Exploiting bone niches: progression of disseminated tumor cells to metastasis

Many solid cancers metastasize to the bone and bone marrow (BM). This process may occur even before the diagnosis of primary tumors, as evidenced by the discovery of disseminated tumor cells (DTCs) in patients without occult malignancies. The cellular fates and metastatic progression of DTCs are determined by complicated interactions between cancer cells and BM niches. Not surprisingly, these niches also play important roles in normal biology, including homeostasis and turnover of skeletal and hematopoiesis systems. In this Review, we summarize recent findings on functions of BM niches in bone metastasis (BoMet), particularly during the early stage of colonization. In light of the rich knowledge of hematopoiesis and osteogenesis, we highlight how DTCs may progress into overt BoMet by taking advantage of niche cells and their activities in tissue turnover, especially those related to immunomodulation and bone repair.

Bone is a remarkable organ that plays complex physiological roles, such as providing structural support and facilitating hematopoiesis (25–27). The unique bones of the body are diverse in size and shape, with differing amounts of cortical bone (compact and dense) as well as trabecular (or spongy) bone. Bone is maintained by cells of the osteoblast and osteoclast lineages (28, 29). Mesenchymal stem cells develop into preosteoblasts, then mature osteoblasts (30, 31). These cells produce both the mineralized portion of bone, hydroxylapatite, and organic components: collagen, osteocalcin, and osteopontin (32). Mature osteoblasts line the mineral surface within the bone (33). The osteoid, or organic, components are deposited first; as the tissue becomes mineralized and new bone is formed, osteoblasts become trapped within and further transform into osteocytes (34, 35). The osteocytes form long membrane protrusions that connect to each other through thin channels called canaliculi (36), communicating through gap junction channels at their tips (37). Osteoclasts, responsible for breaking down the mineralized bone tissue, develop from the monocyte/macrophage lineage upon stimulation by NF-κB/RANKL as well as macrophage colony-stimulating factor (38, 39). Osteoclasts are large, multinucleated cells that become strongly polarized toward the bone surface for resorption, and their ruffled cell edges attach to bone (40). Bone resorption is accomplished by secretion of proteases to dismantle organic bone components and protons to break down inorganic mineral (41).

Hematopoietic stem cells (HSCs) originate during embryogenesis (42, 43), expand in fetal tissues (44), and ultimately home to the BM (45), where they maintain lifelong hematopoiesis. Instead of randomly distributing in the BM, HSCs reside in specialized BM niches. Two types of BM niches harbor HSCs and tightly regulate their fates: the perivascular niche and the endosteal niche (46). The perivascular niche is subdivided into a sinusoidal and an arteriolar portion. The majority of SLAM family markers that label HSCs (Lin^–, CD48⁻, CD41⁻, CD150⁺) are localized in the sinusoidal perivascular niche (47, 48), which comprises endothelial cells and adjacent perivascular stromal cells, including leptin receptor–expressing (LEPR-expressing) cells (49, 50), nestin-expressing cells (50, 51), and CXCL12-abundant reticular cells (52). On the other hand, a small fraction of HSCs are found adjacent to the arteriolar perivascular niche (53, 54), where they come into close contact with LEPR⁺ perivascular cells, non-myelinating Schwann cells (55), and NG2-expressing stromal cells. These perivascular cells secrete important cytokines such as CXCL12 (also known as SDF-1), stem cell factor (SCF), and TGF-β (55), which make distinct contributions to HSC maintenance (50). Although active HSCs are localized to the perivascular niche, some studies showed that quiescent HSCs mainly reside in the endosteal niche with arterioles (47, 56–58), which is composed mainly of osteogenic cells. HSCs may depart from one niche and enter another niche in response to specific signals (53, 59, 60). Interestingly, some studies suggested that HSCs prefer to engraft at the endosteal region after transplantation (61, 62). Although the perivascular niche and the endosteal niche are cellularly distinct niches and may harbor distinct subpopulations of HSCs, a part of these two niches may be spatially close to each other in the endosteum region, since blood vessels are also rich near the bone. However, a cross section of the tibia shows that HSCs are modestly enriched in the central BM and reduced toward the endosteum in the diaphysis (48). Interestingly, evidence reveals that type H endosteal vessels can regulate osteoprogenitors, thereby coupling angiogenesis to bone development, indicating complex crosstalk among BM niche cells (63, 64).

In addition to the endosteal niche and perivascular niche, other studies also revealed that megakaryocytes, a terminally differentiated hematopoietic cell, serve as a niche component that directly or indirectly regulates HSC fate (65–68). Megakaryocytes predominantly occupy the sinusoidal perivascular niche and contribute to maintaining HSC quiescence by producing CXCL4 and TGF-β (69).

The cellular fates of HSCs, namely dormancy, self-renewal, and differentiation, are regulated by microenvironmental signals emitted from specific niches. During homeostasis, niche signals keep a proportion of HSCs dormant to preserve their long-term self-renewal capacity (57, 58, 70), while other homeostatic HSCs are activated to drive normal hematopoiesis. The current model of hematopoiesis states that the differentiation of HSCs follows a strict hierarchy (71). Long-term reconstituting HSCs possess multilineage differentiation potential and differentiate into short-term reconstituting HSCs (ST-HSCs), which exhibit more-limited self-renewal potential. ST-HSCs further generate multipotent progenitors (MPPs) with distinct differentiation potential. These MPPs rapidly divide into oligopotent progenitors, including common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs). CMPs then produce granulocyte-monocyte progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs), and dendritic cell (DC) progenitors. These oligopotent progenitors advance to their lineage-restricted precursors and ultimately give rise to all terminally differentiated blood cells. Specifically, MEPs differentiate into erythrocytes and platelet-producing megakaryocytes. GMPs generate neutrophils, basophils, eosinophils, and monocytes (which can further differentiate into macrophages in the BM and peripheral tissues). CLPs are precursors of DCs, B cells, T cells, and NK cells. However, HSCs may also be heterogeneous and can be organized into a cellular hierarchy with distinct cell differentiation routes, some of which may skip intermediate steps. For instance, the platelet-producing megakaryocytes can skip the intermediate oligopotent progenitors and directly generate from megakaryocyte-primed HSCs (72, 73).

