Nuestros investigadores

Marta María Alonso Roldán

Publicaciones científicas más recientes (desde 2010)

Autores: Varela-Guruceaga M; Tejada, Sonia; García, Marc; et al.
Revista: CANCERS
ISSN 2072-6694  Vol. 10  Nº 7  2018  págs.  E226.
Autores: Tejada, Sonia; Diez Valle, Ricardo; Domínguez, Pablo Daniel; et al.
Revista: FRONTIERS IN ONCOLOGY
ISSN 2234-943X  Vol. 12  Nº 8  2018  págs. 61
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive glial brain tumors that primarily affect children, for which there is no curative treatment. Median overall survival is only one year. Currently, the scientific focus is on expanding the knowledge base of the molecular biology of DIPG, and identifying effective therapies. Oncolytic adenovirus DNX-2401 is a replication-competent, genetically modified virus capable of infecting and killing glioma cells, and stimulating an anti-tumor immune response. Clinical trials evaluating intratumoral DNX-2401 in adults with recurrent glioblastoma have demonstrated that the virus has a favorable safety profile and can prolong survival. Subsequently, these results have encouraged the transition of this biologically active therapy from adults into the pediatric population. To this aim, we have designed a clinical Phase I trial for newly diagnosed pediatric DIPG to investigate the feasibility, safety, and preliminary efficacy of delivering DNX-2401 into tumors within the pons following biopsy. This case report presents a pediatric patient enrolled in this ongoing Phase I trial for children and adolescents with newly diagnosed DIPG. The case involves an 8-year-old female patient with radiologically diagnosed DIPG who underwent stereotactic tumor biopsy immediately followed by intratumoral DNX-2401 in the same biopsy track. Because there were no safety concerns or new neurological deficits, the patient was discharged 3¿days after the procedures. To our knowledge, this is the first report of intratumoral DNX-2401 for a patient with DIPG in a clinical trial. We plan to demonstrate that intratumoral delivery of an oncolytic virus following tumor biopsy for pediatric patients with DIPG is a novel and feasible approach and that DNX-2401 represents an innovative treatment for the disease.
Autores: Lang, F. F., (Autor de correspondencia); Conrad, C.; Gomez-Manzano, C.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 36  Nº 14  2018  págs. 1419 - 27
PurposeDNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients.MethodsA phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens.ResultsIn group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8(+) and T-bet(+) cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration.ConclusionTreatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.
Autores: Aldave, G.; Rubio, A; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 20  Nº 7  2018  págs. 930 - 941
Background: Glioblastoma, the most aggressive primary brain tumor, is genetically heterogeneous. Alternative splicing (AS) plays a key role in numerous pathologies, including cancer. The objectives of our study were to determine whether aberrant AS could play a role in the malignant phenotype of glioma and to understand the mechanism underlying its aberrant regulation. Methods: We obtained surgical samples from patients with glioblastoma who underwent 5-aminolevulinic fluorescence-guided surgery. Biopsies were taken from the tumor center as well as from adjacent normal-appearing tissue. We used a global splicing array to identify candidate genes aberrantly spliced in these glioblastoma samples. Mechanistic and functional studies were performed to elucidate the role of our top candidate splice variant, BAF45d, in glioblastoma. Results: BAF45d is part of the switch/sucrose nonfermentable complex and plays a key role in the development of the CNS. The BAF45d/6A isoform is present in 85% of over 200 glioma samples that have been analyzed and contributes to the malignant glioma phenotype through the maintenance of an undifferentiated cellular state. We demonstrate that BAF45d splicing is mediated by polypyrimidine tract-binding protein 1 (PTBP1) and that BAF45d regulates PTBP1, uncovering a reciprocal interplay between RNA splicing regulation and transcription. Conclusions: Our data indicate that AS is a mechanism that contributes to the malignant phenotype of glioblastoma. Understanding the consequences of this biological process will uncover new therapeutic targets for this devastating disease.
