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1.
Am J Cancer Res ; 12(8): 3932-3946, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36119827

RESUMEN

Breast cancer includes biologically distinct subtypes, and the time between rise in distant metastases and overall survival for the subtypes are different. The mechanisms involved in these differences in tumor metastasis remain to be elucidated. Here, we demonstrated that, luminal type A breast cancer cells, such as MCF7 and T47D, when overexpressed with active mutant form of Snail (6SA-Snail) increased in the expression of EMT markers such as Vimentin, N-cadherin and Fibronectin but decreased in the expression of E-cadherin, compared to control vectors or wild type Snail. Moreover, this mutant increased in migration and invasion ability, while decreased in the capacity to survive and form spheres in tumor spheroid medium. Luciferase reporter assay and chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) analysis revealed that Snail downregulated Src by binding to the E-box of Src promoter. Human luminal type A breast cancer specimens showed an inverse correlation between Vimentin and Src expression. Most importantly, downregulation of Src by Snail was not found in breast cancer cell types other than luminal type A. Therefore, elucidation of the differences in signaling pathways involved in controlling migration, invasion and colonization may have a therapeutically beneficial effect on breast cancer treatment.

2.
Biomedicines ; 9(5)2021 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-34068264

RESUMEN

Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.

3.
Macromol Biosci ; 17(4)2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27792283

RESUMEN

Fluorenyl-9-methoxycarbonyl (Fmoc)-diphenylalanine (Fmoc-FF) and Fmoc-arginine-glycine--aspartate (Fmoc-RGD) peptides self-assemble to form a 3D network of supramolecular hydrogel (Fmoc-FF/Fmoc-RGD), which provides a nanofibrous network that uniquely presents bioactive ligands at the fiber surface for cell attachment. In the present study, mesenchymal stem cells (MSCs) in Fmoc-FF/Fmoc-RGD hydrogel increase in proliferation and survival compared to those in Fmoc-FF/Fmoc-RGE hydrogel. Moreover, MSCs encapsulated in Fmoc-FF/Fmoc-RGD hydrogel and induced in each defined induction medium undergo in vitro osteogenic, adipogenic, and chondrogenic differentiation. For in vivo differentiation, MSCs encapsulated in hydrogel are induced in each defined medium for one week, followed by injection into gelatin sponges and transplantation into immunodeficient mice for four weeks. MSCs in Fmoc-FF/Fmoc-RGD hydrogel increase in differentiation into osteogenic, adipogenic, and chondrogenic differentiation, compared to those in Fmoc-FF/Fmoc-RGE hydrogel. This study concludes that nanofibers formed by the self-assembly of Fmoc-FF and Fmoc-RGD are suitable for the attachment, proliferation, and multi-differentiation of MSCs, and can be applied in musculoskeletal tissue engineering.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Hidrogeles/farmacología , Células Madre Mesenquimatosas/citología , Péptidos/farmacología , Andamios del Tejido/química , Arginina/análogos & derivados , Arginina/química , Adhesión Celular/efectos de los fármacos , Recuento de Células , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fluorenos/química , Humanos , Hidrogeles/síntesis química , Hidrogeles/química , Células Madre Mesenquimatosas/efectos de los fármacos , Péptidos/química
5.
Biochem Biophys Res Commun ; 478(2): 689-95, 2016 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-27498007

RESUMEN

The accumulation of fat, which results in obesity, is related to many metabolic disorders. Besides white and brown adipose tissue, beige adipose tissue has recently been recognized as a new type of accumulated fat. Mesenchymal stem cells (MSCs) have been shown to differentiate into brown adipocytes. Through analyzing levels of mRNA and protein markers associated with beige adipocyte, we found concomitant beige adipocyte differentiation upon induction of MSCs into brown adipocytes in a defined medium containing triiodothyronine, insulin, dexamethasone, and indomethacin. Moreover, we found that protein kinase A (PKA) modulators regulated MSC differentiation into brown or beige adipocytes. Activation of PKA by isobutylmethylxanthine or forskolin increased brown adipocyte differentiation and reduced beige adipocyte differentiation, while inactivation of PKA by KT-5720 or SC-3010 or the knockdown of PKA downstream cAMP response element-binding protein (CREB) decreased brown adipocyte differentiation and increased beige adipocyte differentiation. We also showed that increased brown adipocyte differentiation was accompanied by an increase in mitochondrial mass. In conclusion, we propose a model of beige/brown co-differentiation in MSCs and develop a method for controlling this differentiation via PKA modulation.


