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

Abstract

The power of the latest microscopy techniques is demonstrated in a study of the vascular microenvironment in the bone marrow of mice. Confocal microscopy optimized for live animal imaging reveals that the tissue divides into discrete areas marked out by specialized endothelium. Molecules expressed in these domains mediate highly localized homing of the stem progenitor cells and lymphocytes needed for normal function of the bone marrow. But cancer cells — from an acute lymphoblastic leukaemia cell line, for instance — can also follow the trail to a welcoming microdomian. The vascular structures that create these inner spaces might therefore be potential targets for drugs designed to treat metastatic cancers. 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 metastasis1,2. 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.