title: The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis.
abstract: When carcinoma cells metastasize, they change their phenotype to enhance motility. Cells making this switch selectively express S100A4, a p53-associated, calcium-binding protein known in the fibroblast literature as fibroblast-specific protein-1 (FSP1). FSP1 normally acts as a conversion signal for the local formation of tissue fibroblasts by epithelial-mesenchymal transition. We describe here a novel connection between the process of fibroblast development and the acquisition of a metastatic phenotype in genetically engineered mice with mammary carcinoma. More frequent lung metastases were observed in naïve recipients given purified populations of green fluorescent protein (GFP)(+) tumor cells harvested from PyV-mT x FSP1(+/+.GFP) F1 mice compared with GFP(-) tumor cells (P < or = 0.01), where GFP expression is under the control of the FSP1 promoter. The expression of GFP in these metastases reversibly attenuates with the establishment of secondary tumor nodules. Reduced numbers of metastases were also observed in PyV-mT x FSP1(GFP/GFP) F1 mice carrying null alleles for FSP1 (P < or = 0.04) and in PyV-mT x FSP1.Delta TK(+) F1 mice rescued with nucleoside analogues while expressing thymidine kinase under the control of the FSP1 promoter (P < or = 0.01). We propose that epithelial-mesenchymal transition associated with the expression of FSP1 in tumor cells has a functional role in determining the latency of tumor dispersion and may be a convenient therapeutic target for controlling a key initiating event in metastatic progression.
authors.affiliation: Department of Medicine and the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Chengsen
authors.initials: C
authors.lastname: Xue
authors.forename: David
authors.initials: D
authors.lastname: Plieth
authors.forename: Christo
authors.initials: C
authors.lastname: Venkov
authors.forename: Carol
authors.initials: C
authors.lastname: Xu
authors.forename: Eric G
authors.initials: EG
authors.lastname: Neilson
mesh_terms: D019264:Adoptive Transfer; D000483:Alleles; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002277:Carcinoma / Q000556:secondary*; D002364:Caseins / Q000235:genetics; D002454:Cell Differentiation; D002465:Cell Movement; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009368:Neoplasm Transplantation; D010641:Phenotype; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D017154:Stromal Cells / Q000473:pathology; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D002364:Caseins; D008164:Luminescent Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; D013937:Thymidine Kinase