Asunto(s)
Adipocitos Beige/efectos de los fármacos , Adipocitos Marrones/efectos de los fármacos , Medios de Cultivo/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Células Madre Mesenquimatosas/efectos de los fármacos , 1-Metil-3-Isobutilxantina/farmacología , Adipocitos Beige/citología , Adipocitos Beige/metabolismo , Adipocitos Marrones/citología , Adipocitos Marrones/metabolismo , Carbazoles/farmacología , Diferenciación Celular/efectos de los fármacos , Colforsina/farmacología , Medios de Cultivo/química , AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/antagonistas & inhibidores , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Dexametasona/farmacología , Regulación de la Expresión Génica , Humanos , Indometacina/farmacología , Insulina/farmacología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Cultivo Primario de Células , Pirroles/farmacología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Triyodotironina/farmacología
6.
Nat Commun ; 7: 11798, 2016 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-27306323

RESUMEN

Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen 17 gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin 5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-collagen 17 pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival. Finally, this signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis.


Asunto(s)
Autoantígenos/genética , Neoplasias del Colon/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Células Madre Neoplásicas/metabolismo , Colágenos no Fibrilares/genética , Proteína Fosfatasa 2/genética , Factor de Transcripción STAT3/genética , Animales , Autoantígenos/metabolismo , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/mortalidad , Genes Reporteros , Humanos , Luciferasas/genética , Luciferasas/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Metástasis Linfática , Ratones , Trasplante de Neoplasias , Células Madre Neoplásicas/patología , Colágenos no Fibrilares/metabolismo , Pronóstico , Proteína Fosfatasa 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Análisis de Supervivencia , Kalinina , Colágeno Tipo XVII
7.
Stem Cell Reports ; 3(6): 975-86, 2014 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-25455074

RESUMEN

Many cell therapies currently being tested are based on mesenchymal stromal cells (MSCs). However, MSCs start to enter the senescent state upon long-term expansion. The role of retinoblastoma (RB) protein in regulating MSC properties is not well studied. Here, we show that RB levels are higher in early-passage MSCs compared with late-passage MSCs. RB knockdown induces premature senescence and reduced differentiation potentials in early-passage MSCs. RB overexpression inhibits senescence and increases differentiation potentials in late-passage MSCs. Expression of DNMT1, but not DNMT3A or DNMT3B, is also higher in early-passage MSCs than in late-passage MSCs. Furthermore, DNMT1 knockdown in early-passage MSCs induces senescence and reduces differentiation potentials, whereas DNMT1 overexpression in late-passage MSCs has the opposite effect. These results demonstrate that RB expressed in early-passage MSCs upregulates DNMT1 expression and inhibits senescence in MSCs. Therefore, genetic modification of RB could be a way to improve the efficiency of MSCs in clinical use.


Asunto(s)
Senescencia Celular/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Regulación de la Expresión Génica , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Fase de Descanso del Ciclo Celular/genética , Proteína de Retinoblastoma/genética , Animales , Trasplante de Médula Ósea , Diferenciación Celular/genética , Proliferación Celular , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Trasplante de Células Madre Mesenquimatosas , Ratones , Unión Proteica , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteína de Retinoblastoma/metabolismo , Regulación hacia Arriba
8.
Cancer Lett ; 328(2): 226-34, 2013 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-23017941

RESUMEN

Antiangiogenesis is an efficient therapy for eliminating colon cancers, but because of recurrence it remains only palliative. We hypothesized that certain populations of tumor cells resist antiangiogenesis-induced apoptosis and explored the underlying mechanism. We demonstrated that the CD133(+) population of cells in colon cancer is resistant to anti-angiogenesis therapy. Additionally, we identified an anti-apoptotic signaling pathway responsible for this resistance involving PP2A, p38MAPK, MAPKAPK2, and Hsp27. Thus, this pathway may offer a new avenue to develop target therapy for colorectal cancer.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias del Colon/metabolismo , Células Madre Neoplásicas/metabolismo , Neovascularización Patológica/metabolismo , Antígeno AC133 , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Antígenos CD/metabolismo , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Resistencia a Antineoplásicos , Glicoproteínas/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Péptidos/metabolismo , Proteína Fosfatasa 2/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
9.
PLoS One ; 7(11): e49605, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23185379

