br Dissemination permissive characteristics of the BM
Dissemination-permissive characteristics of the BM vascular niche Sinusoids (type L capillaries) are the most abundant blood vessels in bone and widely distributed throughout the bone marrow cavity . Sinusoids in bone are discontinuous single layer of endothelial daunorubicin devoid of pericytes. Due to the absence of a consistent vessel wall and low level expression of tight junction molecules, sinusoidal endothelium is highly permeable in nature . Additionally, the sinusoidal wall is specialized to facilitate easy two-way trafficking of hematopoietic cells . These characteristics of bone sinusoids are known to expedite invasion, extravasation and docking of circulating tumour cells within the bone marrow (Fig. 2A). In comparison to other capillary beds, sinusoidal vessels have exceptionally large diameter . As a result of the large diameter and voluminous nature of these sinusoidal vessels, blood flow within bone is reduced dramatically. This leads to trapping and arrest of circulating tumour cells in the skeletal system [5,13]. Furthermore, the expression profile of the skeletal vasculature is largely different as compared to blood vessels in other tissues. Of note, the vasculature in bone expresses and secretes high levels of CXCL12 (stromal cell-derived factor-1 (SDF-1)), a member of the CXC family of chemokines, which is known to play a key role in homing and retention of HSCs in the bone marrow microenvironment . High levels of these ligands might draw the circulating tumour cells expressing its receptor, CXCR4 to the bone (Fig. 2A). Therefore, circulating tumour cells commandeer HSC homing pathways to land and establish their footholds within the foreign bone marrow microenvironment. Other players in HSC homing pathways are also predicted to be hijacked by DTCs to facilitate their landing in bone such as matrix molecules like integrin family members, and adhesion molecules like E-selectin and Robo4 . Thus, the morphological, structural, adhesive and paracrine/angiocrine properties of the skeletal vasculature appear to direct the dissemination of cancer cells to bone.
Dormancy-conducive characteristics of the BM vascular niche Cancer cells ingression into the bone vasculature and their admission within the marrow cavity does not guarantee their retention and subsequent colonization in bone. Even though many cancer cells circulate through bone and succeed in entering the bone marrow cavity, only a few persist for metastatic colonization. Subsequent to their successful landing, cancer cells rarely proliferate instantly (Fig. 2B). These DTCs now exposed to the unfamiliar bone microenvironment, survive in the so-called dormant (quiescent/growth-arrested) state for long time period. Recent studies suggest that signals and pathways governing HSC quiescence are also involved in maintaining the dormancy of cancer cells in bone [14,15]. Quiescent HSCs have been found in close proximity to the vasculature and vascular niches are crucial for maintaining HSCs in a quiescent state . Likewise it is possible that specific vascular niches regulate the dormancy of cancer cells in bone. In line with this notion, Ghajar et al. identified that dormant cancer cells in bone are localized in close proximity to the stable vasculature . To gain mechanistic insight into this endothelial and cancer cell interactions authors generated in vitro 3D cultures with human umbilical vein endothelial cells and bone marrow-derived mesenchymal cells. Cancer cells cultured on this organotypic microvasculature exhibited reduced proliferation and growth. Further analysis of the endothelial extracellular matrix revealed up-regulation of thrombospondin-1 (TSP-1), which was secreted by endothelial cells, as a suppressor of cancer cell growth. Antibody driven blocking of TSP-1 to impede cancer cell interaction with endothelium resulted in increased proliferation and growth of cancer cells. This interesting study provides crucial mechanistic insights into the regulation of cancer cell dormancy . Since the study relied on findings from the in vitro 3D co-culture system, further research is needed to delineate and understand the in vivo situation. Another example of angiocrine factors regulating cancer cell dormancy in bone is the chemokine CXCL12. A critical component of the HSC niche, CXCL12 expressed by the bone vasculature may regulate the dormancy of DTCs in bone . Further, stromal cells in bone also contribute to the dormancy of tumour cells by secreting microRNAs (miRs) that target CXCL12 expression. These anti-CXCL12 miRs transported from stromal cells to breast tumour cells induce cell cycle arrest . However, it remains unstudied whether endothelial cells also express these miRs. Similarly, other known regulators of HSC quiescence in the bone marrow such as growth arrest-specific protein 6 (GAS6), transforming growth factor-β2 (TGFβ2), bone morphogenetic protein 4 (BMP4), BMP7 also induce dormancy of DTCs . Interestingly, morphogenetic cues like BMPs and TGFβ family members that induce dormancy in DTCs are expressed by the bone vasculature. Overall, above studies emphasize the importance of bone endothelial cells in supporting the dormancy of DTCs (Fig. 2B), though the detailed identity of functional vascular niches for DTCs remains anonymous.