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VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche 总被引:4,自引:0,他引:4
Kaplan RN Riba RD Zacharoulis S Bramley AH Vincent L Costa C MacDonald DD Jin DK Shido K Kerns SA Zhu Z Hicklin D Wu Y Port JL Altorki N Port ER Ruggero D Shmelkov SV Jensen KK Rafii S Lyden D 《Nature》2005,438(7069):820-827
The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread. 相似文献
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Bhatti S Kozlov S Farooqi AA Naqi A Lavin M Khanna KK 《Cellular and molecular life sciences : CMLS》2011,68(18):2977-3006
ATM is the most significant molecule involved in monitoring the genomic integrity of the cell. Any damage done to DNA relentlessly
challenges the cellular machinery involved in recognition, processing and repair of these insults. ATM kinase is activated
early to detect and signal lesions in DNA, arrest the cell cycle, establish DNA repair signaling and faithfully restore the
damaged chromatin. ATM activation plays an important role as a barrier to tumorigenesis, metabolic syndrome and neurodegeneration.
Therefore, studies of ATM-dependent DNA damage signaling pathways hold promise for treatment of a variety of debilitating
diseases through the development of new therapeutics capable of modulating cellular responses to stress. In this review, we
have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying
the complex phenotypes observed in AT patients. 相似文献
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Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling 总被引:12,自引:0,他引:12
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Steinberg KM Antonacci F Sudmant PH Kidd JM Campbell CD Vives L Malig M Scheinfeldt L Beggs W Ibrahim M Lema G Nyambo TB Omar SA Bodo JM Froment A Donnelly MP Kidd KK Tishkoff SA Eichler EE 《Nature genetics》2012,44(8):872-880
The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08-1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. We identify a likely ancestral H2 haplotype (H2') lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently among Europeans, either because of extraordinary genetic drift or selective sweeps. 相似文献