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1.
Cell ; 183(5): 1219-1233.e18, 2020 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-33242418

RESUMEN

Cancer therapies kill tumors either directly or indirectly by evoking immune responses and have been combined with varying levels of success. Here, we describe a paradigm to control cancer growth that is based on both direct tumor killing and the triggering of protective immunity. Genetic ablation of serine protease inhibitor SerpinB9 (Sb9) results in the death of tumor cells in a granzyme B (GrB)-dependent manner. Sb9-deficient mice exhibited protective T cell-based host immunity to tumors in association with a decline in GrB-expressing immunosuppressive cells within the tumor microenvironment (TME). Maximal protection against tumor development was observed when the tumor and host were deficient in Sb9. The therapeutic utility of Sb9 inhibition was demonstrated by the control of tumor growth, resulting in increased survival times in mice. Our studies describe a molecular target that permits a combination of tumor ablation, interference within the TME, and immunotherapy in one potential modality.


Asunto(s)
Citotoxicidad Inmunológica , Inmunoterapia , Proteínas de la Membrana/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Serpinas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , Progresión de la Enfermedad , Femenino , Eliminación de Gen , Granzimas/metabolismo , Inmunidad/efectos de los fármacos , Melanoma/patología , Ratones Endogámicos C57BL , Neoplasias/prevención & control , Bibliotecas de Moléculas Pequeñas/farmacología , Células del Estroma/efectos de los fármacos , Células del Estroma/patología , Microambiente Tumoral/efectos de los fármacos
2.
Mol Cell ; 78(6): 1207-1223.e8, 2020 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-32504554

RESUMEN

Tumor interferon (IFN) signaling promotes PD-L1 expression to suppress T cell-mediated immunosurveillance. We identify the IFN-stimulated non-coding RNA 1 (INCR1) as a long noncoding RNA (lncRNA) transcribed from the PD-L1 locus and show that INCR1 controls IFNγ signaling in multiple tumor types. Silencing INCR1 decreases the expression of PD-L1, JAK2, and several other IFNγ-stimulated genes. INCR1 knockdown sensitizes tumor cells to cytotoxic T cell-mediated killing, improving CAR T cell therapy. We discover that PD-L1 and JAK2 transcripts are negatively regulated by binding to HNRNPH1, a nuclear ribonucleoprotein. The primary transcript of INCR1 binds HNRNPH1 to block its inhibitory effects on the neighboring genes PD-L1 and JAK2, enabling their expression. These findings introduce a mechanism of tumor IFNγ signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy.


Asunto(s)
Antígeno B7-H1/genética , Interferón gamma/metabolismo , ARN Largo no Codificante/genética , Anciano , Animales , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoterapia , Inmunoterapia Adoptiva/métodos , Interferón gamma/genética , Interferones/genética , Interferones/metabolismo , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Masculino , Ratones , Ratones Endogámicos NOD , Persona de Mediana Edad , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/efectos de los fármacos , Linfocitos T Citotóxicos
3.
Cytotherapy ; 26(10): 1217-1226, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38852095

RESUMEN

Highly malignant brain tumors, glioblastomas (GBM), are immunosuppressive, thereby limiting current promising immunotherapeutic approaches. In this study, we created interferon receptor 1 knockout allogeneic mesenchymal stem cells (MSC) to secrete dual-function pro-apoptotic and immunomodulatory interferon (IFN) ß (MSCKO-IFNß) using a single lentiviral vector CRISPR/Cas9 system. We show that MSCKO-IFNß induces apoptosis in GBM cells and upregulates the cell surface expression of programmed death ligand-1 in tumor cells. Next, we engineered MSCKO to release a secretable single-chain variable fragment (scFv) to block programmed death (PD)-1 and show the ability of MSCKO-scFv-PD1 to enhance T-cell activation and T-cell-mediated tumor cell killing. To simultaneously express both immune modulators, we engineered MSCKO-IFNß to co-express scFv-PD1 (MSCKO-IFNß-scFv-PD1) and show the expression of both IFNß and scFv-PD1 in vitro leads to T-cell activation and lowers the viability of tumor cells. Furthermore, to mimic the clinical scenario of GBM tumor resection and subsequent treatment, we show that synthetic extracellular matrix (sECM) encapsulated MSCKO-IFNß-scFv-PD1 treatment of resected tumors results in the increase of CD4+ and CD8+ T cells, mature conventional dendritic cells type II and activation of microglia as compared to the control treatment group. Overall, these results reveal the ability of MSCKO-IFNß-scFv-PD1 to shape the tumor microenvironment and enhance therapeutic outcomes in GBM.