Autores: Tejada, Sonia; Varela-Guruceaga M; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 20  Nº Supl.2  2018  págs. S52
Autores: Martinez-Velez, N.; Domínguez, Pablo Daniel; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 12  Nº 1  2017  págs. e0170501
Objective In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. Methods It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1 mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. Results The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. Conclusion Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons.
Autores: Moreno, M.; Pedrosa, L.; Pare, L. ; et al.
Revista: CELL REPORTS
ISSN 2211-1247  Vol. 21  Nº 8  2017  págs. 2183 - 2197
A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classicalGBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-kappa B) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM.
Autores: García-Romero, N.; Carrión-Navarro, J.; Esteban-Rubio, S. ; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 8  Nº 1  2017  págs. 1416 - 1428
Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted bloodbrain barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB remains intact, which might limit EVs release. To evaluate the ability of tumor-derived EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of tumor cells-derived EVs-apoptotic bodies, shedding microvesicles and exosomes-cross the intact BBB and can be detected in the peripheral blood, which provides a minimally invasive method for their detection compared to liquid biopsies obtained from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished from total murine EVs, since they carry human-specific DNA sequences relevant for GBM biology. In a small cohort of glioma patients, we finally demonstrated that peripheral blood EVs cargo can be successfully used to detect the presence of IDH1(G395A), an essential biomarker in the current management of human glioma
Autores: Inoges S; Tejada, Sonia; López, A; et al.
Revista: JOURNAL OF TRANSLATIONAL MEDICINE
ISSN 1479-5876  Vol. 15  Nº 1  2017  págs. 104-116
Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival benefit of this therapeutic approach. Trial registration This phase-II trial was registered as EudraCT: 2009-009879-35 and ClinicalTrials.gov Identifier: NCT01006044 retrospectively registered.
Autores: Martínez-Vélez, N.; Aristu, José Javier; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 19  2017  págs. 28 - 28
Autores: García, Marc; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 19  Nº Supl 6  2017  págs. 34
Autores: García, Marc; Martinez-Velez, N.; Gonzalez-Huarriz, M.; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 19  Nº Supl. 4  2017  págs. 42
Primitive Neuroectodermal Tumors (PNETs) are very rare aggressive pediatric tumors characterized by the presence of poorly differentiated tumor cells. Despite formidable advances in targeted therapies and in the knowledge of the molecular make-up of these tumors, the development of curative therapies is still lagging. Therefore, the outcome for children affected with PNETs still remains dismal. Thus, it is critical to propel alternative therapeutic approaches to improve the survival and quality of life of these children. Delta-24-RGD is an oncolytic adenovirus engineered to have a tumor restricted replication and an expanded tropism to cancer cells. Altogether, these modifications result in a potent antitumor and lack of toxicity as shown by preclinical and clinical studies. In this work we describe the antitumor effect mediated by Delta-24-RGD in PNETs (PFSK-1 and SK-PN-DW cells), as well as a in a new unpublished cell line (PBT-25) that we have generated from a tumor biopsy. First, we demonstrated in vitro that Delta-24-RGD transduces efficiently PNET cells leading to an effective replication yielding high titers of new infectious particles when compared with other type of brain tumors such as glioma. Treatment with the virus in vitro resulted in an effective cell killing effect, obtaining IC50 values ranging from 7 to 18 MOIs. In vivo, Delta-24-RGD showed a safety profile since no signs of toxicity were observed upon its administration. Finally, the antitumor effect of Delta-24-RGD was assessed in vivo in two orthotopic models of sPNET. Delta-24-RGD treatment resulted in a significant increase in overall survival of the animals (19 and 21 days for PFSK-1 and SK-PN-DW, respectively) compared to vehicle treated animals (14 days) and led to long-term survivors free of disease. In vivo antitumor effect in PBT-25 is on-going. In summary, these results demonstrate the potential therapeutic benefit of Delta-24-RGD for the treatment of PNETs.