Taken together, all the above-mentioned skeletal and hematopoietic cells constitute an intricate environment for metastatic cancer cells. It should be noted that these cells are not static but are rather highly dynamic in proliferation, differentiation, and relocation. How these dynamics impact seeding and colonization of DTCs remains elusive.

With the above in mind, we will review the roles of various bone-resident cells throughout the metastatic colonization process. Since a large proportion of literature in this area is based on breast cancer (BCa) models, we will focus on this cancer type, and summarize prominent features of other cancer types in separate sections.

The pre-metastatic niches. The impact of BCa on the BM niches starts even before DTCs arrive in the bone, a notion known as the “pre-metastatic niche.” There, BM-derived hematopoietic cells were shown to “prepare the soil” for subsequent metastatic seeding, and subsequent studies supported this finding (74), including some suggesting that the pre-metastatic niche’s impact on metastasis can be bidirectional (75, 76). Although BM-derived cells play major roles in modeling the pre-metastatic niche in other organs, the effects of primary tumors on BM itself were not studied until recently. Cox et al. showed that xenograft mammary tumors secreted lysyl oxidase (LOX), which generates systemic effects and activates osteoclastogenesis, thereby priming the formation of osteolytic lesions once cancer cells have seeded (77). Hoshino et al. reported that the metastatic site can receive exosomes derived from primary tumors, which facilitate subsequent colonization in an organ-specific fashion (78). Although bone-tropic exosomes were not identified in this study, lung-tropic exosomes diverted metastatic seeding of bone-targeting cancer cells from bone to lungs, supporting the notion that exosomes help determine organotropism of metastasis through effects on the pre-metastatic niche. Lung cancers also crosstalk with bone before metastasis occurs. While the presence of tumors increases bone mass, osteoblasts return the favor by supplying a specific subset of neutrophils that promote tumor progression (79). Taken together, it has become increasingly clear that BM niches already begin to change under the influence of primary tumors before metastasis occurs. Further studies are needed to characterize these changes thoroughly to determine their functional impact on subsequent metastatic seeding and colonization.

The perivascular niche. When DTCs arrive via the bloodstream to the bone, they extravasate by interacting with the endothelium, which is particularly permeable in the BM (80) (Figure 1). Here, the cells reside in the perivascular niche (81, 82), which harbors HSCs as described above. This location also contains various immune cells and pericytes that possess activities of mesenchymal stem cells (MSCs) (83–85). There is some debate as to whether MSCs and pericytes are distinct cell types (86); nevertheless, these endothelium-adjacent cells have significant impact on DTCs when they arrive. Multiple signaling pathways may mediate the interactions of cancer cells with the perivascular niche and determine their fate accordingly. For example, the balance between the adhesion molecule E-selectin and CXCL12 may be critical for DTCs to remain in the perivascular niche (82), whereas the counteracting forces between thrombospondin-1 (TSP1) and TGF-β/periostin determine quiescence versus proliferation fate (81). Furthermore, vascular E-selectin may also trigger mesenchymal-to-epithelial transition and the acquisition of stemness traits, thereby fueling further progression (87). Interactions with the perivascular niche also render cancer cells resistant to chemotherapies (88). Overall, it is intriguing to note that the perivascular niche is a common site for DTCs and HSCs, both of which may alternate between quiescence and proliferation states. Interestingly, the perivascular region has the highest degree of hypoxia in the bone, an already hypoxic organ in general (89). Hypoxia plays both direct and indirect roles in the promotion of metastatic progression and is expounded upon in further reading (90, 91). Given the BM’s complicated and heterogeneous vascular network, further work will be needed to compare the exact DTC and HSC distribution and the molecular compositions in the corresponding niches.

Figure 1

Disseminated tumor cells utilize bone marrow niches to survive and colonize. Disseminated tumor cells (DTCs) occupy many niches in the bone after they arrive in the organ via the bloodstream. When cells first extravasate from the vessels, they may reside in the perivascular niche. DTCs occupy and compete with the HSC niche through recruitment by CXCR4/CXCL12 signaling to the perivascular niche. Several signaling pathways and molecules govern the dormancy/proliferation fate of cancer cells in this niche, including pericyte-derived thrombospondin-1 (TSP1). Cancer cells can also interact with cells of the osteoblast lineage, namely mesenchymal stem cells, preosteoblasts, and osteoblasts, which constitute the osteogenic niche. Here they use heterotypic cellular junctions as well as Jagged-1–mediated Notch signaling to crosstalk with the niche. Gap junctions formed between the cancer cells and osteogenic cells facilitate calcium transfer into the cancer cells. These interactions collectively promote DTC proliferation and chemoresistance. Osteoclastogenesis may be activated by multiple mechanisms, which leads to a feed-forward loop known as the vicious cycle. In this cycle, tumor cells produce both pro-osteoblastic and pro-osteolytic factors, stimulating both osteoblasts and osteoclast activity. The destruction of the bone releases embedded growth factors that act on tumor cells, further stimulating their growth. HSC, hematopoietic stem cell; LOX, lysyl oxidase; MSC, mesenchymal stem cell; PTHrP, parathyroid hormone–related protein.

The osteogenic/endosteal niche. The endosteal niche is located, as the name suggests, adjacent to the endosteum, or the lining of the BM cavity in adult bone. This niche is composed of osteoclasts, osteoblasts (and their progenitors), and fibroblasts in multiple stages of development (92) (Figure 1). As described above, the endosteal niche also plays an important role in harboring and sustaining HSCs. HSC-DTC competition for the endosteal niche was first reported in 2011 (93), thereby connecting the distinct fields of metastasis and hematopoiesis. Subsequently, an overlapping osteogenic niche has been described that promotes proliferation and early-stage bone colonization of BCa DTCs (94–96). In the osteogenic niche, luminal BCa DTCs form heterotypic adherens junctions with MSCs and preosteoblast and osteoblast cells, with E-cadherin on the cancer cell side and N-cadherin on the mesenchymal cell side (96). In fact, as the niche develops and the lesion progresses, the DTCs become completely surrounded by the osteoblast-lineage cells. These junctions facilitate Notch signaling, which in turn renders metastasis resistant to chemotherapies (97). The junctions also lead to the formation of functional gap junctions between the cells through which cancer cells receive a calcium flux from osteogenic cells (95). The tumor cells are inefficient at absorbing calcium from the matrix and therefore depend on osteogenic cells in the niche (95). The DTCs receive a growth advantage in the form of mTOR signaling activation in this niche and are able to progress from single cells to multicellular lesions (96). Perturbation of cadherins, gap junctions, or mTOR signaling decreases luminal cell colonization. Importantly, bone histomorphometry revealed active osteogenesis within the niche (96), suggesting ongoing tissue hemostasis.

