In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment.
The organization of cellular niches is known to have a key role in regulating normal stem cell differentiation and regeneration, but relatively little is known about the architecture of microenvironments that support malignant metastasis. Using dynamic in vivo confocal imaging, here we show that murine bone marrow contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant stromal-cell-derived factor 1 (SDF-1) in discrete, discontinuous areas that influence the homing of a variety of tumour cell lines. Disruption of the interactions between SDF-1 and its receptor CXCR4 inhibits the homing of Nalm-6 cells (an acute lymphoblastic leukaemia cell line) to these vessels. Further studies revealed that circulating leukaemic cells can engraft around these vessels, suggesting that this molecularly distinct vasculature demarcates a microenvironment for early metastatic tumour spread in bone marrow. Finally, purified haematopoietic stem/progenitor cells and lymphocytes also localize to the same microdomains, indicating that this vasculature might also function in benign states to demarcate specific portals for the entry of cells into the marrow space. Specialized vascular structures therefore appear to delineate a microenvironment with unique physiology that can be exploited by circulating malignant cells.
Sipkins
Dorothy A
DA
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, Massachusetts 02114, USA. dsipkins1@partners.org
Wei
Xunbin
X
Wu
Juwell W
JW
Runnels
Judith M
JM
Côté
Daniel
D
Means
Terry K
TK
Luster
Andrew D
AD
Scadden
David T
DT
Lin
Charles P
CP
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D018613:Microscopy, Confocal / Q000379:methods*; D009369:Neoplasms / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D012886:Skull / Q000166:cytology
D016207:Cytokines; D019040:E-Selectin; D019718:Receptors, CXCR4