RESUMO
The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-ß receptor (LTßR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTßR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTßR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTßR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTßR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.
Assuntos
Diferenciação Celular , Autorrenovação Celular , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Receptor beta de Linfotoxina/metabolismo , Células-Tronco Neoplásicas/patologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Antígenos CD34/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Autorrenovação Celular/genética , Dano ao DNA , Fluoruracila/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Alterations of DNA methylation patterns have been suggested as biomarkers for diagnostics and therapy of cancers. Every novel discovery in the epigenetic landscape and every development of an improved approach for accurate analysis of the events may offer new opportunity for the management of patients. Using a novel high-throughput mass spectrometry on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) silico-chips, we determined semiquantitative methylation changes of 22 candidate genes in breast cancer tissues. For the first time we analysed the methylation status of a total of 42 528 CpG dinucleotides on 22 genes in 96 different paraffin-embedded tissues (48 breast cancerous tissues and 48 paired normal tissues). A two-way hierarchical cluster analysis was used to classify methylation profiles. In this study, 10 hypermethylated genes (APC, BIN1, BMP6, BRCA1, CST6, ESRb, GSTP1, P16, P21 and TIMP3) were identified to distinguish between cancerous and normal tissues according to the extent of methylation. Individual assessment of the methylation status for each CpG dinucleotide indicated that cytosine hypermethylation in the cancerous tissue samples was mostly located near the consensus sequences of the transcription factor binding sites. These hypermethylated genes may serve as biomarkers for clinical molecular diagnosis and targeted treatments of patients with breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adulto , Idoso , Automação , Análise por Conglomerados , Ilhas de CpG , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Fatores de Transcrição/metabolismoRESUMO
Cancer-related mortality is caused in a large part by the metastasis of primary tumor. Each cancer has a particular way of spreading cancerous cells. Recently, genetic and pharmacological analysis identified the set of genes, such as epidermal growth factor receptor ligand epiregulin (EREG), cyclooxygenase-2 (COX2) and matrix metalloproteinases 1 and 2 (MMP-1 and MMP-2) that have been found to be associated with metastasis of breast cancer to lung. Inhibition of EGFR and COX2 could minimize lung metastasis of breast cancer in a clinical setting. In this review, we summarized the current knowledge on EREG, COX2, MMP-1 and MMP-2 in tumor development and metastasis.