods: From January 2012 to December 2017, the patients admitted to our hospital who met the inclusion criteria were selected, including 92 patients with Marjolin ulcer [56 males and 36 females, aged (55±15) years], 100 patients with chronic non-cancerous skin ulcer [59 males and 41 females, aged (51±16) years], and 100 patients performed with other skin-related surgery [58 males and 42 females, aged (52±15) years], and they were enrolled into Marjolin ulcer group (MU), chronic non-cancerous ulcer group (CNU), and other skin surgery group (OSS) respectively. The etiology, pathogenic site, ulcer diameter, and course of patients in group MU were retrospectively analyzed. Ulcer tissue specimens from patients of group MU and group CNU and specimens of normal skin tissue attached to the tissue resected during operation from patients of group OSS were collected. The expressions of VEGF, HIF-1α, EGFR, and CD34 in the above-mentioned tissue and the surrounding normal skin, ulcer, epitheliomatous hyperplasia, and canceration areas in Marjolin ulcer tissue were detected by immunohistochemical method, and the positive expression rate and protein expression level were calculated. Data were processed with Pearson chi-square test, Mann-Whitney U test, Bonferroni method, and Bonferroni correction, and Spearman correlation analysis was used to analyze the relationship among the total protein expression levels. Results: In group MU, burns accounted for 91.3% (84/92) of the causes of patients, 44.6% (41/92) of the patients had tumors in the lower extremities, 62.0% (57/92) of the patients had skin ulcer diameter of 2.1-5.0 cm, and 75.0% (69/92) of the patients had a course of disease of more than 20 years. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group CNU were 41.0% (41/100), 77.0% (77/100), and 83.0% (83/100), respectively, significantly higher than those of normal skin tissue of patients in group OSS [12.0% (12/100), 45.0% (45/100), and 67.0% (67/100), χ(2)=21.589, 21.522, 6.827, P<0.01]. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group MU were 91.3% (84/92), 100.0% (92/92), and 100.0% (92/92), respectively, which were significantly higher than those in corresponding tissue of patients in group CNU and group OSS (χ(2)=53.372, 24.772, 17.159; 120.543, 72.777, 36.661, P<0.01). In ulcer tissue of patients in group MU, the positive expression rates of VEGF in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area (χ(2)=87.120, 42.368, 89.624, P<0.01); the positive expression rates of VEGF in canceration and ulcer areas were significantly higher than the rate in epitheliomatous hyperplasia area (χ(2)=22.586, 16.060, P<0.01). In ulcer tissue of patients in group MU, the positive expression rates of EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area (χ(2)=21.679, 27.600, 27.600, P<0.01), but the positive expression rates of HIF-1α in four morphological areas were similar (χ(2)=3.008, P>0.05). In ulcer tissue of patients in group MU, the protein expression levels of VEGF and CD34 in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area (Z=-6.765, -6.819; -6.765, -6.640; -6.765, -6.819, P<0.01), the protein expression levels of VEGF and CD34 in epitheliomatous hyperplasia area were significantly lower than those in ulcer area (Z=-4.484, -5.266, P<0.01), and the protein expression levels of VEGF and CD34 in canceration area were significantly higher than those in ulcer area (Z=-6.427, -6.723, P<0.01) and epitheliomatous hyperplasia area (Z=-6.427, -6.462, P<0.01). In ulcer tissue of patients in group MU, the protein expression levels of HIF-1α and EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area (Z=-6.819, -6.393; -6.819, -6.393; -6.819, -6.393, P<0.01), the protein expression levels of HIF-1α and EGFR in ulcer area were significantly lower than those in epitheliomatous hyperplasia and canceration areas (Z=-6.118, -5.638; -6.640, -6.393, P<0.01), and the protein expression levels of HIF-1α and EGFR in canceration area were significantly higher than those in epitheliomatous hyperplasia area (Z=-6.558, -6.819, P<0.01). In ulcer tissue of patients in group MU, the total protein expression levels of VEGF, HIF-1α, and EGFR were significantly positively correlated with the total protein expression level of CD34 (r=0.772, 0.415, 0.502, P<0.01) respectively; the total protein expression level of EGFR was significantly positively correlated with that of HIF-1α (r=0.839, P<0.01), both of which were significantly positively correlated with the total protein expression level of VEGF (r=0.531, 0.440, P<0.01) respectively. Conclusions: The expressions of VEGF, HIF-1α, and EGFR are the highest in Marjolin ulcer canceration area, and EGFR may promote angiogenesis through HIF-1α or directly increasing the expression of VEGF.


Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neovascularización Patológica/genética , Úlcera Cutánea/genética , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Receptores ErbB/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/patología , Estudios Retrospectivos , Úlcera Cutánea/patología
10.
World Neurosurg ; 132: e178-e184, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31505280

RESUMEN

OBJECTIVE: We aimed to evaluate the combined effect of ellagic acid (EA) and temozolomide (TEM) on the cadherin switch and angiogenesis in the C6 glioma cell line. METHODS: A total of 100 µM EA and 100 µM TEM were applied to rat C6 glioma cells for 24, 48, and 72 hours. Cell proliferation was detected by 5-bromo-2'-deoxyuridine immunohistochemistry. The messenger RNA and protein levels of E-cadherin, N-cadherin, and vascular endothelial growth factor (VEGF) were determined by real-time polymerase chain reaction and their immunohistochemistry, respectively, subsequent to EA treatment combined with TEM. RESULTS: EA in combination with TEM conspicuously reduced the viability of C6 glioma cells at all incubation times (P < 0.001). EA upregulated the expression of E-cadherin at the gene and protein levels in a time-independent manner (P < 0.05 and P < 0.001, respectively). By the presence of TEM, the increase was exaggerated at 24-hour incubation (P < 0.01). Conversely, EA reduced N-cadherin expression and immunoreactivity in a time-independent manner (P < 0.05 and P < 0.001, respectively), and combination with TEM enhanced this effect at the 24th hour (P < 0.001). Combination also downregulated the gene expression (P < 0.001) and immunoreactivity of VEGF only at 72 hours (P < 0.001). CONCLUSIONS: A successful therapeutic efficacy of EA combined with TEM is suggested probably by inhibiting the cadherin switch and angiogenesis.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cadherinas/efectos de los fármacos , Glioblastoma/patología , Neovascularización Patológica/patología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Ácido Elágico/farmacología , Ratas , Temozolomida/farmacología
11.
Int J Nanomedicine ; 14: 5911-5924, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31534330

RESUMEN

Purpose: Magnetoliposomes (MLs) have shown great potential as magnetic resonance imaging contrast agents and as delivery vehicles for cancer therapy. Targeting the MLs towards the tumor cells or neovascularization could ensure delivery of drugs at the tumor site. In this study, we evaluated the potential of MLs targeting the αvß3 integrin overexpressed on tumor neovascularization and different tumor cell types, including glioma and ovarian cancer. Methods: MLs functionalized with a Texas Red fluorophore (anionic MLs), and with the fluorophore and the cyclic Arginine-Glycine-Aspartate (cRGD; cRGD-MLs) targeting the αvß3 integrin, were produced in-house. Swiss nude mice were subcutaneously injected with 107 human ovarian cancer SKOV-3 cells. Tumors were allowed to grow for 3 weeks before injection of anionic or cRGD-MLs. Biodistribution of MLs was followed up with a 7T preclinical magnetic resonance imaging (MRI) scanner and fluorescence imaging (FLI) right after injection, 2h, 4h, 24h and 48h post injection. Ex vivo intratumoral ML uptake was confirmed using FLI, electron paramagnetic resonance spectroscopy (EPR) and histology at different time points post injection. Results: In vivo, we visualized a higher uptake of cRGD-MLs in SKOV-3 xenografts compared to control, anionic MLs with both MRI and FLI. Highest ML uptake was seen after 4h using MRI, but only after 24h using FLI indicating the lower sensitivity of this technique. Furthermore, ex vivo EPR and FLI confirmed the highest tumoral ML uptake at 4 h. Last, a Perl's stain supported the presence of our iron-based particles in SKOV-3 xenografts. Conclusion: Uptake of cRGD-MLs can be visualized using both MRI and FLI, even though the latter was less sensitive due to lower depth penetration. Furthermore, our results indicate that cRGD-MLs can be used to target SKOV-3 xenograft in Swiss nude mice. Therefore, the further development of this particles into theranostics would be of interest.