The perivascular and osteogenic niches are not completely separated. Some niche components are linked by lineage. For instance, a subset of pericytes have MSC activities and can differentiate into osteoprogenitor cells (83), raising the possibility of conversion from the perivascular niche into the osteogenic niche. In fact, a specific subtype of vessels has been shown to couple angiogenesis and osteogenesis in the BM (63). These vessels, termed type H, express endomucin and CD31, often localize to the growth plate and endosteum, and are closely associated with osteogenic cells and promote their progression via Noggin secretion (63, 64). Interestingly, in prostate cancer, endothelial cells can transdifferentiate into osteoblasts, thereby facilitating the formation of osteoblastic lesions (98). Bone turnover and remodeling may change the dynamics of both niches and strengthen their crosstalk. Therefore, it is possible that DTCs may affect their neighborhoods and alter their cellular fates accordingly. This will be elaborated in a subsequent section.

The vicious cycle. While DTCs and bone micrometastases predominantly interact with perivascular and osteogenic niches where the roles of osteoclasts are limited, the advanced pathogenic bone metastases are often characterized by a feed-forward loop of bone cells and osteoclasts. This feed-forward loop has been described as the “vicious cycle” (3, 99–101) (Figure 1). Tumor cells can secrete parathyroid hormone–related protein (PTHrP) to stimulate osteoblasts, which in turn produce osteolytic factors such as IL-11 and RANKL and promote osteoclast proliferation and activation (102, 103). The resultant increase in osteolytic activity causes lesions to form in the mineralized bone tissue, releasing factors that have been sequestered in the bone, including tumor cell–stimulating growth factors such as IGFs and TGF-β (104–107), thereby fueling the feed-forward loop.

Recent studies uncovered additional molecular players involved in the feed-forward loop. Jagged-1, a TGF-β target gene in cancer cells, activates Notch signaling in osteoblasts and enhances the expression of IL-6, which consequently stimulates osteoclastogenesis (105). IL-6 can also be generated during senescence of osteoblasts (108). Integrin β₃ represents another TGF-β target gene that is specifically induced in the bone microenvironment and confers proliferative advantages on cancer cells (109). Cancer cells and osteoclasts sometimes depend on the same signaling pathways, such as the RON kinase (110). Taken together, these new findings provide additional therapeutic targets for treatment of advanced osteolytic metastases.

Little is known about the transition from the early niches predominantly composed of endothelial and osteogenic cells to the osteoclast-driven vicious cycle that is a hallmark of advanced bone metastases. One possible mechanism is that the development of the osteogenic niche may alter the secretome of both cancer cells and osteoblasts. Indeed, it was shown that some dormant cancer cells in the BM may recruit osteoclast progenitors by secreting a soluble form of VCAM1, of which integrin α₄β₁ is the cognate receptor (111) (Figure 1).

Prostate cancer. Prostate cancer bone metastases also activate a vicious cycle similar to that seen in BCa that can be both osteoblastic and osteolytic (112, 113). However, these metastases tend to be more osteoblastic in nature, as they express high levels of alkaline phosphatase (ALP) and osteocalcin (114). The increased bone formation is poorly regulated and dysfunctional, often leading to very dense lesions and rigid zones of bone with decreased overall bone strength (115, 116). Endothelin-1, a stimulator of osteoblasts, is overexpressed by prostate cancer cells, and thereby increases osteogenesis, ALP expression, and osteoblastic bone metastases (115, 117, 118). PTHrP produced by the tumor stimulates osteoblasts to produce the osteoclastogenesis-promoting factors MCP-1 and RANKL (119). Paradoxically, PTHrP-expressing tumor foci have areas of both increased osteoblastogenesis and osteclastogenesis adjacent to them in the bone, indicating a more complex role for PTHrP (120, 121). Prostate-specific antigen can also tip the balance toward osteoblastic lesions by cleaving PTHrP (119, 121). To avoid detection and modulate bone homeostasis, prostate cancer cells may use osteomimicry, in which cells undergo osteoblastic-like differentiation, including expression of the osteogenesis markers BMP-2, RUNX2, and others, even to the point of actual mineral deposition (122).

Multiple myeloma and other cancers. Multiple myeloma, a cancer of plasma cells in the BM, can also cause lesions to form in the bone itself (123, 124). Patients can develop myeloma bone disease, when bony lesions cause fractures, pain, and other defects (125). In myeloma bone disease, cancer cells secrete osteoclastogenesis-promoting factors, including RANKL, IL-3, and IL-6 (126, 127), and also interact with BM stromal cells to produce such factors (128). This increased level of osteoclastogenesis is coupled with decreased or halted osteoblastogenesis, which is stimulated by IL-7, secreted frizzled-related protein, and other factors (125, 129). This results in characteristic lytic lesions in the bone that cause pain and fractures, and eventually patients can develop even more severe outcomes such as renal failure and anemia (130). More rarely, kidney, lung, skin, and thyroid cancers can also form osteolytic bone metastases (131).

An often overlooked fact in bone metastasis (BoMet) research is that the bone is a major immunological organ. The hematopoietic niche within the bone is responsible for the production of erythrocytes and leukocytes, which requires a special environment that reduces aberrant immune activation. It was previously shown that the IRF7 pathway could facilitate escape of BoMet from immunosurveillance (132), which represents one of the earliest findings on the immunosuppressive milieu in BoMet. Given the complexity of BM niches, there might be multiple profound mechanisms contributing to the unique immune microenvironment. In this section, we summarize three likely cell types/pathways that may be responsible for immunosuppression: regulatory T cells, immature myeloid cells, and osteoblasts. Together, these mechanisms provide directions for further investigations into the evolving interactions between BoMet and the BM niches from the perspectives of tumor immunology and immunotherapies.

