In vivo imaging of specialized bone marrow endothelial microdomains for tumor engraftment

摘要

The organization of cellular niches has been shown to play a key role in regulating normal stem cell differentiation and regeneration, yet relatively little is known about the architecture of microenvironments that support malignant metastasis.^, Using dynamic in vivo confocal imaging, we show that the murine bone marrow (BM) contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant SDF-1 in discrete, discontinuous areas that localize the homing of a variety of tumor cell lines. Disruption of SDF-1/CXCR4 interactions inhibits Nalm-6 cell (acute lymphoblastic leukaemia) homing to these vessels. Further studies revealed that circulating leukemic cells engraft surrounding these vessels, suggesting that this molecularly distinct vasculature denotes a microenvironment for early metastatic tumor spread in BM. Finally, purified hematopoietic stem/progenitor cells and lymphocytes also localize to the same microdomains, indicating that this vasculature may function in benign states to demarcate specific portals for entry of cells into the marrow space. Specialized vascular structures therefore appear to delineate a microenvironment with unique physiology that is exploited by circulating malignant cells.