RESUMO
Cell adhesion and motility are central aspects in the pathophysiology of B cell chronic lymphocytic leukemia (B-CLL), but the role of specific extracellular matrix proteins is still to be completely unveiled. Purified peripheral blood neoplastic cells of B-CLL patients migrated poorly on laminins-111,-411,-511, but showed pronounced motility on laminin (LM)-332 in a high percentage of cases. B-CLL cell motility on LM-332 was mediated by the alpha3beta1 integrin and was preferentially observed in cells carrying a mutated IgV(H) gene profile. Within normal lymph nodes, LM-332 was circumscribed around blood vessels and to areas corresponding to marginal zones, where it was deposited in a pattern reminiscent of reticular fibers. Conversely, in B-CLL involved lymph nodes, a positive LM-332 reticular mesh was diffusely evident, throughout the disrupted nodal architecture. In the present study we identified LM-332 as a crucial motility-promoting factor for B-CLL lymphocytes and as a potential constituent favoring the dissemination of B-CLL lymphocytes through vascular basement membranes and possibly lymph node compartments.
Assuntos
Moléculas de Adesão Celular/fisiologia , Movimento Celular/fisiologia , Leucemia Linfocítica Crônica de Células B/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Feminino , Fibronectinas/metabolismo , Expressão Gênica , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Imuno-Histoquímica , Integrina alfa3beta1/genética , Integrina alfa3beta1/imunologia , Integrina alfa3beta1/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfonodos/metabolismo , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Mutação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , CalininaRESUMO
Although malignant fibrous histiocytoma (MFH) is one of the most diffuse and highly aggressive tumors among soft tissue sarcomas in adults, it is poorly characterized from the molecular point of view. The overt lack of expression of phenotypic markers in MFH cells and the hypothesis that MFH may originate from transformed multipotent stem/progenitor cells with mesenchymal features has led us to investigate this notion and search for 'MFH-specific' genes. To address this problem, we have undertaken a differential display-based three-pair comparative mRNA profiling of bone-marrow derived mesenchymal stem cells (MSC) and cells isolated by primary MFH, leiomyosarcoma and smooth muscle cells, fibrosarcoma and dermal fibroblasts. This approach highlighted pair-wise analogies in gene expression patterns between matched tumor and healthy cells and yielded direct access to 43 genes differentially expressed between MSC and MFH cells. Eleven of the identified genes were selected for comparative evaluation of their expression levels in other sarcoma types, as well as potential markers for the detection of circulating tumor cells. Several of these genes defined the stem/progenitor versus MFH cell and some of them have the potential to be exploited for disclosure of circulating sarcoma cells. The striking similarity in the gene expression patterns observed in the two cell types was further corroborated by a remarkable similarity in the cell phenotypic markers that these cells expressed ex vivo. The findings open now the possibility to examine, also functionally, genes not previously known to be implicated in MFH development and strengthen the hypothesis that MFH originates from a mesenchymal progenitor cell.