[HTML][HTML] Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids

RC Bates, JD Goldsmith, RE Bachelder, C Brown… - Current Biology, 2003 - cell.com
RC Bates, JD Goldsmith, RE Bachelder, C Brown, M Shibuya, P Oettgen, AM Mercurio
Current Biology, 2003cell.com
Aberrant cell survival and resistance to apoptosis are hallmarks of tumor invasion and
progression to metastatic disease [1], 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 …
Abstract
Aberrant cell survival and resistance to apoptosis are hallmarks of tumor invasion and progression to metastatic disease [1], 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 [2]. 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.
cell.com