Autores: García, Marc; Martínez-Velez, N; Patiño-Garcia, Ana; et al.
Revista: JOURNL OF BONE ONCOLOGY
ISSN 2212-1366  Vol. 9  2016  págs. 41-47
Osteosarcoma is the most common bone cancer among those with non-hematological origin and affects mainly pediatric patients. In the last 50 years, refinements in surgical procedures, as well as the introduction of aggressive neoadjuvant and adjuvant chemotherapeutic cocktails, have increased to nearly 70% the survival rate of these patients. Despite the initial therapeutic progress the fight against osteosarcoma has not substantially improved during the last three decades, and almost 30% of the patients do not respond or recur after the standard treatment. For this group there is an urgent need to implement new therapeutic approaches. Oncolytic adenoviruses are conditionally replicative viruses engineered to selectively replicate in and kill tumor cells, while remaining quiescent in healthy cells. In the last years there have been multiple preclinical and clinical studies using these viruses as therapeutic agents in the treatment of a broad range of cancers, including osteosarcoma. In this review, we summarize some of the most relevant published literature about the use of oncolytic adenoviruses to treat human osteosarcoma tumors in subcutaneous, orthotopic and metastatic mouse models. In conclusion, up to date the preclinical studies with oncolytic adenoviruses have demonstrated that are safe and efficacious against local and metastatic osteosarcoma. Knowledge arising from phase I/II clinical trials with oncolytic adenoviruses in other tumors have shown the potential of viruses to awake the patient¿s own immune system generating a response against the tumor. Generating osteosarcoma immune-competent adenoviruses friendly models will allow to better understand this potential. Future clinical trials with oncolytic adenoviruses for osteosarcoma tumors are warranted.
Autores: Aragón, Tomás; Martínez-Velez, N.; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 18  Nº 8  2016  págs. 1109-1119
These findings provide a strong rationale for combining temozolomide with ER stress-inducing drugs as an alternative therapeutic strategy for glioblastoma.
Autores: Martínez-Vélez, N.; Vera, B.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 22  Nº 9  2016  págs. 2217-25
These results uncover VCN-01 as a promising strategy for osteosarcoma, setting the bases to propel a phase I/II trial for kids with this disease.
Autores: Latasa, María Ujué; et al.
Revista: ONCOGENE
ISSN 0950-9232  Vol. 35  Nº 36  2016  págs. 4719 - 4729
Resisting death is a central hallmark of cancer cells. Tumors rely on a number of genetic mechanisms to avoid apoptosis, and alterations in mRNA alternative splicing are increasingly recognized to have a role in tumorigenesis. In this study, we identify the splicing regulator SLU7 as an essential factor for the preservation of hepatocellular carcinoma (HCC) cells viability. Compared with hepatocytes, SLU7 expression is reduced in HCC cells; however, further SLU7 depletion triggered autophagy-related cellular apoptosis in association with the overproduction of reactive oxygen species. Remarkably, these responses were not observed in primary human hepatocytes or in the well-differentiated HepaRG cell line. Mechanistically, we demonstrate that SLU7 binds the C13orf25 primary transcript in which the polycistronic oncomir miR-17-92 cluster is encompassed, and is necessary for its processing and expression. SLU7 knockdown altered the splicing of the C13orf25 primary transcript, and markedly reduced the expression of its miR-17, miR-20 and miR-92a constituents. This led to the upregulation of CDKN1A (P21) and BCL2L11 (BIM) expression, two bona fide targets of the miR-17-92 cluster and recognized mediators of its pro-survival and tumorigenic activity. Interestingly, altered splicing of miR-17-92 and downregulation of miR-17 and miR-20 were not observed upon SLU7 knockdown in non-transformed hepatocytes, but was found in other (HeLa, H358) but not in all (Caco2) non-hepatic tumor cells. The functional relevance of miR-17-92 dysregulation upon SLU7 knockdown was established when oxidative stress, autophagy and apoptosis were reversed by co-transfection of HCC cells with a miR-17 mimic. Together, these findings indicate that SLU7 is co-opted by HCC cells and other tumor cell types to maintain survival, and identify this splicing regulator as a new determinant for the expression of the oncogenic miR-17-92 cluster. This novel mechanism may be exploited for the development of antitumoral strategies in cancers displaying such SLU7-miR-17-92 crosstalk.
