Extensive vascularization of the skeletal tissue suggests th

Extensive vascularization of the skeletal tissue suggests the importance of blood vessels in regulating its physiological functions. Endothelium, the innermost cellular layer of blood vessels forms a central component of the bone marrow vascular microenvironment [7]. Recent evidence support that a pivotal role is played by the vascular niche during the early stages of bone metastasis [5]. During the later stages of the disease, blood vessels enhance the metastatic outgrowth by mediating the delivery of oxygen, nutrients and growth factors. This implies that altering the vascular microenvironment of DTCs during the early stages of metastasis can lead to the elimination of DTCs; thereby preventing the relapse, while targeting the vasculature at the later stages can slow down the metastatic growth. This review highlights the significance of vascular niches during skeletal metastases and discusses the potential therapeutic interventions for targeting the vascular niche.
Properties of the bone vasculature Organ specificity of the vasculature and heterogeneity among vascular beds has been suggested to guide the differential extravasation of tumour catalase inhibitor to various organs. Therefore, understanding the morphological, cellular, molecular and functional properties of the bone vasculature is critical for deciphering the role of the vascular niche during skeletal metastases [8]. Like vascular beds in other organs, endothelial cells in the skeletal system are also organized as a widespread hierarchical network of blood vessels that perform multiple functions. Apart from being a transport network, blood vessels in the skeletal system provide inductive signals to regulate skeletal development, homeostasis and remodeling [7]. Emerging studies reveal that the vasculature of the skeletal system plays crucial roles in osteogenesis (bone formation) and haematopoiesis through direct cellular interactions and paracrine (angiocrine) signalling pathways [9–11]. Haematopoietic Stem Cells (HSCs) are frequently detected within vascular microenvironments, which involve different vessel subtypes comprising of both endothelial and perivascular cells. Specific vascular microenvironments are required to support HSC homing, self-renewal and quiescence [10]. The skeletal vascular microenvironment is thus often denoted as the “bone-marrow vascular niche”. Consequently, there has been a tremendous interest in understanding the structural and functional properties of the skeletal endothelium. However, the progress has been hampered by the lack of understanding of the precise organization of the vasculature. Bone vasculature is vaguely defined as a network of sinusoids and arterioles. The discontinuous and fenestrated sinusoidal endothelium constitutes the predominant vascular surface in the skeletal system [12]. We have recently unravelled the fundamental aspects of the basic hierarchical organization of bone arteries, capillaries and veins. We found that the molecular signature, metabolic activity and functional properties vary between metaphysis and diaphysis blood vessels. In addition, we have identified and characterized a distinct capillary and endothelial cell subpopulations, one of which (termed type H) plays critical roles in the regulation of osteoprogenitor cells and thereby bone formation [9,11]. Different vessel subtypes have distinct functional roles in the vertebrate skeletal system. Veins drain the sinusoids and type H capillaries, while arteries deliver oxygen-rich blood and terminate into the type H capillaries. Columnar type H capillaries oriented towards the growth plate are characterized by high expression of markers CD31 and Endomucin and are physically connected to distal arterioles in the metaphysis and endosteum of long bone (Fig. 1). Type H capillaries are surrounded by bone-forming osteoprogenitor cells and release pro-osteogenic growth factors. In contrast, type L (CD31lo Endomucinlo) blood vessels, which correspond to the highly branched network of sinusoidal endothelium of the bone marrow cavity, are not directly connected to arterioles and lack association with bone forming osteoprogenitor cells [9,11]. Such unique properties of the bone vasculature combined with its heterogeneous nature and expression of growth factors suggest the existence of distinct microenvironments in bone which may support the early events during skeletal metastasis and can also accelerate disease progression in the late stage.