Regulatory T cells. As previously described, hematopoiesis occurs in the BM, leading to the formation of erythrocytes and leukocytes. Leukocytes can be further divided into two populations: myeloid and lymphoid cells. Among leukocytes, T cells are cells that mature in the thymus. Although maturation occurs in the thymus, mature T cell subsets can be found in the bone. A large portion of bone CD4⁺ T cells are regulatory T cells (Tregs) that contribute to immune suppression (133). FoxP3⁺ Tregs suppress the activity of proinflammatory cells, such as CD8⁺ T cells and Th1 CD4⁺ T cells. This immunosuppression occurs via Treg secretion of antiinflammatory cytokines such as IL-10, IL-35, and TGF-β (134, 135) (Figure 2). These cytokines may play a dichotomous role in promoting dormancy of metastatic seeds and increasing tumor cell proliferation.

Figure 2

The immunosuppressive microenvironment in the bone and bone marrow. DTCs residing in the bone marrow niches may produce many immunosuppressive factors that also interfere with cytotoxic CD8⁺ T cells. Among these factors are regulatory T cells (Tregs), immature myeloid cells, and osteoblasts. DTCs occupy and compete with the HSC niche to occupy the immune-privileged environment maintained by Tregs. Tregs secrete immunosuppressive cytokines (IL-10, TGF-β) and traffic to the HSC niche via the chemokine CXCL12. Immature myeloid cells develop in the bone marrow and generate immunosuppressive molecules (iNOS, ROS). Osteoblasts are a major source of the chemokine CXCL12 that attract Tregs and produce lactate as a metabolic by-product. Lactate is utilized by cancer cells as an intermediate in the production of ATP. Lactate has also been shown to inhibit cytotoxic CD8⁺ T cells, while Tregs maintain immunosuppressive function. Taken together, these factors within the bone marrow niches maintain an immune-privileged environment for DTCs to colonize.

The reduction of proinflammatory signaling near the perivascular niche may offer opportunity for dormant cancer cells to evade immune surveillance. As previously stated, bone is a privileged immunological organ that benefits from a reduction in immune activity; therefore, the further reduction of an inherently low baseline of immune activity may create a favorable location for dormant cell immune evasion (136). Additionally, TGF-β production increases the proliferation of metastatic seeds and further perpetuates the vicious cycle of macrometastasis (102, 104). Tregs within the bone have also been shown to affect metastasis through attraction by chemokines. Previous studies showed the importance of CXCL12/CXCR4 signaling both in trafficking of Tregs to the bone and in the attracting of metastatic seeds in prostate cancer and BCa (93, 137). Patients with prostate cancer displayed an increase in the number of Tregs within the bone through an increase in the expansion of Tregs by RANK signaling on DCs (138).

Metabolic effects may also enhance Treg function in the bone microenvironment. Micrometastatic lesions interact with osteoblasts that are found in the endosteum where Tregs localize and may lead to an increase in proliferation to catalyze the formation of the vicious cycle (96). These osteoblasts, as will be discussed in a subsequent section, prefer aerobic glycolysis that results in the accumulation of lactate, thereby creating an environment suitable for Treg function while inhibiting cytolytic T cell function. The presence of Tregs in the HSC niche and adjacent regions of the bone may provide metastatic seeds with an evasive environment for dormancy and proliferation.

Immature myeloid cells. Along with the production of lymphocytes, HSCs give rise to myeloid cell populations including neutrophils, monocytes, and macrophages. However, during development, a group of myeloid cells remains immature and can exert immunosuppressive function. Therefore, this subset of immature myeloid cells is often referred to as myeloid-derived suppressor cells (MDSCs). Immature myeloid cells (IMCs) are among the most abundant immune cell types found within the bone, because they are directly produced within the HSC niche. IMCs are a heterogeneous population of cells containing polymorphonuclear (PMN) and monocytic (M) MDSCs based on their morphology. Functionally, PMN-MDSCs contain higher levels of reactive oxygen species (ROS), while M-MDSCs contain higher levels of nitric oxide (NO) and inducible NO synthase (iNOS/NOS2) (139) (Figure 2). Previous studies have shown that there is an increase in the production of IMCs, including MDSCs, in cancer patients (140). This increase in abundance of immunosuppressive IMCs could further promote metastatic seeding, similar to the effects of Tregs. MDSCs have also been shown to produce TSP1, a factor that promotes dormancy, which may aid the early DTCs in remaining undetected in an immunosuppressive environment (75). The overlap of the metastatic niche with the location of IMC production may allow micrometastatic lesions to skew myeloid cell development down an immunosuppressive path. As explained by the model of immunoediting, cancer cells must evade the initial immune surveillance to progress to a state of immune evasion by recruiting immunosuppressive cells and promoting their development (141). Therefore, outgrowth of these micrometastatic lesions may lead to secretion of many antiinflammatory cytokines along with factors to skew development of HSCs toward myelopoiesis.

Osteoblast metabolism. The endosteal region of the bone undergoes constant remodeling as bone resorption and bone formation occur on the endosteal surface. Osteoblasts are responsible for bone formation and develop from MSCs/osteoprogenitors that differentiate into preosteoblasts (31), all of which play a major role in early-stage bone colonization as previously described in The osteogenic/endosteal niche section above.

The influence of osteoblasts during early-stage metastasis may also involve suppression of the immune system due to aerobic glycolysis, the preferred form of osteoblast metabolism. Under conditions of aerobic glycolysis, osteoblasts convert glucose into lactate in the presence of oxygen (142). This lactate-rich environment has been shown to be beneficial to metastatic seeds, and the inhibition of lactate dehydrogenase (LDH) reduces metastasis (143). Cancer cells have the ability to uptake and metabolize lactate, allowing for proliferative capacity in lactate-rich environments (144, 145). Lactate accumulation has been shown to have an inhibitory effect on cytotoxic CD8⁺ T cells. However, the transcription factor FoxP3 induces oxidative phosphorylation, giving FoxP3⁺ Tregs an advantage over cytotoxic CD8⁺ T cells in high-lactate environments (146) (Figure 2). Therefore, the interaction between osteoblasts and metastatic seeds may not be limited to increased proliferation, but could also aid in the evasion of immune surveillance by providing an environment unsuitable for cytotoxic interactions while preserving immunosuppressive function. Osteoblasts express CXCL12, which allows for the homing of HSCs, Tregs, and metastatic seeds to the endosteum (Figure 2). Recruiting these cell types into an environment rich in lactate may further enhance metastatic targeting to the immune-privileged HSC niche.

In summary, multiple cell types in the bone microenvironment may cooperate to establish an immunosuppressive environment. This environment is evolutionarily conserved due to the need for hematopoiesis, but may coincidentally facilitate the survival of DTCs and micrometastases. Future studies are needed to dissect the molecular mechanisms underlying DTC–immune system crosstalk and to identify actionable targets for therapeutic interventions.

