Remodeling of endogenous mammary epithelium by breast cancer stem cells.
Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC.
Molecular Imaging Program @Stanford, Department of Radiology, Division of Nuclear Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Natesh
N
Parashurama
Neethan A
NA
Lobo
Ken
K
Ito
Adriane R
AR
Mosley
Frezghi G
FG
Habte
Maider
M
Zabala
Bryan R
BR
Smith
Jessica
J
Lam
Irving L
IL
Weissman
Michael F
MF
Clarke
Sanjiv S
SS
Gambhir
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D004848:Epithelium / Q000648:ultrastructure; D005260:Female; D005456:Fluorescent Dyes; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D057054:Molecular Imaging; D014411:Neoplastic Stem Cells / Q000637:transplantation / Q000648:ultrastructure*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D051155:Wnt1 Protein / Q000378:metabolism
D005456:Fluorescent Dyes; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D049452:Green Fluorescent Proteins