Asunto(s)
Fenómenos Magnéticos , Neoplasias/irrigación sanguínea , Neovascularización Patológica/terapia , Oligopéptidos/química , Animales , Línea Celular Tumoral , Dispersión Dinámica de Luz , Femenino , Humanos , Integrina alfaVbeta3/metabolismo , Liposomas , Imagen por Resonancia Magnética , Ratones Desnudos , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Neovascularización Patológica/patología , Imagen Óptica , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Chem Soc Rev ; 48(21): 5381-5407, 2019 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-31495856

RESUMEN

The ever-growing use of inorganic nanoparticles (NPs) in biomedicine provides an exciting approach to develop novel imaging and drug delivery systems, owing to the ease with which these NPs can be functionalized to cater to various applications. In cancer therapeutics, nanomedicine generally relies on the enhanced permeability and retention (EPR) effect observed in tumour vasculature to deliver anti-cancer drugs across the endothelium. However, such a phenomenon is dependent on the tumour microenvironment and is not consistently observed in all tumour types, thereby limiting drug transport to the tumour site. On the other hand, there is a rise in utilizing inorganic NPs to intentionally induce endothelial leakiness, creating a window of opportunity to control drug delivery across the endothelium. While this active targeting approach creates a similar phenomenon compared to the EPR effect arising from tumour tissues, its drug delivery applications extend beyond cancer therapeutics and into other vascular-related diseases. In this review, we summarize the current findings of the EPR effect and assess its limitations in the context of anti-cancer drug delivery systems. While the EPR effect offers a possible route for drug passage, we further explore alternative uses of NPs to create controllable endothelial leakiness within short exposures, a phenomenon we coined as nanomaterial-induced endothelial leakiness (NanoEL). Furthermore, we discuss the main mechanistic features of the NanoEL effect that make it unique from conventionally established endothelial leakiness in homeostatic and pathologic conditions, as well as examine its potential applicability in vascular-related diseases, particularly cancer. Therefore, this new paradigm changes the way inorganic NPs are currently being used for biomedical applications.


Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanomedicina , Nanopartículas/química , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias/patología , Neovascularización Patológica/patología
13.
Jpn J Radiol ; 37(10): 701-709, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31401722

RESUMEN

OBJECTIVES: To evaluate quantitative three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) in the assessment of tumor angiogenesis using an orthotropic liver tumor model. METHODS: Nine New Zealand white rabbits with liver orthotropic VX2 tumors were established and imaged by two-dimensional (2D) and 3D DCE-US after SonoVue® bolus injections. The intraclass correlation coefficients of perfusion parameters, including peak intensity (PI), mean transit time, time to peak, and area under the curve, were calculated based on time-intensity curve. The percentage area of microvascular (PAMV) and the expression of vascular endothelial growth factor (VEGF) were both evaluated by immunohistochemical analysis and weighted by the tumor activity area ratio. Correlations between quantitative and histologic parameters were analyzed. RESULTS: The reproducibility of 3D DCE-US quantitative parameters was excellent (ICC 0.91-0.99); but only PI showed high reproducibility (ICC 0.97) in 2D. None of the parameters of quantitative 2D DCE-US were significantly correlated with weighted PAMV or VEGF. For 3D DCE-US, there was a positive correlation between PI and weighted PAMV (r = 0.74, P = 0.04) as well as VEGF (r = 0.79, P = 0.02). CONCLUSION: Quantitative parameters of 3D DCE-US show feasibility, higher reproducibility and accuracy for the assessment of tumor angiogenesis using an orthotropic liver tumor model compared with 2D DCE-US.