Asunto(s)
Glioblastoma , Interferón beta , Células Madre Mesenquimatosas , Receptor de Muerte Celular Programada 1 , Anticuerpos de Cadena Única , Microambiente Tumoral , Glioblastoma/terapia , Glioblastoma/patología , Glioblastoma/metabolismo , Humanos , Receptor de Muerte Celular Programada 1/metabolismo , Anticuerpos de Cadena Única/genética , Interferón beta/metabolismo , Células Madre Mesenquimatosas/metabolismo , Línea Celular Tumoral , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Animales , Apoptosis , Ratones
4.
Sensors (Basel) ; 23(17)2023 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-37687841

RESUMEN

With the increasing use of automated vehicles (AVs) in the coming decades, government authorities and private companies must leverage their potential disruption to benefit society. Few studies have considered the impact of AVs towards mode shift by considering a range of factors at the city level, especially in Australia. To address this knowledge gap, we developed a system dynamic (SD)-based model to explore the mode shift between conventional vehicles (CVs), AVs, and public transport (PT) by systematically considering a range of factors, such as road network, vehicle cost, public transport supply, and congestion level. By using Melbourne's Transport Network as a case study, the model simulates the mode shift among AVs, CVs, and PT modes in the transportation system over 50 years, starting from 2018, with the adoption of AVs beginning in 2025. Inputs such as current traffic, road capacity, public perception, and technological advancement of AVs are used to assess the effects of different policy options on the transport systems. The data source used is from the Victorian Integrated Transport Model (VITM), provided by the Department of Transport and Planning, Melbourne, Australia, data from the existing literature, and authors' assumptions. To our best knowledge, this is the first time using an SD model to investigate the impacts of AVs on mode shift in the Australian context. The findings suggest that AVs will gradually replace CVs as another primary mode of transportation. However, PT will still play a significant role in the transportation system, accounting for 50% of total trips by person after 2058. Cost is the most critical factor affecting AV adoption rates, followed by road network capacity and awareness programs. This study also identifies the need for future research to investigate the induced demand for travel due to the adoption of AVs and the application of equilibrium constraints to the traffic assignment model to increase model accuracy. These findings can be helpful for policymakers and stakeholders to make informed decisions regarding AV adoption policies and strategies.

5.
J Biol Chem ; 297(5): 101223, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34597666

RESUMEN

Malignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the pleura, with few available treatment options. We recently reported that loss of function of the nuclear deubiquitinase BRCA1-associated protein 1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptor 4 (DR4) and death receptor 5 (DR5). Using tissue microarrays of tumor samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptor expression. BAP1 knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wt-BAP1, but not catalytically inactive BAP1 mutant, reduced promoter activities of DR4 and DR5, suggesting deubiquitinase activity is required for the regulation of gene expression. Co-immunoprecipitation studies demonstrated direct binding of BAP1 to the transcription factor Ying Yang 1 (YY1), and chromatin immunoprecipitation assays revealed BAP1 and YY1 to be enriched in the promoter regions of DR4 and DR5. Knockdown of YY1 also increased DR4 and DR5 expression and sensitivity to TRAIL. These results suggest that BAP1 and YY1 cooperatively repress transcription of TRAIL receptors. Our finding that BAP1 directly regulates the extrinsic apoptotic pathway will provide new insights into the role of BAP1 in the development of MPM and other cancers with frequent BAP1 mutations.


Asunto(s)
Mesotelioma Maligno/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Factor de Transcripción YY1/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Mesotelioma Maligno/genética , Mutación , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genética , Factor de Transcripción YY1/genética
6.
Stem Cells ; 39(6): 707-722, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33586320

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic has grown to be a global public health crisis with no safe and effective treatments available yet. Recent findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus pathogen that causes COVID-19, could elicit a cytokine storm that drives edema, dysfunction of the airway exchange, and acute respiratory distress syndrome in the lung, followed by acute cardiac injury and thromboembolic events leading to multiorgan failure and death. Mesenchymal stem cells (MSCs), owing to their powerful immunomodulatory abilities, have the potential to attenuate the cytokine storm and have therefore been proposed as a potential therapeutic approach for which several clinical trials are underway. Given that intravenous infusion of MSCs results in a significant trapping in the lung, MSC therapy could directly mitigate inflammation, protect alveolar epithelial cells, and reverse lung dysfunction by normalizing the pulmonary microenvironment and preventing pulmonary fibrosis. In this review, we present an overview and perspectives of the SARS-CoV-2 induced inflammatory dysfunction and the potential of MSC immunomodulation for the prevention and treatment of COVID-19 related pulmonary disease.