In addition to their unique immune properties, bone and BM are also remarkable in their quick turnover. Bone is remodeled constantly, with old bones removed by osteoclasts and new bones deposited by osteoblasts, resulting in roughly 5%–25% of a total skeleton being replenished every year (147). Hematopoiesis is also a perpetual process generating new blood and immune cells, and 1% of hematopoietic cells are replaced every day. These activities accelerate during tissue repair and may also perturb the seeding and colonization of metastatic seeds. In this section, we summarize knowledge related to bone remodeling and repair and illustrate the potential link to metastasis.

Bone remodeling and repair. Adult bone is continually remodeling to respond to the changing mechanical needs of the body due to aging and environmental perturbations, and to address stress-induced microscopic damages (26, 148, 149). This complex process is regulated by local paracrine and systemic factors, such as calcium and the hormonal regulators PTH, calcitonin, and estrogen (148, 150). Local factors influence bone remodeling by acting on osteoblasts and osteoclasts, including BMPs, TGF-β, and WNTs (151, 152). When bones fracture, the first event that occurs is the formation of a hematoma by clotting blood (153, 154). This is followed by chondrocytes, the cartilage-producing cells of the bone, infiltrating the hematoma and laying down a callus between the broken bone surfaces (154, 155). Osteoblasts and chondrocytes lay down cartilage and hydroxyapatite, respectively, that slowly harden this callus (154, 156). Over the following weeks, both osteoclasts and osteoblasts remove dead bone and debris from the area, and lay down even more new mineral. These osteoblasts are derived from marrow MSCs and migrate into the callus in order to accomplish this repair (157). MSCs respond to chemotactic signals during the callus formation, causing them to migrate toward the sites of repair and undergo osteogenic differentiation (158). Once the callus is totally ossified, it is replaced with trabecular bone, and repair is complete, with new cortical bone forming on the exterior surface (152).

Exploitation of bone homeostasis by cancer cells. DTCs and fully pathogenic metastases may exploit bone homeostasis, remodeling, and repair in a multitude of ways. As noted earlier, DTCs residing in the perivascular niche after extravasation are nearby or in contact with perivascular MSCs and are held in quiescence by these pericytes/NG2⁺ MSCs as well as by endothelial cells (159–162). Therefore, relocation from the perivascular niche may be advantageous for the DTCs to progress to colonization. Fractures and subsequent remodeling stimulate the chemotaxis of MSCs toward the injured or remodeling site, where local factors subsequently promote MSC osteogenesis (158, 163). This process may coincide with migration of DTCs from the perivascular niche, where they are kept dormant, to the osteogenic niche, which supports their proliferation (Figure 3). New evidence suggests that BCa cells can attach to and migrate with osteogenic cells via specialized protrusions, and this collective migration phenomenon may facilitate such a transition (164).

Figure 3

A potential connection between bone repair/remodeling and bone colonization of DTCs. One process that bridges different bone marrow niches is bone repair/remodeling. In this process, MSCs migrate from their perivascular origin to areas of bone repair or turnover. Recent evidence suggests that adhesion and collective migration with osteogenic cells enable DTCs to “ride” MSCs and traffic from the perivascular niche to the osteogenic niche in response to osteogenic signals. This may couple bone homeostasis and metastatic colonization.

Thus, osteogenic activity in bone remodeling or in the soft callus, and later hard callus, stage of repairs is an opportunity for BCa DTCs to encounter and be supported by the osteogenic niche. The same process may also provide access to active osteoclasts and therefore facilitate the transition toward late-stage osteolytic vicious cycle as osteoclasts are recruited to clear the soft callus and resorb the unneeded bone in normal remodeling.

A majority of BoMet treatments are palliative, with limited ability to eradicate the bone lesions entirely (165). However, much progress has been made in recent years. BoMet treatments, like many cancer treatments, can be chemical or radiological in nature. Below, we discuss some of the current BoMet treatments.

Antiresorption therapies. Bisphosphonates are a class of drugs originally developed for the treatment of osteoporosis (166). These drugs are chemically similar to inorganic phosphate and thus have high affinity for the calcium ions in hydroxyapatite (167). As calcium is released during bone resorption, bisphosphonates are especially targeted to areas of high osteoclast activity/bone resorption (168). These drugs act by disrupting the key osteoclast enzymes, farnesyl diphosphate synthases (169), thereby impairing their recruitment and differentiation and promoting osteoclast apoptosis (170). Zoledronic acid is the most potent bisphosphonate and was more recently developed to be more potent than earlier-generation bisphosphonates by modifying side chain functional groups (171, 172). Zoledronic acid improves outcomes compared with palliative maintenance of BoMet, with studies showing significant decreases in skeletal-related events and increased overall survival in BCa patients (173). Interestingly, in postmenopausal women, bisphosphonates exhibit significant efficacy in the adjuvant setting in terms of bone recurrence as well as overall survival (174). This observation cannot be explained by the inhibition of osteoclasts, as the vicious cycle has not started during adjuvant therapies. However, it is consistent with the fact that bisphosphonates reduce bone turnover (175), a potential driving force of DTCs to relocate between BM niches as previously discussed.

More recently, denosumab, a RANKL inhibitor/neutralizing antibody, has also been demonstrated to prevent osteoclast differentiation (176). This activity decreases osteolytic metastases in BCa patients (177). A reduction in skeletal-related events and clinical fracture risk was also seen in prostate cancer patients (178) as well as some other solid cancer types (179).

Radiation. External beam radiation treatments can be problematic for treatment of bone metastases because it is difficult to penetrate the mineralized bone tissue. However, radiation treatment is used in palliative care/bone-pain relief and the prevention of skeletal complications (180, 181). Ionizing beam radiation is able to both kill tumor cells and decrease osteoclast activation, both of which can alleviate metastasis-associated pain (182, 183). Other options include radiopharmaceuticals that produce β or α particles like samarium and radium-223 (Rad-223), respectively (184–187). Samarium and strontium have been used for prostate cancer lesions, again for pain management and palliative care, but survival benefits are minimal (188, 189). However, Rad-223 therapy has been shown to prolong survival and increase quality of life in patients with advanced cancer (184, 190). As radium localizes to the mineralized bone tissue, recent work shows it to be much more effective when the initial cell load is smaller, and a higher proportion of tumor cells are physically closer to the bone surface. These data suggest that Rad-223 treatment may be more effective when given to patients at an earlier stage (191, 192).

