RESUMEN
Interactive signaling between cancer cells and stroma plays an important role in determining tumor development. We recently found tumor cell-derived factors to induce fibroblast clustering, and that the high amounts of hepatocyte growth factor/scatter factor (HGF/SF) produced by these cell-cell contact-activated fibroblasts enhanced the invasiveness of c-Met-expressing cancer cells. We now observed that leukemia cells lacking c-Met respond to this novel type of fibroblast activation, nemosis, with growth arrest and differentiation to a dendritic cell-like phenotype. This effect was counteracted by introduction of c-Met expression into these cells. Moreover, those leukemia cell lines harboring properly processed c-Met showed no effect in response to nemosis. We propose this effect to be mediated by nemosis-derived cytokine signals, and present the potential candidates induced in the nemotic fibroblasts: interleukins-1, -6, -8, -11, leukemia inhibitory factor and granulocyte-macrophage-colony-stimulating factor. Our results emphasize the role of activated stromal fibroblasts in controlling progression of certain hematologic malignancies in a c-Met expression-dependent manner.
Asunto(s)
Diferenciación Celular , Fibroblastos/citología , Leucemia/patología , Antígenos de Superficie/inmunología , Apoptosis , Línea Celular Tumoral , Técnicas de Cocultivo , Citocinas/biosíntesis , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Leucemia/inmunología , Leucemia/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismoRESUMEN
After each leukemia therapy phase, characteristics of normal regenerating B-cells may be reminiscent of and mistaken for a relapse. We compared the incidence and phenotypic characteristics of hematogone stages in a total of 669 bone marrow aspirates from 107 patients with B-ALL, 97 patients of AML, and 27 patients with T-ALL at diagnosis, during, and after therapy. The three individual physiological maturation phases of B-lymphocytes (hematogone stages 1, 2, and 3) were studied by four-color flow cytometry in the course of bone marrow regeneration in leukemia patients. Multiple stages of hematogones were observed twice as frequently in B-ALL (73.8%) and T-ALL (69.2%) samples as in AML aspirates (34.1%). Stage 3 hematogones were found usually in children and were thus frequent in B-ALL. The hematogones had an extremely high phenotypic stability unaffected by disease or therapy or by their coincidence with leukemia cells.