Asunto(s)
Medios de Contraste , Aumento de la Imagen/métodos , Imagen Tridimensional/métodos , Neoplasias Hepáticas/diagnóstico por imagen , Neovascularización Patológica/diagnóstico por imagen , Ultrasonografía/métodos , Animales , Modelos Animales de Enfermedad , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Neoplasias Hepáticas/patología , Neovascularización Patológica/patología , Conejos , Reproducibilidad de los Resultados
14.
Curr Top Med Chem ; 19(22): 2069-2078, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31385773

RESUMEN

BACKGROUND: Disintegrins from snake venoms bind with high specificity cell surface integrins, which are important pharmacological targets associated with cancer development and progression. OBJECTIVE: In this study, we isolated a disintegrin from the Porthidium lansbergii lansbergii venom and evaluated its antitumoral effects on breast cancer cells. METHODS: The isolation of the disintegrin was performed on RP-HPLC and the inhibition of platelet aggregation was evaluated on human platelet-rich plasma. The inhibition of cell adhesion was also evaluated in vitro on cultures of cell lines by the MTT method as well as the inhibition of breast cancer cell migration by the wound healing assay. The binding of the disintegrin to integrin subunits was verified by flow cytometry and confocal microscopy. Finally, inhibition of angiogenesis was assessed in vitro on HUVEC cells and the concentration of VEGF was measured in the cellular supernatants. RESULTS: The disintegrin, named Lansbermin-I, is a low molecular weight protein (< 10 kDa) that includes an RGD on its sequence identified previously. Lansbermin-I showed potent inhibition of ADP and collagen-induced platelet aggregation on human plasma and also displayed inhibitory effects on the adhesion and migration of breast cancer MCF7 and MDA-MB 231cell lines, without affecting nontumorigenic breast MCF-10A and lung BEAS cells. Additionally, Lansbermin-I prevented MCF7 cells to adhere to fibronectin and collagen, and also inhibited in vitro angiogenesis on human endothelial HUVEC cells. CONCLUSION: Our results display the first report on the antitumor and anti-metastatic effects of an RGDdisintegrin isolated from a Porthidium snake venom by possibly interfering with α2 and/or ß1-containing integrins. Thus, Lansbermin-I could be an attractive model to elucidate the role of disintegrins against breast cancer development.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Venenos de Crotálidos/farmacología , Desintegrinas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Venenos de Crotálidos/química , Venenos de Crotálidos/aislamiento & purificación , Desintegrinas/química , Desintegrinas/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Integrinas/análisis , Integrinas/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Relación Estructura-Actividad , Viperidae , Cicatrización de Heridas/efectos de los fármacos
15.
Future Oncol ; 15(22): 2571-2576, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31407939

RESUMEN

Fruquintinib is a potent, highly selective and orally active inhibitor of VEGFR1, 2, 3 tyrosine kinases. It inhibits VEGF-induced VEGFR2 phosphorylation, endothelial cell proliferation and tubule formation. Currently, it has been approved for the treatment of metastatic colorectal cancer in patients who have failed at least two prior systemic antineoplastic therapies in China. However, it is not approved outside China, and there is another similar small molecular VEGFR multitarget drug approved in China, USA, Europe, etc. Here, we summarize the mechanism characteristics and clinical development of fruquintinib supporting its use in the treatment of metastastic colorectal cancer as well as explorations in other tumor types.


