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1.
Exp Cell Res ; 397(2): 112368, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33220260

RESUMO

Mixed lineage leukemia (MLL) arises from several KMT2A-gene chromosomal translocations. Shb gene deficiency has been found to exhibit pleiotropic effects in different models of leukemia, and consequently, this study aimed to investigate MLL-AF9-induced leukemia in Shb deficiency. Bone marrow cells from wild type and Shb knockout (KO) mice were transduced with the MLL-AF9 gene. Shb KO MLL-AF9 cells proliferated at an increased rate, exhibited altered expression of certain cytokine genes (Kitl, Csf3, IL6, IL1b) and higher expression of cell cycle genes (Ccnd2, Ccne1). Mice receiving Shb KO MLL-AF9 cells showed longer latency without displaying any difference in rates of leukemic cell proliferation, indicating a dichotomy between the in vitro and in vivo phenotypes. The mice with Shb deficient MLL-AF9 cells had a lower content of leukemic bone marrow cells allowing elevated normal hematopoiesis, explaining the longer latency. Finally, Shb knockout GFP-positive bone marrow cells showed a higher percentage of cells expressing myeloid markers. The result suggests a role of Shb in the progression of leukemia and that the relevance of the Shb gene is context-dependent as inferred from the differences between the in vivo and in vitro responses. These findings help to obtain an increased understanding of human MLL-AF9 leukemia.


Assuntos
Proliferação de Células , Transformação Celular Neoplásica/patologia , Regulação Leucêmica da Expressão Gênica , Leucemia Experimental/patologia , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas/fisiologia , Animais , Apoptose , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Humanos , Leucemia Experimental/genética , Leucemia Experimental/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Tumorais Cultivadas
2.
Int J Mol Sci ; 22(21)2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34768912

RESUMO

Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The Shb gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the Shb gene using the Cdh5-CreERt2 transgene, resulting in inactivation of the Shb-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of Shb expression. Instead, Shb deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific Shb deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.


Assuntos
Células Endoteliais/patologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Animais/patologia , Células Supressoras Mieloides/patologia , Neovascularização Patológica/patologia , Proteínas Proto-Oncogênicas/fisiologia , Microambiente Tumoral , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/genética , Caderinas/metabolismo , Células Endoteliais/metabolismo , Feminino , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Neoplasias Mamárias Animais/etiologia , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Monócitos/patologia , Células Supressoras Mieloides/metabolismo , Neovascularização Patológica/metabolismo
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