RESUMEN
The molecular biology of human glioma is a complex and fast-growing field in which basic research needs to meet clinical expectations in terms of anti-tumor efficacy. Although much effort is being done in molecular biology research, significant contribution to the quality of life and overall survival still lacks. The vastness of molecular biology literature makes it virtually impossible for clinicians to keep up to date in the field. This paper reviews some practical concepts regarding glioma tumorigenesis from the clinician's perspective. Five main aspects are discussed: major intracellular signaling pathways involved in glioma formation; genomic, epigenetic and transcriptomic relevant features of glioma; the prognostic and predictive values of molecular markers according to the new WHO classification of glial tumors; the importance of molecular and cellular heterogeneity in glioblastoma, responsible for its therapy resistance; and the interaction between glioma and the immune system, in view of the novel and promising targeted therapies.
Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/patología , Glioma/irrigación sanguínea , Glioma/etiología , Glioma/patología , Humanos , Biología Molecular , Transducción de Señal/fisiología , TranscriptomaRESUMEN
Wild-type p53 (wtp53) is described as a tumour suppressor gene; mutations in this gene occur in many human cancers and promote oncogenic capacity. Here, we establish that the oncogenic activity of mutant p53 (mtp53) is driven by the WASP-interacting protein (WIP). WIP knockdown from mtp53-expressing glioblastoma and breast cancer cells (BCC) greatly reduced proliferation and growth capacity of cancer stem cell (CSC)-like cells and decreased CSC-like markers (CD133, CD44 or YAP/TAZ). mtp53 overexpression in human astrocytes enhanced their proliferative capacity in suspension culture and increased expression of CSC markers and WIP. WIP knockdown compromised tumour glioblastoma and BCC growth capacity in vivo. We show that WIP is phosphorylated by AKT2 and is regulated by mtp53/p63 through enhancement of PI3K/AKT2-mediated integrin/receptor recycling pathways. WIP regulates this oncogenic pathway by controlling YAP/TAZ stability. We thus establish a new CSC signalling pathway downstream of mtp53 in which AKT2 regulates WIP and controls YAP/TAZ stability.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/metabolismo , Proteínas del Citoesqueleto/metabolismo , Glioblastoma/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mutación , Células Madre Neoplásicas/metabolismo , Fosfoproteínas/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteínas del Citoesqueleto/genética , Femenino , Glioblastoma/genética , Glioblastoma/patología , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Células MCF-7 , Masculino , Células Madre Neoplásicas/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfoproteínas/genética , Fosforilación/genética , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Señalizadoras YAPRESUMEN
In order to evaluate the usefulness of liposomes as possible vaccine vehicles (oral and subcutaneous), the stability of liposomes in buffer, plasma and saliva at 25 and 37 degrees C was analyzed via fluorescence and enzymatic methodology. The tested mixtures included [EggPC/Chol] 1 : 1 (mixture I), [EggPC/Chol/SM] 1 : 1 : 1 (mixture II), [EggPC/Chol/SM/GM typeIII] 1 : 1 : 1 : 0.14 (mixture III), [EggPC/Chol/SM/GM1] 1 : 1 : 1 : 0.14 (mixture IV) and [DIAPC/DMPC] 1 : 1 non polymerized (mixture V) and polymerized (mixture VI); all mole ratio. Liposome mixtures I and II were more stable in buffer at 25 degrees C. On the other hand, mixtures III and IV were more stable in plasma at 37 degrees C; mixture VI was more stable in plasma at 37 degrees C than in buffer or saliva. Mixtures IV and V liposomes were both stable in saliva for at least one hour. Blood and feces anti-GM1 response to antigen associated liposomes after subcutaneous and oral administration was also examined. After mixture IV mice immunization, no detectable anti-ganglioside GM1 antibody response was detected. Negative stain transmission electron microscopy, shows that liposomes containing SM, GM1, GM typeIII and DIAPC : DMPC were twice the size of those made with EggPC/Chol. The hydrophobicity factor expressed as A(570/500) was obtained using the probe merocynine 540 (MC540). The order of fluidity increased from: mixture II < mixture I < mixture III < mixture IV < mixtureV < mixture VI. Although the high hydrophobicity factor for polymerizable lipids there are other factors like stability must be taken into account according to the administration via selected. Also, the hydrophilicity of the groups protruding from the membrane interphase into the solution in the case of subcutaneous inoculation is very relevant and for oral administration stability is the property to take into account, as long as they have to last through the different fluids of the gastrointestinal tract. The results obtained suggest that liposomes that showed stability in saliva and plasma at 37 degrees C containing GM1, GM typeIII or DIAPC/DMPC would serve effectively as a delivery vehicle for oral and subcutaneous non-viral vaccines.