Asunto(s)
Benzofuranos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Inhibidores de la Angiogénesis/uso terapéutico , Proliferación Celular/efectos de los fármacos , China , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Europa (Continente) , Humanos , Metástasis de la Neoplasia , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Fosforilación/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/genética
16.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-31370155

RESUMEN

Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating evidence that a plethora of cellular and molecular factors is implicated in drug-induced phenotypical switching of GC cells. Among them, epithelial-mesenchymal transition (EMT), autophagy, drug detoxification, DNA damage response and drug target alterations, have been reported as major determinants. Intriguingly, resistant GC phenotype may be the result of GC cell-induced tumor microenvironment (TME) remodeling, which is currently emerging as a key player in promoting drug resistance and overcoming cytotoxic effects of drugs. In this review, we discuss the possible mechanisms of drug resistance and their involvement in determining current GC therapies failure.


Asunto(s)
Autofagia/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Neovascularización Patológica/genética , Neoplasias Gástricas/genética , Microambiente Tumoral/genética , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Antineoplásicos/uso terapéutico , Autofagia/efectos de los fármacos , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Supervivencia Celular/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Transición Epitelial-Mesenquimal/genética , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/patología , Helicobacter pylori/crecimiento & desarrollo , Helicobacter pylori/patogenicidad , Humanos , Hipoxia/tratamiento farmacológico , Hipoxia/genética , Hipoxia/metabolismo , Hipoxia/patología , Inactivación Metabólica/genética , MicroARNs/genética , MicroARNs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Microambiente Tumoral/efectos de los fármacos
17.
Molecules ; 24(15)2019 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-31370204

RESUMEN

Some polyphenols have been shown to inhibit, at physiological levels, the VEGF-induced VEGF receptor-2 signaling that causes angiogenesis, allegedly by direct interaction with VEGF and reducing the binding to its receptor VEGFR2. Surface plasmon resonance was used to measure the parameters of binding between VEGF and polyphenols as well as the nature of the interactions by assessing the effect of physico-chemical changes in the solution. CD spectrometry was used to determine any change in the secondary structure of the protein upon binding. The kinetic parameters (ka, kd, and KD) that characterise the binding to VEGF were measured for both inhibitor and non-inhibitor polyphenolic molecules. The effect of changes in the physico-chemical conditions of the solution where the binding occurred indicated that the nature of the interactions between VEGF and EGCG was predominantly of a hydrophobic nature. CD studies suggested that a change in the secondary structure of the protein occurred upon binding. Direct interaction and binding between VEGF and polyphenol molecules acting as inhibitors of the signaling of VEGFR2 has been measured for the first time. The binding between VEGF and EGCG seemed to be based on hydrophobic interactions and caused a change in the secondary structure of the protein.


Asunto(s)
Neovascularización Patológica/tratamiento farmacológico , Polifenoles/química , Factor A de Crecimiento Endotelial Vascular/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química , Catequina/análogos & derivados , Catequina/química , Catequina/farmacología , Proliferación Celular/efectos de los fármacos , Dicroismo Circular , Flavonoides/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas/efectos de los fármacos , Cinética , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Polifenoles/farmacología , Unión Proteica/efectos de los fármacos , Estructura Secundaria de Proteína/efectos de los fármacos , Transducción de Señal/genética , Resonancia por Plasmón de Superficie , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética
18.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-31370263

RESUMEN

Chemerin is a multifunctional adipokine with established roles in inflammation, adipogenesis and glucose homeostasis. Increasing evidence suggest an important function of chemerin in cancer. Chemerin's main cellular receptors, chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) are expressed in most normal and tumor tissues. Chemerin's role in cancer is considered controversial, since it is able to exert both anti-tumoral and tumor-promoting effects, which are mediated by different mechanisms like recruiting innate immune defenses or activation of endothelial angiogenesis. For this review article, original research articles on the role of chemerin and its receptors in cancer were considered, which are listed in the PubMed database. Additionally, we included meta-analyses of publicly accessible DNA microarray data to elucidate the association of expression of chemerin and its receptors in tumor tissues with patients' survival.


