RESUMO
PURPOSE: Recent evidence suggests that at least some sarcomas arise through aberrant differentiation of mesenchymal stromal cells (MSCs), but MSCs have never been isolated directly from human sarcoma specimens. EXPERIMENTAL DESIGN: We examined human sarcoma cell lines and primary adherent cultures derived from human sarcoma surgical samples for features of MSCs. We further characterized primary cultures as either benign or malignant by the presence of tumor-defining genetic lesions and tumor formation in immunocompromised mice. RESULTS: We show that a dedifferentiated liposarcoma cell line DDLS8817 posesses fat, bone, and cartilage trilineage differentiation potential characteristic of MSCs. Primary sarcoma cultures have the morphology, surface immunophenotype, and differentiation potential characteristic of MSCs. Surprisingly, many of these cultures are benign, as they do not form tumors in mice and lack sarcoma-defining genetic lesions. Consistent with the recently proposed pericyte origin of MSCs in normal human tissues, sarcoma-derived benign MSCs (SDBMSCs) express markers of pericytes and cooperate with endothelial cells in tube formation assays. In human sarcoma specimens, a subset of CD146-positive microvascular pericytes expresses CD105, an MSC marker, whereas malignant cells largely do not. In an in vitro coculture model, SDBMSCs as well as normal human pericytes markedly stimulate the growth of sarcoma cell lines. CONCLUSIONS: SDBMSCs/pericytes represent a previously undescribed stromal cell type in sarcoma that may contribute to tumor formation.
Assuntos
Células-Tronco Mesenquimais/patologia , Células-Tronco Mesenquimais/fisiologia , Sarcoma/patologia , Células Estromais/patologia , Células Estromais/fisiologia , Animais , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Separação Celular/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Transplante HeterólogoRESUMO
Imatinib, the treatment of choice for chronic myeloid leukemia, is generally well tolerated. We present here data from a retrospective analysis on metabolic abnormalities occurring during therapy which show increased creatine kinase, inverse creatine kinase-phosphate correlation, cholesterol and triglyceride values.
Assuntos
Antineoplásicos/efeitos adversos , Creatina Quinase/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas/induzido quimicamente , Fosfatos/metabolismo , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Adulto , Idoso , Antineoplásicos/administração & dosagem , Benzamidas , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Estudos RetrospectivosAssuntos
Insuficiência Cardíaca/induzido quimicamente , Neoplasias/tratamento farmacológico , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzamidas , Insuficiência Cardíaca/patologia , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
Despite the positive results achieved by Imatinib mesylate (Imatinib) in the treatment of chronic myeloid leukemia (CML), over the past several years, Imatinib does not eradicate the leukemic clone. The long-term duration of response to the drug is not known. Long-term follow-up of CML patients treated with Imatinib will ultimately define the durability of such treatment and the frequency of reemergence of progressive disease. We present the results of a 6-year follow-up of 40 CML patients either in chronic or accelerated phase who obtained a durable (>6 months) complete cytogenetic remission (CCyR) after treatment with Imatinib in a single center. In 34 cases CCyR was obtained at an Imatinib dose of 400-600 mg/day and in 6 cases after a dose increase to 600-800 mg/day. At a median follow-up of 68 months, 6 cytogenetic relapses (15%) were observed. No progressions to more advanced phases of disease have been detected during the follow-up period. Cytogenetic relapse was predicted by either a decrease in the amount of BCR-ABL transcript of less than 2 logs after the achievement of CCyR (p=0.0041) or a time-to-CCyR of more than 12 months (p<0.0001). This 6-year follow-up of the efficacy of Imatinib therapy in CML patients who obtained a durable CCyR indicates that the relapses rate is low over this period of observation and that the rate of relapse does not increase over time.