Autores: Vera, B.; Martínez-Vélez, N.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 11  Nº 1  2016  págs. e0147211
Despite the recent advances in the development of antitumor therapies, the prognosis for patients with malignant gliomas remains dismal. Therapy with tumor-selective viruses is emerging as a treatment option for this devastating disease. In this study we characterize the anti-glioma effect of VCN-01, an improved hyaluronidase-armed pRB-pathway-selective oncolytic adenovirus that has proven safe and effective in the treatment of several solid tumors. VCN-01 displayed a significant cytotoxic effect on glioma cells in vitro. In vivo, in two different orthotopic glioma models, a single intra-tumoral administration of VCN-01 increased overall survival significantly and led to long-term survivors free of disease.
Autores: Martinez-Irujo, Juan J; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 7  Nº 21  2016  págs. 30626-30641
Glioblastoma is the most frequent malignant brain tumor. Even with aggressive treatment, prognosis for patients is poor. One characteristic of glioblastoma cells is its intrinsic resistance to apoptosis. Therefore, drugs that induce alternative cell deaths could be interesting to evaluate as alternative therapeutic candidates for glioblastoma. Salinomycin (SLM) was identified through a chemical screening as a promising anticancer drug, but its mechanism of cell death remains unclear. In the present work we set out to elucidate how SLM causes cell death in glioblastoma cell lines (both established cell lines and brain tumor stem cell lines), aiming to find a potential antitumor candidate. In addition, we sought to determine the mechanism of action of SLM so that this mechanism can be can be exploited in the fight against cancer. Our data showed that SLM induces a potent endoplasmic reticulum (ER) stress followed by the trigger of the unfolded protein response (UPR) and an aberrant autophagic flux that culminated in necrosis due to mitochondria and lysosomal alterations. Of importance, the aberrant autophagic flux was orchestrated by the production of Reactive Oxygen Species (ROS). Alleviation of ROS production restored the autophagic flux. Altogether our data suggest that in our system the oxidative stress blocks the autophagic flux through lipid oxidation. Importantly, oxidative stress could be instructing the type of cell death in SLM-treated cells, suggesting that cell deat
Autores: Martinez Velez, N.; Domínguez, Pablo Daniel; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 18  Nº Supl.6  2016  págs. 61
Autores: Tejada, Sonia; Diez Valle, Ricardo; Gállego, Jaime; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 18  Nº Supl.6  2016  págs. 4
Autores: Vera, B.; Martínez-Vélez, N.; Xipell, E.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 11  Nº 1  2015  págs. e0147211
Despite the recent advances in the development of antitumor therapies, the prognosis for patients with malignant gliomas remains dismal. Therapy with tumor-selective viruses is emerging as a treatment option for this devastating disease. In this study we characterize the anti-glioma effect of VCN-01, an improved hyaluronidase-armed pRB-pathway-selective oncolytic adenovirus that has proven safe and effective in the treatment of several solid tumors. VCN-01 displayed a significant cytotoxic effect on glioma cells in vitro. In vivo, in two different orthotopic glioma models, a single intra-tumoral administration of VCN-01 increased overall survival significantly and led to long-term survivors free of disease.
Autores: Martínez-Velez, N.; Xipell, E.; et al.