Immunotherapy. The use of immunotherapies aims to provide patients with more targeted approaches to treat cancer. Cancer cells or immune cells can express checkpoint inhibitor molecules that inhibit CD8⁺ cytotoxic T cells. A study looking at the effects of immune checkpoint blockade in combination with chemotherapy in triple-negative BCa demonstrated the ability of immune checkpoint blockade to prolong progression-free survival (193). However, in patients with BoMet, this prolonged survival was abrogated. Although this may be due to these patients suffering from additional metastatic burden in other organs, it may also indicate that the BM microenvironment influences patient responses to immunotherapy. TGF-β has been implicated in the effectiveness of immune checkpoint blockade therapy in metastatic urothelial cancer, where a high TGF-β signature resulted in a lower response to immune checkpoint blockade (194). This may have implications in the BM, where TGF-β is produced at various stages of metastasis.

When DTCs arrive in the bone and BM, they encounter a new environment composed of residential cells that are actively maintaining homeostasis of the skeletal and hematopoietic systems. These cells are highly organized and constitute distinctive niches that together fulfill diverse functions. Interactions with different niches may dictate the cellular fates and therapeutic responses of DTCs and microscopic metastases. Cancer cells may exploit the niches’ normal roles, including protection from aberrant immune activation and remodeling/repair of bones, to facilitate metastatic progression. Therefore, identification of the cancer-niche crosstalk pathways, especially those involved in immunosurveillance and tissue repair, may lead to novel mechanistic insights and therapeutic targets.

There are challenges and opportunities in our further investigations of BM niches in metastatic colonization. Bone-resident cells apparently of the same type may actually be heterogeneous with regard to the location, lineage, and functions. This is exemplified by pericytes/MSCs (195, 196) and endothelial cells (197), which may reconcile the seemingly contradictory findings (e.g., refs. 81, 87). Future studies are needed for more precise definition of various niches. To this end, single-cell transcriptomic or proteomic analyses that preserve the spatial information may be highly valuable. It should be noted that fast progress has been made in dissecting and targeting BM niches in blood cancers (198). Systematic comparisons of BM niches between metastatic solid cancers and hematological malignancies will likely provide interesting mechanistic insights. In particular, therapies targeting the niches of the latter may inform future clinical studies of the former.

XHFZ is supported by US Department of Defense grants DAMD W81XWH-16-1-0073 (Era of Hope Scholarship) and DAMD W81XWH-20-1-0375; National Cancer Institute (NCI) grants CA183878, CA251950, CA221946, and CA253553; the Breast Cancer Research Foundation; and McNair Medical Institute.

Address correspondence to: Xiang H.-F. Zhang, Baylor College of Medicine, BCM600, One Baylor Plaza, Houston, Texas 77030, USA. Phone: 713.798.6239; Email: xiangz@bcm.edu.

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2021, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2021;131(6):e143764.https://doi.org/10.1172/JCI143764.

1. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2(8):584–593.
   View this article via: PubMed CrossRef Google Scholar
2. Weilbaecher KN, et al. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11(6):411–425.
   View this article via: PubMed CrossRef Google Scholar
3. Kingsley LA, et al. Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6(10):2609–2617.
   View this article via: PubMed CrossRef Google Scholar
4. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127(4):679–695.
   View this article via: PubMed CrossRef Google Scholar
5. American Cancer Society. Cancer Facts & Figures 2016. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016.html#:~:text=In%202016%2C%20there%20will%20be,cancer%20deaths%20in%20the%20US Accessed January 13, 2021.
6. Suva LJ, et al. Bone metastasis: mechanisms and therapeutic opportunities. Nat Rev Endocrinol. 2011;7(4):208–218.
   View this article via: PubMed CrossRef Google Scholar
7. Ghajar CM. Metastasis prevention by targeting the dormant niche. Nat Rev Cancer. 2015;15(4):238–247.
   View this article via: PubMed CrossRef Google Scholar
8. Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007;7(11):834–846.
   View this article via: PubMed CrossRef Google Scholar
9. Pantel K, et al. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008;8(5):329–340.
   View this article via: PubMed CrossRef Google Scholar
10. Kang Y, Pantel K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell. 2013;23(5):573–581.
    View this article via: PubMed CrossRef Google Scholar
11. Hartkopf AD, et al. Disseminated tumor cells from the bone marrow of patients with nonmetastatic primary breast cancer are predictive of locoregional relapse. Ann Oncol. 2015;26(6):1155–1160.
    View this article via: PubMed CrossRef Google Scholar
12. Sanger N, et al. Disseminated tumor cells in the bone marrow of patients with ductal carcinoma in situ. Int J Cancer. 2011;129(10):2522–2526.
    View this article via: PubMed CrossRef Google Scholar
13. Bidard FC, et al. Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res. 2008;14(11):3306–3311.
    View this article via: PubMed CrossRef Google Scholar
14. Janni W, et al. Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse—a European pooled analysis. Clin Cancer Res. 2011;17(9):2967–2976.
    View this article via: PubMed CrossRef Google Scholar
15. Vashist YK, et al. Disseminated tumor cells in bone marrow and the natural course of resected esophageal cancer. Ann Surg. 2012;255(6):1105–1112.
    View this article via: PubMed CrossRef Google Scholar
16. Hosseini H, et al. Early dissemination seeds metastasis in breast cancer. Nature. 2016;540(7634):552–558.
    View this article via: PubMed CrossRef Google Scholar
17. Harper KL, et al. Mechanism of early dissemination and metastasis in Her2(+) mammary cancer. Nature. 2016;540(7634):588–592.
    View this article via: PubMed CrossRef Google Scholar
18. Zhang XH, et al. Metastasis dormancy in estrogen receptor-positive breast cancer. Clin Cancer Res. 2013;19(23):6389–6397.
    View this article via: PubMed CrossRef Google Scholar
19. Follain G, et al. Fluids and their mechanics in tumour transit: shaping metastasis. Nat Rev Cancer. 2020;20(2):107–124.
    View this article via: PubMed CrossRef Google Scholar
20. Mohme M, et al. Circulating and disseminated tumour cells — mechanisms of immune surveillance and escape. Nat Rev Clin Oncol. 2017;14(3):155–167.
    View this article via: PubMed CrossRef Google Scholar
21. Lo HC, et al. Resistance to natural killer cell immunosurveillance confers a selective advantage to polyclonal metastasis. Nature Cancer. 2020;1(7):709–722.
    View this article via: CrossRef Google Scholar
22. Strilic B, Offermanns S. Intravascular survival and extravasation of tumor cells. Cancer Cell. 2017;32(3):282–293.
    View this article via: PubMed CrossRef Google Scholar
23. Azevedo AS, et al. Metastasis of circulating tumor cells: favorable soil or suitable biomechanics, or both? Cell Adh Migr. 2015;9(5):345–356.
    View this article via: PubMed CrossRef Google Scholar
24. Brizzi MF, et al. Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr Opin Cell Biol. 2012;24(5):645–651.
    View this article via: PubMed CrossRef Google Scholar
25. Florencio-Silva R, et al. Biology of bone tissue: structure, function, and factors that influence bone cells. BioMed Res Int. 2015;2015:421746.
    View this article via: PubMed Google Scholar
26. Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3(suppl 3):S131–S139.
    View this article via: PubMed Google Scholar
27. Ho MSH, et al. The dynamics of adult haematopoiesis in the bone and bone marrow environment. Br J Haematol. 2015;170(4):472–486.
    View this article via: PubMed CrossRef Google Scholar
28. Tanaka Y, et al. Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy. 2005;4(3):325–328.
    View this article via: PubMed CrossRef Google Scholar
29. Rodan GA. Bone homeostasis. Proc Natl Acad Sci U S A. 1998;95(23):13361–13362.
    View this article via: PubMed CrossRef Google Scholar
30. Long F. Building strong bones: molecular regulation of the osteoblast lineage. Nat Rev Mol Cell Biol. 2011;13(1):27–38.
    View this article via: PubMed Google Scholar
31. Rutkovskiy A, et al. Osteoblast differentiation at a glance. Med Sci Monit Basic Res. 2016;22:95–106.
    View this article via: PubMed CrossRef Google Scholar
32. Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2(4):389–406.
    View this article via: PubMed CrossRef Google Scholar
33. Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature. 2003;423(6937):349–355.
    View this article via: PubMed CrossRef Google Scholar
34. Bonewald LF. Osteocytes as dynamic multifunctional cells. Ann N Y Acad Sci. 2007;1116:281–290.
    View this article via: PubMed CrossRef Google Scholar
35. Bonewald LF. The amazing osteocyte. J Bone Miner Res. 2011;26(2):229–238.
    View this article via: PubMed CrossRef Google Scholar
36. Palumbo C, et al. Morphological study of intercellular junctions during osteocyte differentiation. Bone. 1990;11(6):401–406.
    View this article via: PubMed CrossRef Google Scholar
37. Loiselle AE, et al. Gap junction and hemichannel functions in osteocytes. Bone. 2013;54(2):205–212.
    View this article via: PubMed CrossRef Google Scholar
38. Xu F, Teitelbaum SL. Osteoclasts: new insights. Bone Res. 2013;1(11):11–26.
    View this article via: PubMed Google Scholar
39. Udagawa N. The mechanism of osteoclast differentiation from macrophages: possible roles of T lymphocytes in osteoclastogenesis. J Bone Miner Metab. 2003;21(6):337–343.
    View this article via: PubMed CrossRef Google Scholar
40. Charles JF, Aliprantis AO. Osteoclasts: more than ‘bone eaters’. Trends Mol Med. 2014;20(8):449–459.
    View this article via: PubMed CrossRef Google Scholar
41. Suda T, et al. Regulation of osteoclast function. J Bone Miner Res. 1997;12(6):869–879.
    View this article via: PubMed CrossRef Google Scholar
42. Medvinsky A, Dzierzak E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell. 1996;86(6):897–906.
    View this article via: PubMed CrossRef Google Scholar
43. Muller AM, et al. Development of hematopoietic stem cell activity in the mouse embryo. Immunity. 1994;1(4):291–301.
    View this article via: PubMed CrossRef Google Scholar
44. Ema H, Nakauchi H. Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood. 2000;95(7):2284–2288.
    View this article via: PubMed Google Scholar
45. Coskun S, et al. Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells. Cell Rep. 2014;9(2):581–590.
    View this article via: PubMed CrossRef Google Scholar
46. Calvi LM, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425(6960):841–846.
    View this article via: PubMed CrossRef Google Scholar
47. Kiel MJ, et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121(7):1109–1121.
    View this article via: PubMed CrossRef Google Scholar
48. Acar M, et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature. 2015;526(7571):126–130.
    View this article via: PubMed CrossRef Google Scholar
49. Ding L, et al. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481(7382):457–462.
    View this article via: PubMed CrossRef Google Scholar
50. Asada N, et al. Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat Cell Biol. 2017;19(3):214–223.
    View this article via: PubMed CrossRef Google Scholar
51. Mendez-Ferrer S, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829–834.
