Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Immunol Lett ; 168(2): 260-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26462434

RESUMO

Induction of myeloid-derived suppressor cells is an important mechanism leading to tolerance against tumors. Phenotypic characterization of MDSC has been established and heterogeneous populations with monocytic or granulocytic features have been characterized. Increased levels of MDSC have been described in metastatic renal cell carcinoma and seem to correlate with an adverse outcome. As MDSC constitute only small populations in peripheral blood of cancer patients, it is highly important to achieve technically optimized conditions for quantification. Different cell preparation techniques--besides freezing and thawing--are potential sources of substantial variation. Our study was focused on an optimized quantification of MDSC in pB of healthy donors and patients with mRCC, in whom major technical sources of variation were analyzed. Whole blood and peripheral blood mononuclear cells were used for the flow cytometric quantification of MDSC in the pB of mRCC patients and healthy donors. We compared (1) analysis in whole blood vs. PBMC after Ficoll gradient centrifugation and (2) immediate analysis after blood drawing vs. analysis one day later. Finally, in order to evaluate our optimized technical approach, pB of 15 patients with histologically confirmed mRCC under treatment with either sunitinib or sorafenib was analyzed. No difference in the number of MDSC was observed after analysis in whole blood vs. PBMC. In contrast, the time point of analysis was a source of substantial variation (one day later vs. immediate analysis after blood drawing). In conclusion, for optimal analysis of MDSC, immediate analysis of whole blood after blood drawing rather than one day later seems to be most appropriate under the aspect of practical feasibility and reliability. Using this method, we were able to confirm both (a) increased numbers of MDSC in patients with mRCC and (b) a decrease of MDSC under sunitinib therapy.


Assuntos
Doadores de Sangue , Carcinoma de Células Renais/sangue , Neoplasias Renais/sangue , Células Mieloides/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Coleta de Amostras Sanguíneas/métodos , Carcinoma de Células Renais/patologia , Estudos de Viabilidade , Feminino , Citometria de Fluxo , Humanos , Neoplasias Renais/patologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Reprodutibilidade dos Testes , Fatores de Tempo
2.
Nature ; 501(7467): 421-5, 2013 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-23945590

RESUMO

Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eµ-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1(-) lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.


Assuntos
Autofagia , Senescência Celular , Glucose/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Caspase 12/metabolismo , Caspase 3/metabolismo , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Feminino , Linfoma de Células B/genética , Linfoma de Células B/patologia , Masculino , Camundongos , Camundongos Transgênicos , Proteólise , Estresse Fisiológico , Taxa de Sobrevida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...