RESUMEN
Microenvironments within the lymph node and bone marrow promote proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Successful treatment of CLL must therefore target the leukemic cells within these compartments. A better understanding of the interaction between CLL cells and the tumor microenvironment has led to the development of in vitro models that mimic the mechanisms that support leukemic cell survival and proliferation in vivo. Employing these models as part of the pre-clinical evaluation of novel therapeutic agents enables a better approximation of their potential clinical efficacy. In this review we summarize the current literature describing how different aspects of the tumor microenvironment have been modeled in vitro and detail how these models have been employed to study the biology of the disease and potential efficacy of novel therapeutic agents.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Microambiente Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Factor Activador de Células B/metabolismo , Antígenos CD40/metabolismo , Ligando de CD40/metabolismo , Comunicación Celular , Resistencia a Antineoplásicos , Humanos , Hipoxia/metabolismo , Interleucinas/metabolismo , Leucemia Linfocítica Crónica de Células B/terapia , Unión Proteica , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal , Células del Estroma/metabolismo , Receptores Toll-Like/metabolismo , Microambiente Tumoral/efectos de los fármacos , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismoRESUMEN
Patients with a stable chronic lymphocytic leukemia (CLL) double their blood lymphocyte count in >5 years, but may develop progressive disease with lymphocytes doubling in <12 months. To identify a protein signature for progressive CLL, whole cell extracts of peripheral blood mononuclear cells from patients with CLL (n=27) were screened using iTRAQ (isobaric tags for relative and absolute quantification) analysis. A total of 84 differentially abundant proteins were identified from patients with stable and progressive CLL. Subsequently, 32 of these proteins were quantified by SRM (selected reaction monitoring) using extracts of purified CD19+ CLL cells from patients (n=50). Hierarchical clustering of these protein profiles showed two clusters of patients that correlated with progressive and stable CLL, providing signatures that should be useful for triaging patients. Some of the proteins in the progressive cluster have not been linked with CLL, for example, glutamate dehydrogenase 1 and transcription intermediary factor 1-beta.
Asunto(s)
Biomarcadores de Tumor , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Proteoma , Proteómica , Cromatografía Liquida , Análisis por Conglomerados , Progresión de la Enfermedad , Humanos , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/diagnóstico , Estadificación de Neoplasias , Fenotipo , Pronóstico , Proteómica/métodos , Espectrometría de Masas en TándemRESUMEN
Tissue transglutaminase (tgase2) is a multifunctional enzyme that crosslinks proteins but also acts as a G-protein, differential functions regulated by calcium and GTP. In the epithelial cell membrane, we show that manipulation of tgase2 function by monodansylcadaverine or retinoic acid (RA) alters the activity of a membrane-bound protein kinase, nucleoside diphosphate kinase (NDPK, nm23-H1/H2) that is known to control G-protein function. We find that NDPK function is abnormally low in cystic fibrosis but can be restored by RA treatment in vitro. Our data suggest that tgase2 is overexpressed in cystic fibrosis and affects NDPK function.