Revista: JOURNAL OF BONE AND MINERAL RESEARCH
ISSN 0884-0431  Vol. 29  Nº 10  2014  págs. 2287 - 2296
Osteosarcoma is the most common malignant bone tumor in children and adolescents. The presence of metastases and the lack of response to conventional treatment are the major adverse prognostic factors. Therefore, there is an urgent need for new treatment strategies that overcome both of these problems. Our purpose was to elucidate whether the use of the oncolytic adenovirus ¿24-RGD alone or in combination with standard chemotherapy would be effective, in vitro and in vivo, against osteosarcoma. Our results showed that ¿24-RGD exerted a potent antitumor effect against osteosarcoma cell lines that was increased by the addition of cisplatin. ¿24-RGD osteosarcoma treatment resulted in autophagy in vitro that was further enhanced when combined with cisplatin. Of importance, administration of ¿24-RGD and/or cisplatin, in novel orthotopic and two lung metastatic models in vivo resulted in a significant reduction of tumor burden meanwhile maintaining a safe toxicity profile. Together, our data underscore the potential of ¿24-RGD to become a realistic therapeutic option for primary and metastatic pediatric osteosarcoma. Moreover, this study warrants a future clinical trial to evaluate the safety and efficacy of ¿24-RGD for this devastating disease.
Autores: García-Orti, L.; Cirauqui, C.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 25  Nº 4  2011  págs. 606 - 614
Protein phosphatase 2A (PP2A) is a human tumor suppressor that inhibits cellular transformation by regulating the activity of several signaling proteins critical for malignant cell behavior. PP2A has been described as a potential therapeutic target in chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia and B-cell chronic lymphocytic leukemia. Here, we show that PP2A inactivation is a recurrent event in acute myeloid leukemia (AML), and that restoration of PP2A phosphatase activity by treatment with forskolin in AML cells blocks proliferation, induces caspase-dependent apoptosis and affects AKT and ERK1/2 activity. Moreover, treatment with forskolin had an additive effect with Idarubicin and Ara-c, drugs used in standard induction therapy in AML patients. Analysis at protein level of the PP2A activation status in a series of patients with AML at diagnosis showed PP2A hyperphosphorylation in 78% of cases (29/37). In addition, we found that either deregulated expression of the endogenous PP2A inhibitors SET or CIP2A, overexpression of SETBP1, or downregulation of some PP2A subunits, might be contributing to PP2A inhibition in AML. In conclusion, our results show that PP2A inhibition is a common event in AML cells and that PP2A activators, such as forskolin or FTY720, could represent potential novel therapeutic targets in AML.
Autores: Alonso, Marta María, (Autor de correspondencia); Diez Valle, Ricardo; Rubio, A; et al.
Revista: PLoS One
ISSN 1932-6203  Vol. 6  Nº 11  2011  págs.  -
We undertook this study to understand how the transcription factor Sox2 contributes to the malignant phenotype of glioblastoma multiforme (GBM), the most aggressive primary brain tumor. We initially looked for unbalanced genomic rearrangements in the Sox2 locus in 42 GBM samples and found that Sox2 was amplified in 11.5% and overexpressed in all the samples. These results prompted us to further investigate the mechanisms involved in Sox2 overexpression in GBM. We analyzed the methylation status of the Sox2 promoter because high CpG density promoters are associated with key developmental genes. The Sox2 promoter presented a CpG island that was hypomethylated in all the patient samples when compared to normal cell lines. Treatment of Sox2-negative glioma cell lines with 5-azacitidine resulted in the re-expression of Sox2 and in a change in the methylation status of the Sox2 promoter. We further confirmed these results by analyzing data from GBM cases generated by The Cancer Genome Atlas project. We observed Sox2 overexpression (86%; N¿=¿414), Sox2 gene amplification (8.5%; N¿=¿492), and Sox 2 promoter hypomethylation (100%; N¿=¿258), suggesting the relevance of this factor in the malignant phenotype of GBMs. To further explore the role of Sox2, we performed in vitro analysis with brain tumor stem cells (BTSCs) and established glioma cell lines. Downmodulation of Sox2 in BTSCs resulted in the loss of their self-renewal properties. Surprisingly, ectopic expression of Sox2 in esta
Autores: Boni, V.; et al.