Asunto(s)
Quimiocinas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neovascularización Patológica/genética , Receptores de Quimiocina/genética , Receptores Acoplados a Proteínas G/genética , Animales , Quimiocinas/inmunología , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Humanos , Inmunidad Innata , Inflamación , Neoplasias/inmunología , Neoplasias/mortalidad , Neoplasias/patología , Neovascularización Patológica/inmunología , Neovascularización Patológica/mortalidad , Neovascularización Patológica/patología , Receptores CCR/genética , Receptores CCR/inmunología , Receptores de Quimiocina/inmunología , Receptores Acoplados a Proteínas G/inmunología , Transducción de Señal , Análisis de Supervivencia
19.
BMC Bioinformatics ; 20(1): 442, 2019 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-31455206

RESUMEN

BACKGROUND: Contemporary biological observations have revealed a large variety of mechanisms acting during the expansion of a tumor. However, there are still many qualitative and quantitative aspects of the phenomenon that remain largely unknown. In this context, mathematical and computational modeling appears as an invaluable tool providing the means for conducting in silico experiments, which are cheaper and less tedious than real laboratory experiments. RESULTS: This paper aims at developing an extensible and computationally efficient framework for in silico modeling of tumor growth in a 3-dimensional, inhomogeneous and time-varying chemical environment. The resulting model consists of a set of mathematically derived and algorithmically defined operators, each one addressing the effects of a particular biological mechanism on the state of the system. These operators may be extended or re-adjusted, in case a different set of starting assumptions or a different simulation scenario needs to be considered. CONCLUSION: In silico modeling provides an alternative means for testing hypotheses and simulating scenarios for which exact biological knowledge remains elusive. However, finer tuning of pertinent methods presupposes qualitative and quantitative enrichment of available biological evidence. Validation in a strict sense would further require comprehensive, case-specific simulations and detailed comparisons with biomedical observations.


Asunto(s)
Modelos Biológicos , Modelos Teóricos , Neoplasias/patología , Algoritmos , Proliferación Celular , Simulación por Computador , Difusión , Glucosa/metabolismo , Glucólisis , Humanos , Necrosis , Neoplasias/irrigación sanguínea , Neovascularización Patológica/patología , Oxígeno/metabolismo , Factores de Tiempo , Remodelación Vascular
20.
Biomed Res Int ; 2019: 7259691, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31428643

RESUMEN

Vasculogenic mimicry (VM), the novel approach for tumor cells to obtain blood supply, was reported to be involved in antiangiogenic resistance and poor prognosis in renal cell carcinoma (RCC). However, the molecular mechanisms underlying VM formed by RCC cells are still not clearly depicted. In the present study, we found that OS-RC-2 acquired the VM forming ability accompanied with the increased expressions of Vimentin and AXL and decreased expression of E-Cadherin by CoCl2 treatment. Downregulation of Vimentin by siRNA severely impaired the capability of OS-RC-2 and 786-O to form VM structures induced by cell hypoxia in vitro. Moreover, knockdown of Vimentin inhibited cell migration and invasion, which could be prompted by hypoxia induction in RCC cells. In our clear cell RCC tissues, we found that VM was positively correlated with Vimentin overexpression and both predicted poor prognosis. In conclusion, Vimentin plays an important role in hypoxia induced VM formation of RCC cells and targeted Vimentin might be beneficial for RCC therapy.


Asunto(s)
Carcinoma de Células Renales/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/metabolismo , Proteínas de Neoplasias/biosíntesis , Neovascularización Patológica/metabolismo , Vimentina/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/irrigación sanguínea , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/patología , Hipoxia de la Célula , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Cobalto/farmacología , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/diagnóstico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Neovascularización Patológica/diagnóstico , Neovascularización Patológica/patología , Pronóstico
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