1. The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis.
- Author
-
Xue C, Plieth D, Venkov C, Xu C, and Neilson EG
- Subjects
- Adoptive Transfer, Alleles, Animals, Calcium-Binding Proteins genetics, Caseins genetics, Cell Differentiation, Cell Movement, Female, Genes, Reporter, Green Fluorescent Proteins, Luminescent Proteins genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Neoplasm Transplantation, Phenotype, S100 Calcium-Binding Protein A4, S100 Proteins, Stromal Cells pathology, Thymidine Kinase biosynthesis, Thymidine Kinase genetics, Tumor Suppressor Protein p53 metabolism, Calcium-Binding Proteins physiology, Carcinoma secondary, Epithelial Cells physiology, Fibroblasts pathology, Gene Expression Regulation, Neoplastic, Lung Neoplasms secondary, Mammary Neoplasms, Experimental pathology, Mesoderm physiology, Neoplasm Metastasis physiopathology
- 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.
- Published
- 2003