Revista: STEM CELLS
ISSN 1066-5099  Vol. 29  Nº 11  2011  págs. 1661 - 1671
Autores: Liu, D.; Fueyo, J.; Lee, OH.; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 1  Nº 8  2010  págs. 700-709
Malignant gliomas are the prototype of highly infiltrative tumors and this characteristic is the main factor for the inevitable tumor recurrence and short survival after most aggressive therapies. The aberrant communication between glioma cells and tumor microenvironment represents one of the major factors regulating brain tumor dispersal. Our group has previously reported that the tyrosine kinase receptor Tie2/TEK is expressed in glioma cells and brain tumor stem cells and is associated with the malignant progression of these tumors. In this study, we sought to determine whether the angiopoietin 1 (Ang1)/Tie2 axis regulates crosstalk between glioma cells and endothelial cells. We found that Ang1 enhanced the adhesion of Tie2-expressing glioma and brain tumor stem cells to endothelial cells. Conversely, specific small interfering RNA (siRNA) knockdown of Tie2 expression inhibited the adhesion capability of glioma cells. Tie2 activation induced integrin ß1 and N-cadherin upregulation, and neutralizing antibodies against these molecules inhibited the adhesion of Tie2-positive glioma cells to endothelial cells. In 2D and 3D cultures, we observed that Ang1/Tie2 axis activation was related to increased glioma cell invasion, which was inhibited by using Tie2 siRNA. Importantly, intracranial co-implantation of Tie2-positive glioma cells and endothelial cells in a mouse model resulted in diffusely invasive tumors with cell clusters surrounding glomeruloid vessels mimicking a tumoral niche distribution. Collectively, our results provide new information about the Tie2 signaling in glioma cells that regulates the cross-talk between glioma cells and tumor microenvironment, envisioning Tie2 as a multi-compartmental target for glioma therapy.
Autores: Jiang, H.; Martin, V.; Alonso, Marta María; et al.
Revista: AUTOPHAGY
ISSN 1554-8627  Vol. 6  Nº 8  2010  págs. 1216-1217
Autores: Conchillo, Ana; Vázquez, Iria; et al.
Revista: BRITISH JOURNAL OF CANCER
ISSN 0007-0920  Vol. 103  Nº 8  2010  págs. 1292 - 1296
BAKGROUND: The EVI1(ecotropic virus integration site 1) gene codes for a zinc-finger transcription factor, whose transcriptional activation leads to a particularly aggressive form of acute myeloid leukaemia (AML). Although, EVI1 interactions with key proteins in hematopoiesis have been previously described, the precise role of this transcription factor in promoting leukaemic transformation is not completely understood. Recent works have identified specific microRNA (miRNA) signatures in different AML subgroups. However, there is no analysis of miRNAs profiles associated with EVI1 overexpression in humans. METHODS: We performed QT-RT-PCR to assess the expression of 250 miRNAs in cell lines with or without EVI1 overexpression and in patient samples. We used ChIP assays to evaluated the possible binding of EVI1 binding to the putative miRNA promoter. Proliferation of the different cell lines transfected with the anti-or pre-miRs was quantified by MTT. RESULTS: Our data showed that EVI1 expression was significantly correlated with the expression of miR-1-2 and miR-133-a-1 in established cell lines and in patient samples. ChIP assays confirmed that EVI1 binds directly to the promoter of these two miRNAs. However, only miR-1-2 was involved in abnormal proliferation in EVI1 expressing cell lines. CONCLUSIONS: Our data showed that EVI1 controls proliferation in AML through modulation of miR-1-2. This study contributes to further understand the transcriptional networks involving transcription factors and miRNAs in AML.