RESUMEN

Hypoxia and serum depletion are common features of solid tumors that occur upon antiangiogenesis, irradiation and chemotherapy across a wide variety of malignancies. Here we show that tumor cells expressing CD133, a marker for colorectal cancer initiating or stem cells, are enriched and survive under hypoxia and serum depletion conditions, whereas CD133- cells undergo apoptosis. CD133+ tumor cells increase cancer stem cell and epithelial-mesenchymal transition properties. Moreover, via screening a panel of tyrosine and serine/threonine kinase pathways, we identified Hsp27 is constitutively activated in CD133+ cells rather than CD133- cell under hypoxia and serum depletion conditions. However, there was no difference in Hsp27 activation between CD133+ and CD133- cells under normal growth condition. Hsp27 activation, which was mediated by the p38MAPK-MAPKAPK2-Hsp27 pathway, is required for CD133+ cells to inhibit caspase 9 and 3 cleavage. In addition, inhibition of Hsp27 signaling sensitizes CD133+ cells to hypoxia and serum depletion -induced apoptosis. Moreover, the antiapoptotic pathway is also activated in spheroid culture-enriched CD133+ cancer stem cells from a variety of solid tumor cells including lung, brain and oral cancer, suggesting it is a common pathway activated in cancer stem cells from multiple tumor types. Thus, activation of PP2A or inactivation of the p38MAPK-MAPKAPK2-Hsp27 pathway may develop new strategies for cancer therapy by suppression of their TIC population.


Asunto(s)
Proteínas de Choque Térmico HSP27/metabolismo , Hipoxia , Células Madre Neoplásicas/citología , Proteína Fosfatasa 2/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Antígeno AC133 , Animales , Antígenos CD/biosíntesis , Apoptosis , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica , Glicoproteínas/biosíntesis , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones SCID , Invasividad Neoplásica , Péptidos , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Tirosina/química
10.
Infect Immun ; 72(7): 4114-26, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15213157

RESUMEN

Mosquito-borne diseases, including dengue, malaria, and lymphatic filariasis, exact a devastating toll on global health and economics, killing or debilitating millions every year (54). Mosquito innate immune responses are at the forefront of concerted research efforts aimed at defining potential target genes that could be manipulated to engineer pathogen resistance in vector populations. We aimed to describe the pivotal role that circulating blood cells (called hemocytes) play in immunity by generating a total of 11,952 Aedes aegypti and 12,790 Armigeres subalbatus expressed sequence tag (EST) sequences from immune response-activated hemocyte libraries. These ESTs collapsed into 2,686 and 2,107 EST clusters, respectively. The clusters were used to adapt the web-based interface for annotating bacterial genomes called A Systematic Annotation Package for Community Analysis of Genomes (ASAP) for analysis of ESTs. Each cluster was categorically characterized and annotated in ASAP based on sequence similarity to five sequence databases. The sequence data and annotations can be viewed in ASAP at https://asap.ahabs.wisc.edu/annotation/php/ASAP1.htm. The data presented here represent the results of the first high-throughput in vivo analysis of the transcriptome of immunocytes from an invertebrate. Among the sequences are those for numerous immunity-related genes, many of which parallel those employed in vertebrate innate immunity, that have never been described for these mosquitoes. The sequences and annotations presented in this paper have been submitted to GenBank under accession numbers AY 431103 to AY 433788 (Aedes aegypti) and AY 439334 to AY 441440 (Armigeres subalbatus).


Asunto(s)
Aedes/genética , Hemocitos/metabolismo , Sistema Inmunológico/metabolismo , ARN/metabolismo , Aedes/inmunología , Aedes/metabolismo , Animales , Citoesqueleto/genética , Citoesqueleto/metabolismo , Etiquetas de Secuencia Expresada , Hemocitos/inmunología , Sistema Inmunológico/inmunología , Datos de Secuencia Molecular , Transducción de Señal/genética , Transducción de Señal/fisiología
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