Asunto(s)
COVID-19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Células Madre Mesenquimatosas/inmunología , SARS-CoV-2/inmunología , COVID-19/terapia , COVID-19/virología , Síndrome de Liberación de Citoquinas/terapia , Síndrome de Liberación de Citoquinas/virología , Humanos , Inmunomodulación , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/virología , Pandemias , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/terapia , Fibrosis Pulmonar/virología , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/terapia , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2/genética
7.
Stem Cells ; 38(1): 34-44, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31381835

RESUMEN

Multiple stem cell types exhibit inherent tropism for cancer, and engineered stem cells have been used as therapeutic agents to specifically target cancer cells. Recently, stem cells have been engineered to target multiple surface receptors on tumor cells, as well as endothelial and immune cells in the tumor microenvironment. In this review, we discuss the rationales and strategies for developing multiple receptor-targeted stem cells, their mechanisms of action, and the promises and challenges they hold as cancer therapeutics.


Asunto(s)
Terapia Molecular Dirigida/métodos , Células Madre Neoplásicas/metabolismo , Ingeniería de Tejidos/métodos , Microambiente Tumoral/fisiología , Humanos
11.
Proc Natl Acad Sci U S A ; 114(30): E6157-E6165, 2017 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-28710334

RESUMEN

The recent Food and Drug Administration approval of immunogenic oncolytic virus (OV) has opened a new era in the treatment of advanced melanoma; however, approximately 50% of patients with melanoma develop brain metastasis, and currently there are no beneficial treatment options for such patients. To model the progression of metastases seen in patients and to overcome the hurdles of systemic delivery of OV, we developed melanoma brain metastasis models in immunocompromised and immunocompetent mice, and tested the fate and efficacy of oncolytic herpes simplex virus (oHSV)-armed mesenchymal stem cells (MSCs). Using brain-seeking patient-derived melanoma cells and real-time in vivo imaging, we show a widespread distribution of micrometastases and macrometastases in the brain, recapitulating the progression of multifoci metastases seen in patients. We armed MSCs with different oHSV variants (MSC-oHSV) and found that intracarotid administration of MSC-oHSV, but not of purified oHSV alone, effectively tracks metastatic tumor lesions and significantly prolongs the survival of brain tumor-bearing mice. In a syngeneic model of melanoma brain metastasis, a combination of MSC-oHSV and PD-L1 blockade increases IFNγ-producing CD8+ tumor-infiltrating T lymphocytes and results in a profound extension of the median survival of treated animals. This study thus demonstrates the utility of MSCs as OV carriers to disseminated brain lesions, and provides a clinically applicable therapeutic platform to target melanoma brain metastasis.


Asunto(s)
Neoplasias Encefálicas/terapia , Melanoma Experimental/terapia , Células Madre Mesenquimatosas , Viroterapia Oncolítica/métodos , Animales , Neoplasias Encefálicas/patología , Línea Celular , Humanos , Ratones , Metástasis de la Neoplasia , Virus Oncolíticos/genética , Simplexvirus/genética , Células Tumorales Cultivadas
13.
Nat Mater ; 22(12): 1444-1445, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38036624
14.
Stem Cells ; 36(6): 932-942, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29451340

RESUMEN

Stem cells are emerging as promising treatment strategies for several brain disorders and pathologies. In this study, we explored the potential of creating induced pluripotent stem cell-derived neural stem cells (ipNSC) by using either unmodified or gene-modified somatic cells and tested their fate and therapeutic efficacies in vitro and in vivo. We show that cells engineered in somatic state lose transgene-expression during the neural induction process, which is partially restored by histone deacetylase inhibitor treatment whereas cells engineered at the ipNSC state have sustained expression of transgenes. In vivo, bimodal mouse and human ipNSCs engineered to express tumor specific death-receptor ligand and suicide-inducing therapeutic proteins have profound anti-tumor efficacy when encapsulated in synthetic extracellular matrix and transplanted in mouse models of resected-glioblastoma. This study provides insights into using somatic cells for treating CNS disorders and presents a receptor-targeted cancer therapeutic approach for brain tumors. Stem Cells 2018;36:932-942.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Ingeniería Celular/métodos , Reprogramación Celular/fisiología , Células-Madre Neurales/fisiología , Animales , Humanos , Ratones
15.
Int J Cancer ; 141(8): 1671-1681, 2017 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-28567859

