title: Epithelial-mesenchymal plasticity is a decisive feature for the metastatic outgrowth of disseminated WAP-T mouse mammary carcinoma cells.
abstract: BACKGROUND
  Experimental analysis of the metastatic cascade requires suitable model systems which allow tracing of disseminated tumor cells and the identification of factors leading to metastatic outgrowth in distant organs. Such models, especially models using immune-competent mice, are rather scarce. We here analyze tumor cell dissemination and metastasis in an immune-competent transplantable mouse mammary tumor model, based on the SV40 transgenic WAP-T mouse mammary carcinoma model.
  
  
  METHODS
  We orthotopically transplanted into immune-competent WAP-T mice two tumor cell lines (H8N8, moderately metastatic, and G-2, non-metastatic), developed from primary WAP-T tumors. G-2 and H8N8 cells exhibit stem cell characteristics, form homeostatic, heterotypic tumor cell systems in vitro, and closely mimic endogenous primary tumors after orthotopic transplantation into syngeneic, immune-competent WAP-T mice. Tumor cell transgene-specific PCR allows monitoring of tumor cell dissemination into distinct organs, and immunohistochemistry for SV40 T-antigen tracing of single disseminated tumor cells (DTC).
  
  
  RESULTS
  While only H8N8 cell-derived tumors developed metastases, tumors induced with both cell lines disseminated into a variety of organs with similar efficiency and similar organ distribution. H8N8 metastases arose only in lungs, indicating that organ-specific metastatic outgrowth depends on the ability of DTC to re-establish a tumor cell system rather than on invasion per se. Resection of small tumors (0.5 cm(3)) prevented metastasis of H8N8-derived tumors, most likely due to the rather short half-life of DTC, and thus to shorter exposure of the mice to DTC. In experimental metastasis by tail vein injection, G-2 and H8N8 cells both were able to form lung metastases with similar efficiency. However, after injection of sorted "mesenchymal" and "epithelial" G-2 cell subpopulations, only the "epithelial" subpopulation formed lung metastases.
  
  
  CONCLUSIONS
  We demonstrate the utility of our mouse model to analyze factors influencing tumor cell dissemination and metastasis. We suggest that the different metastatic capacity of G-2 and H8N8 cells is due to their different degrees of epithelial-mesenchymal plasticity (EMP), and thus the ability of the respective disseminated cells to revert from a "mesenchymal" to an "epithelial" differentiation state.
authors.affiliation: Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), D-20246, Hamburg, Germany. c.maenz@uke.de.|Department of Tumor Virology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, D-20251, Hamburg, Germany. c.maenz@uke.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Maenz
authors.affiliation: Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), D-20246, Hamburg, Germany. e.lenfert@uke.de.|Department of Tumor Virology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, D-20251, Hamburg, Germany. e.lenfert@uke.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Lenfert
authors.affiliation: Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), D-20246, Hamburg, Germany. pantel@uke.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.affiliation: Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf (UKE), D-20246, Hamburg, Germany. u.schumacher@uke.de.
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.affiliation: Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), D-20246, Hamburg, Germany. w.deppert@uke.de.|Department of Tumor Virology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, D-20251, Hamburg, Germany. w.deppert@uke.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Deppert
authors.affiliation: Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), D-20246, Hamburg, Germany. fwegwit@uni-goettingen.de.|Department of Tumor Virology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, D-20251, Hamburg, Germany. fwegwit@uni-goettingen.de.|Department of Translational Cancer Research, University Medical Center Göttingen, D-37075, Göttingen, Germany. fwegwit@uni-goettingen.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegwitz
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D014408:Biomarkers, Tumor