title: Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers.
abstract: BACKGROUND
  It is still uncertain whether metastasis is predominantly an early or late event in tumor progression. The detection of early metastases and cells responsible for the dissemination may therefore have significant clinical implications.
  
  
  METHODS
  Lung dissemination and/or metastasis were investigated in mice carrying the polyomavirus middle-T oncogene (PyMT) during different stages of mammary tumorigenesis using the colony forming assay. Immunocytochemical or immunohistochemical staining was used to identify subpopulations of cells responsible for lung dissemination and metastasis. Histological examination was used to show primary and metastatic tumors. The tumor-initiating and metastatic capacity of cells expressing stem cell markers was assessed in syngeneic wild-type (WT) mice whose mammary fat pads were injected with these cells.
  
  
  RESULTS
  Metastatic mammary epithelial cells were detected in the lungs of mice carrying the PyMT oncogene (MMT mice). These cells were observed early in breast tumorigenesis when the mammary tree appeared by histological inspection to be normal (or at a premalignant stage), suggesting the possession of disseminating and metastatic capacity even before full malignant transformation. Some of the disseminated cells and lung metastases displayed surface stem cell markers. These findings suggest that stem cells from apparently precancerous primary lesions could be a source of metastasis. Indeed, injection of lung tissue cells from MMT mice into syngeneic WT mice resulted in the formation of mammary tumors. These tumors resembled their parent mammary tumors in the MMT donors as well as grafted tumors derived from mammary tumor cells. Furthermore, when we injected lung tissue cells from GFP MMT mice into the fat pads of recipient WT mice, disseminated or metastatic GFP-expressing cells were detected in the lungs, lymph nodes and blood of the recipient WT mice. We finally identified a subpopulation of mammary epithelial/tumor cells expressing CD44 and Sca1 that was largely responsible for dissemination and metastasis in MMT mice.
  
  
  CONCLUSIONS
  The tumorigenic and metastatic potential of a subpopulation of mammary epithelial/tumor cells in MMT mice is endowed relatively early in mammary neoplasms and suggests a potential role for cancer stem cell sub-populations in metastasis.
authors.affiliation: Department of Medicine, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118, USA. jgong@bu.edu
authors.forename: Desheng
authors.initials: D
authors.lastname: Weng
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Penzner
authors.forename: Baizheng
authors.initials: B
authors.lastname: Song
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koido
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Calderwood
authors.forename: Jianlin
authors.initials: J
authors.lastname: Gong
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism / Q000556:secondary*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D018960:Hyaluronan Receptors / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000950:Antigens, Ly; D000952:Antigens, Polyomavirus Transforming; D014408:Biomarkers, Tumor; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D018396:Mucin-1; C577056:muc1 protein, mouse; D049452:Green Fluorescent Proteins