RESUMEN

Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients with glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance to chemo-radiotherapy, and effective treatment is not available for recurrent disease. In this study we identified TMZ resistant patient-derived primary and previously treated recurrent GBM stem cells (GSC), and investigated the therapeutic activity of a pro-apoptotic variant of oHSV (oHSV-TRAIL) in vitro and in vivo. We show that oHSV-TRAIL modulates cell survival and MAP Kinase proliferation signaling pathways as well as DNA damage response pathways in both primary and recurrent TMZ-resistant GSC. Utilizing real time in vivo imaging and correlative immunohistochemistry, we show that oHSV-TRAIL potently inhibits tumor growth and extends survival of mice bearing TMZ-insensitive recurrent intracerebral GSC tumors via robust and selective induction of apoptosis-mediated death in tumor cells, resulting in cures in 40% of the treated mice. In comparison, the anti-tumor effects in a primary chemoresistant GSC GBM model exhibiting a highly invasive phenotype were significant but less prominent. This work thus demonstrates the ability of oHSV-TRAIL to overcome the therapeutic resistance and recurrence of GBM, and provides a basis for its testing in a GBM clinical trial.


Asunto(s)
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Células Madre Neoplásicas/virología , Viroterapia Oncolítica/métodos , Simplexvirus/fisiología , Animales , Apoptosis/fisiología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/virología , Línea Celular Tumoral , Estudios de Cohortes , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Resistencia a Antineoplásicos , Glioblastoma/tratamiento farmacológico , Glioblastoma/virología , Células HEK293 , Humanos , Ratones , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/terapia , Recurrencia Local de Neoplasia/virología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Simplexvirus/genética , Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Temozolomida
16.
Acute Med ; 16(3): 104-106, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29072867

RESUMEN

The Society for Acute Medicine's Benchmarking Audit (SAMBA) was undertaken for the 5th time in June 2016. For the first time, data on telephone triage calls prior to admission to Acute Medical Units were collected: 1238 patients were referred from Emergency Departments, 925 from General Practitioners (GPs), 52 from clinics and 147 from other sources. Calls from Emergency Departments rarely resulted in admission avoidance. Calls from Primary Care resulted in avoidance of an admission in 115 (12%) patients; the percentage of avoided admissions was highest if the call was taken by a Consultant. Consultant triage might result in admission avoidance but the impact of local context on the effectiveness is not clear.

17.
Stem Cells ; 33(1): 101-10, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25186100

RESUMEN

Despite advances in standard therapies, the survival of glioblastoma multiforme (GBM) patients has not improved. Limitations to successful translation of new therapies include poor delivery of systemic therapies and use of simplified preclinical models which fail to reflect the clinical complexity of GBMs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis specifically in tumor cells and we have tested its efficacy by on-site delivery via engineered stem cells (SC) in mouse models of GBM that mimic the clinical scenario of tumor aggressiveness and resection. However, about half of tumor lines are resistant to TRAIL and overcoming TRAIL-resistance in GBM by combining therapeutic agents that are currently in clinical trials with SC-TRAIL and understanding the molecular dynamics of these combination therapies are critical to the broad use of TRAIL as a therapeutic agent in clinics. In this study, we screened clinically relevant chemotherapeutic agents for their ability to sensitize resistant GBM cell lines to TRAIL induced apoptosis. We show that low dose cisplatin increases surface receptor expression of death receptor 4/5 post G2 cycle arrest and sensitizes GBM cells to TRAIL induced apoptosis. In vivo, using an intracranial resection model of resistant primary human-derived GBM and real-time optical imaging, we show that a low dose of cisplatin in combination with synthetic extracellular matrix encapsulated SC-TRAIL significantly decreases tumor regrowth and increases survival in mice bearing GBM. This study has the potential to help expedite effective translation of local stem cell-based delivery of TRAIL into the clinical setting to target a broad spectrum of GBMs.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Animales , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Línea Celular Tumoral , Cisplatino/administración & dosificación , Terapia Combinada , Glioblastoma/patología , Glioblastoma/cirugía , Humanos , Ratones , Ratones Desnudos , Ligando Inductor de Apoptosis Relacionado con TNF/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Stem Cells ; 33(2): 589-600, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25346520

