Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids
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Authors
Bates, Richard C.Goldsmith, Jeffrey D.
Bachelder, Robin E.
Brown, Courtney
Shibuya, Masabumi
Oettgen, Peter
Mercurio, Arthur M.
UMass Chan Affiliations
Department of Cancer BiologyDocument Type
Journal ArticlePublication Date
2003-10-03Keywords
ApoptosisCell Survival
Cell Transformation, Neoplastic
DNA Primers
Epithelium
Extracellular Matrix Proteins
Genetic Vectors
Humans
Immunohistochemistry
Organoids
Polymerase Chain Reaction
Signal Transduction
Tumor Cells, Cultured
Up-Regulation
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factors
Amino Acids, Peptides, and Proteins
Cancer Biology
Cells
Neoplasms
Metadata
Show full item recordAbstract
Aberrant cell survival and resistance to apoptosis are hallmarks of tumor invasion and progression to metastatic disease, but the mechanisms involved are poorly understood. The epithelial-mesenchymal transition (EMT), a process that facilitates progression to invasive cancer, provides a superb model for studying such survival mechanisms. Here, we used a unique spheroid culture system that recapitulates the structure of the colonic epithelium and undergoes an EMT in response to cytokine stimulation to study this problem. Our data reveal that the EMT results in the increased expression of both VEGF and Flt-1, a tyrosine kinase VEGF receptor, and that the survival of these cells depends on a VEGF/Flt-1 autocrine pathway. Perturbation of Flt-1 function by either a blocking antibody or adenoviral expression of soluble Flt-1, which acts in a dominant-negative fashion, caused massive apoptosis only in cells that underwent EMT. This pathway was critical for the survival of other invasive colon carcinoma cell lines, and we observed a correlative upregulation of Flt-1 expression linked to in vivo human cancer progression. A role for Flt-1 in cell survival is unprecedented and has significant implications for Flt-1 function in tumor progression, as well as in other biological processes, including angiogenesis and development.Source
Curr Biol. 2003 Sep 30;13(19):1721-7.
DOI
10.1016/j.cub.2003.09.002Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26254PubMed ID
14521839Related Resources
ae974a485f413a2113503eed53cd6c53
10.1016/j.cub.2003.09.002