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dc.contributor.authorBates, Richard C.
dc.contributor.authorGoldsmith, Jeffrey D.
dc.contributor.authorBachelder, Robin E.
dc.contributor.authorBrown, Courtney
dc.contributor.authorShibuya, Masabumi
dc.contributor.authorOettgen, Peter
dc.contributor.authorMercurio, Arthur M.
dc.date2022-08-11T08:08:02.000
dc.date.accessioned2022-08-23T15:39:47Z
dc.date.available2022-08-23T15:39:47Z
dc.date.issued2003-10-03
dc.date.submitted2010-11-07
dc.identifier.citation<p>Curr Biol. 2003 Sep 30;13(19):1721-7.</p>
dc.identifier.issn0960-9822 (Linking)
dc.identifier.doi10.1016/j.cub.2003.09.002
dc.identifier.pmid14521839
dc.identifier.urihttp://hdl.handle.net/20.500.14038/26254
dc.description.abstractAberrant 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=14521839&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1016/j.cub.2003.09.002
dc.subjectApoptosis
dc.subjectCell Survival
dc.subjectCell Transformation, Neoplastic
dc.subjectDNA Primers
dc.subjectEpithelium
dc.subjectExtracellular Matrix Proteins
dc.subjectGenetic Vectors
dc.subjectHumans
dc.subjectImmunohistochemistry
dc.subjectOrganoids
dc.subjectPolymerase Chain Reaction
dc.subjectSignal Transduction
dc.subjectTumor Cells, Cultured
dc.subjectUp-Regulation
dc.subjectVascular Endothelial Growth Factor Receptor-1
dc.subjectVascular Endothelial Growth Factors
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCancer Biology
dc.subjectCells
dc.subjectNeoplasms
dc.titleFlt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids
dc.typeArticle
dc.source.journaltitleCurrent biology : CB
dc.source.volume13
dc.source.issue19
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/cancerbiology_pp/168
dc.identifier.contextkey1633393
html.description.abstract<p>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.</p>
dc.identifier.submissionpathcancerbiology_pp/168
dc.contributor.departmentDepartment of Cancer Biology
dc.source.pages1721-7


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