RESUMEN

Pseudomonas exotoxin (PE) potently blocks protein synthesis by catalyzing the inactivation of elongation factor-2 (EF-2). Targeted PE-cytotoxins have been used as antitumor agents, although their effective clinical translation in solid tumors has been confounded by off-target delivery, systemic toxicity, and short chemotherapeutic half-life. To overcome these limitations, we have created toxin-resistant stem cells by modifying endogenous EF-2, and engineered them to secrete PE-cytotoxins that target specifically expressed (interleukin-13 receptor subunit alpha-2) or overexpressed (epidermal growth factor receptor) in glioblastomas (GBM). Molecular analysis correlated efficacy of PE-targeted cytotoxins with levels of cognate receptor expression, and optical imaging was applied to simultaneously track the kinetics of protein synthesis inhibition and GBM cell viability in vivo. The release of IL13-PE from biodegradable synthetic extracellular matrix (sECM) encapsulated stem cells in a clinically relevant GBM resection model led to increased long-term survival of mice compared to IL13-PE protein infusion. Moreover, multiple patient-derived GBM lines responded to treatment, underscoring its clinical relevance. In sum, integrating stem cell-based engineering, multimodal imaging, and delivery of PE-cytotoxins in a clinically relevant GBM model represents a novel strategy and a potential advancement in GBM therapy.


Asunto(s)
Proteínas Bacterianas , Neoplasias Encefálicas/terapia , Resistencia a Medicamentos/genética , Exotoxinas , Interleucina-13 , Factor 2 de Elongación Peptídica , Proteínas Recombinantes de Fusión , Trasplante de Células Madre , Células Madre/metabolismo , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular , Exotoxinas/genética , Exotoxinas/metabolismo , Ingeniería Genética , Xenoinjertos , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , Ratones , Factor 2 de Elongación Peptídica/genética , Factor 2 de Elongación Peptídica/metabolismo , Pseudomonas/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Células Madre/patología
19.
Brain ; 138(Pt 6): 1710-21, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25910782

RESUMEN

Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications.


Asunto(s)
Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Neoplasias de la Mama/patología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/trasplante , Trasplante de Células Madre/métodos , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Supervivencia Celular , Femenino , Vectores Genéticos/genética , Humanos , Masculino , Ratones , Simplexvirus/enzimología , Simplexvirus/genética , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Timidina Quinasa/genética , Timidina Quinasa/metabolismo , Timidina Quinasa/uso terapéutico
20.
Mol Ther ; 23(1): 108-18, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25352242

RESUMEN

Despite the proven safety of oncolytic viruses (OV) in clinical trials for glioblastoma (GBM), their efficacy has been hindered by suboptimal spreading within the tumor. We show that hyaluronan or hyaluronic acid (HA), an important component of extracellular matrix (ECM), is highly expressed in a majority of tumor xenografts established from patient-derived GBM lines that present both invasive and nodular phenotypes. Intratumoral injection of a conditionally replicating adenovirus expressing soluble hyaluronidase (ICOVIR17) into nodular GBM, mediated HA degradation and enhanced viral spread, resulting in a significant antitumor effect and mice survival. In an effort to translate OV-based therapeutics into clinical settings, we encapsulated human adipose-derived mesenchymal stem cells (MSC) loaded with ICOVIR17 in biocompatible synthetic extracellular matrix (sECM) and tested their efficacy in a clinically relevant mouse model of GBM resection. Compared with direct injection of ICOVIR17, sECM-MSC loaded with ICOVIR17 resulted in a significant decrease in tumor regrowth and increased mice survival. This is the first report of its kind revealing the expression of HA in GBM and the role of OV-mediated HA targeting in clinically relevant mouse model of GBM resection and thus has clinical implications.


Asunto(s)
Adenoviridae/genética , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Hialuronoglucosaminidasa/genética , Células Madre Mesenquimatosas/metabolismo , Viroterapia Oncolítica/métodos , Proteínas Virales/genética , Adenoviridae/metabolismo , Animales , Materiales Biomiméticos/química , Materiales Biomiméticos/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Expresión Génica , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/patología , Células HEK293 , Humanos , Ácido Hialurónico/metabolismo , Hialuronoglucosaminidasa/metabolismo , Inyecciones Intralesiones , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/virología , Ratones , Ratones Desnudos , Análisis de Supervivencia , Proteínas Virales/metabolismo , Replicación Viral , Ensayos Antitumor por Modelo de Xenoinjerto
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