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1.
Int J Cancer ; 134(11): 2583-94, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24214914

RESUMO

Mesenchymal stem/stromal cells (MSC) are multipotent precursors endowed with the ability to home to primary and metastatic tumor sites, where they can integrate into the tumor-associated stroma. However, molecular mechanisms and outcome of their interaction with cancer cells have not been fully clarified. In this study, we investigated the effects mediated by bone marrow-derived MSC on human colorectal cancer (CRC) cells in vitro and in vivo. We found that MSC triggered epithelial-to-mesenchymal transition (EMT) in tumor cells in vitro, as indicated by upregulation of EMT-related genes, downregulation of E-cadherin and acquisition of mesenchymal morphology. These effects required cell-to-cell contact and were mediated by surface-bound TGF-ß newly expressed on MSC upon coculture with tumor cells. In vivo tumor masses formed by MSC-conditioned CRC cells were larger and characterized by higher vessel density, decreased E-cadherin expression and increased expression of mesenchymal markers. Furthermore, MSC-conditioned tumor cells displayed increased invasiveness in vitro and enhanced capacity to invade peripheral tissues in vivo. Thus, by promoting EMT-related phenomena, MSC appear to favor the acquisition of an aggressive phenotype by CRC cells.


Assuntos
Adesão Celular , Comunicação Celular , Membrana Celular/metabolismo , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal , Células-Tronco Mesenquimais/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose , Western Blotting , Medula Óssea/metabolismo , Medula Óssea/patologia , Caderinas/genética , Caderinas/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Quimiocinas/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Citocinas/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Citometria de Fluxo , Imunofluorescência , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/citologia , Pele/metabolismo , Fator de Crescimento Transformador beta/genética
2.
Cancer Res ; 71(12): 4117-29, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21505102

RESUMO

Fusion oncogenes in acute myeloid leukemia (AML) promote self-renewal from committed progenitors, thereby linking transformation and self-renewal pathways. Like most cancers, AML is a genetically and biologically heterogeneous disease, but it is unclear whether transformation results from common or overlapping genetic programs acting downstream of multiple mutations or by the engagement of unique genetic programs acting cooperatively downstream of individual mutations. This distinction is important, because the involvement of common programs would imply the existence of common molecular targets to treat AML, no matter which oncogenes are involved. Here we show that the ability to promote self-renewal is a generalized property of leukemia-associated oncogenes. Disparate oncogenes initiated overlapping transformation and self-renewal gene expression programs, the common elements of which were defined in established leukemic stem cells from an animal model as well as from a large cohort of patients with differing AML subtypes, where they strongly predicted pathobiological character. Notably, individual genes commonly activated in these programs could partially phenocopy the self-renewal function of leukemia-associated oncogenes in committed murine progenitors. Furthermore, they could generate AML following expression in murine bone marrow. In summary, our findings reveal the operation of common programs of self-renewal and transformation downstream of leukemia-associated oncogenes, suggesting that mechanistically common therapeutic approaches to AML are likely to be possible, regardless of the identity of the driver oncogene involved.


Assuntos
Leucemia Mieloide Aguda/etiologia , Oncogenes , Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Perfilação da Expressão Gênica , Proteínas de Homeodomínio/fisiologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/fisiologia , Proteínas de Fusão Oncogênica/fisiologia , Proteína 1 Parceira de Translocação de RUNX1
3.
PLoS One ; 6(1): e16330, 2011 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-21297973

RESUMO

Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation that were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors including Gata2, Gfi1 and Sfpi1/Pu.1. In particular, downregulation of Gata2 expression was mirrored by abundant GATA motifs in regions of reduced histone acetylation suggesting an important role in leukaemogenic transcriptional reprogramming. Forced re-expression of Gata2 was not compatible with sustained growth of leukaemic cells thus suggesting a previously unrecognised role for Gata2 in downregulation during the development of AML. Additionally, large scale human AML datasets revealed significantly higher expression of GATA2 in CD34+ cells from healthy controls compared with AML blast cells. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer.


Assuntos
Fator de Transcrição GATA2/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Transcrição Gênica , Acetilação , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos , Células-Tronco Neoplásicas , Análise de Sequência de DNA , Fatores de Transcrição/genética
4.
Nat Struct Mol Biol ; 17(5): 617-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20400950

RESUMO

Trimethylation of Lys36 in histone H3 (H3K36me3) coordinates events associated with the elongation phase of transcription and is also emerging as an important epigenetic regulator of cell growth and differentiation. We have identified the PWWP domain of bromo and plant homeodomain (PHD) finger-containing protein 1 (BRPF1) as a H3K36me3 binding module and have determined the structure of this domain in complex with an H3K36me3-derived peptide.


Assuntos
Histonas/química , Histonas/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Cristalografia por Raios X , Proteínas de Ligação a DNA , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Estrutura Terciária de Proteína
5.
Expert Opin Ther Targets ; 11(7): 915-27, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17614760

RESUMO

Recent evidence has demonstrated the existence of a small subset of the tumour mass that is wholly responsible for the sustained growth and propagation of the tumour. This cancer stem cell (CSC) compartment is also likely to be responsible both for disease relapse and the resistance to therapy that often accompanies relapse. The evidence for CSCs in various malignancies is presented. The failure of existing therapeutics to eradicate CSCs suggests that they are relatively resistant to present cancer treatments. This resistance may reflect the preservation of normal stem cell protective mechanisms, such as an increased expression of drug efflux pumps or alterations in apoptotic, cell cycle and DNA repair mechanisms. Targeting these mechanisms, and taking advantage of potential differences in the biology of normal stem cells and CSCs, such as differences in surface phenotype, self renewal/quiescence and stem cell-niche interactions are discussed and preliminary preclinical or clinical data are presented. Finally, the authors give their opinion of the direction in which one must travel to successfully target the CSC and improve treatment outcomes in malignant disease.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo
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