    View this article via: PubMed CrossRef Google Scholar
52. Sugiyama T, et al. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25(6):977–988.
    View this article via: PubMed CrossRef Google Scholar
53. Kunisaki Y, et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013;502(7473):637–643.
    View this article via: PubMed CrossRef Google Scholar
54. Itkin T, et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature. 2016;532(7599):323–328.
    View this article via: PubMed CrossRef Google Scholar
55. Yamazaki S, et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell. 2011;147(5):1146–1158.
    View this article via: PubMed CrossRef Google Scholar
56. Siclari VA, et al. Mesenchymal progenitors residing close to the bone surface are functionally distinct from those in the central bone marrow. Bone. 2013;53(2):575–586.
    View this article via: PubMed CrossRef Google Scholar
57. Arai F, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149–161.
    View this article via: PubMed CrossRef Google Scholar
58. Yoshihara H, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007;1(6):685–697.
    View this article via: PubMed CrossRef Google Scholar
59. Cancelas JA, et al. Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization. Nat Med. 2005;11(8):886–891.
    View this article via: PubMed CrossRef Google Scholar
60. Wilson A, et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 2004;18(22):2747–2763.
    View this article via: PubMed CrossRef Google Scholar
61. Lam BS, et al. Pharmacologic modulation of the calcium-sensing receptor enhances hematopoietic stem cell lodgment in the adult bone marrow. Blood. 2011;117(4):1167–1175.
    View this article via: PubMed CrossRef Google Scholar
62. Adams GB, et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature. 2006;439(7076):599–603.
    View this article via: PubMed CrossRef Google Scholar
63. Kusumbe AP, et al. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014;507(7492):323–328.
    View this article via: PubMed CrossRef Google Scholar
64. Ramasamy SK, et al. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature. 2014;507(7492):376–380.
    View this article via: PubMed CrossRef Google Scholar
65. Bruns I, et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med. 2014;20(11):1315–1320.
    View this article via: PubMed CrossRef Google Scholar
66. Heazlewood SY, et al. Megakaryocytes co-localise with hemopoietic stem cells and release cytokines that up-regulate stem cell proliferation. Stem Cell Res. 2013;11(2):782–792.
    View this article via: PubMed CrossRef Google Scholar
67. Olson TS, et al. Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning. Blood. 2013;121(26):5238–5249.
    View this article via: PubMed CrossRef Google Scholar
68. Nakamura-Ishizu A, et al. Megakaryocytes are essential for HSC quiescence through the production of thrombopoietin. Biochem Biophys Res Commun. 2014;454(2):353–357.
    View this article via: PubMed CrossRef Google Scholar
69. Zhao M, et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med. 2014;20(11):1321–1326.
    View this article via: PubMed CrossRef Google Scholar
70. Arai F, Suda T. Maintenance of quiescent hematopoietic stem cells in the osteoblastic niche. Ann N Y Acad Sci. 2007;1106:41–53.
    View this article via: PubMed CrossRef Google Scholar
71. Seita J, Weissman IL. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med. 2010;2(6):640–653.
    View this article via: PubMed CrossRef Google Scholar
72. Sanjuan-Pla A, et al. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. Nature. 2013;502(7470):232–236.
    View this article via: PubMed CrossRef Google Scholar
73. Notta F, et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science. 2016;351(6269):aab2116.
    View this article via: PubMed CrossRef Google Scholar
74. Peinado H, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017;17(5):302–317.
    View this article via: PubMed CrossRef Google Scholar
75. Catena R, et al. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov. 2013;3(5):578–589.
    View this article via: PubMed CrossRef Google Scholar
76. Castano Z, et al. IL-1β inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization. Nat Cell Biol. 2018;20(9):1084–1097.
    View this article via: PubMed CrossRef Google Scholar
77. Cox TR, et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature. 2015;522(7554):106–110.
    View this article via: PubMed CrossRef Google Scholar
78. Hoshino A, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–335.
    View this article via: PubMed CrossRef Google Scholar
79. Engblom C, et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF(high) neutrophils. Science. 2017;358(6367):eaal5081.
    View this article via: PubMed CrossRef Google Scholar
80. Inoue S, Osmond DG. Basement membrane of mouse bone marrow sinusoids shows distinctive structure and proteoglycan composition: a high resolution ultrastructural study. Anat Rec. 2001;264(3):294–304.
    View this article via: PubMed CrossRef Google Scholar
81. Ghajar CM, et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013;15(7):807–817.
    View this article via: PubMed CrossRef Google Scholar
82. Price TT, et al. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med. 2016;8(340):340ra73.
    View this article via: PubMed CrossRef Google Scholar
83. Crisan M, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301–313.
    View this article via: PubMed CrossRef Google Scholar
84. Sacchetti B, et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007;131(2):324–336.
    View this article via: PubMed CrossRef Google Scholar
85. da Silva Meirelles L, et al. In search of the in vivo identity of mesenchymal stem cells. Stem Cells. 2008;26(9):2287–2299.
    View this article via: PubMed CrossRef Google Scholar
86. Guimaraes-Camboa N, et al. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell. 2017;20(3):345–359.
    View this article via: PubMed CrossRef Google Scholar
87. Esposito M, et al. Bone vascular niche E-selectin induces mesenchymal-epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat Cell Biol. 2019;21(5):627–639.
    View this article via: PubMed CrossRef Google Scholar
88. Carlson P, et al. Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy. Nat Cell Biol. 2019;21(2):238–250.
    View this article via: PubMed CrossRef Google Scholar
89. Spencer JA, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature. 2014;508(7495):269–273.
    View this article via: PubMed CrossRef Google Scholar
90. Johnson RW, et al. Hypoxia and bone metastatic disease. Curr Osteoporos Rep. 2017;15(4):231–238.
    View this article via: PubMed CrossRef Google Scholar
91. Hiraga T. Hypoxic microenvironment and metastatic bone disease. Int J Mol Sci. 2018;19(11):E3523.
    View this article via: PubMed Google Scholar
92. Haider MT, et al. The endosteal niche in breast cancer bone metastasis. Front Oncol. 2020;10:335.
    View this article via: PubMed Google Scholar
93. Shiozawa Y, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011;121(4):1298–1312.
    View this article via: JCI PubMed CrossRef Google Scholar
94. Wang H, et al. Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies. Nat Commun. 2017;8:15045.
    View this article via: PubMed Google Scholar
95. Wang H, et al. The osteogenic niche is a calcium reservoir of bone micrometastases and confers unexpected therapeutic vulnerability. Cancer Cell. 2018;34(5):823–839.
    View this article via: PubMed CrossRef Google Scholar
96. Wang H, et al. The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell. 2015;27(2):193–210.
    View this article via: PubMed CrossRef Google Scholar
97. Zheng H, et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell. 2017;32(6):731–747.
    View this article via: PubMed CrossRef Google Scholar
98. Lin SC, et al. Endothelial-to-osteoblast conversion generates osteoblastic metastasis of prostate cancer. Dev Cell. 2017;41(5):467–480.
    View this article via: PubMed CrossRef Google Scholar
99. MacKiewicz-Wysocka M, et al. Progress in the treatment of bone metastases in cancer patients. Expert Opin on Investig Drugs. 2012;21(6):785–795.
    View this article via: PubMed CrossRef Google Scholar
100. Waning DL, Guise TA. Molecular mechanisms of bone metastasis and associated muscle weakness. Clin Cancer Res. 2014;20(12):3071–3077.
     View this article via: PubMed Google Scholar
101. Ell B, Kang Y. SnapShot: bone metastasis. Cell. 2012;151(3):690–690.
     View this article via: PubMed CrossRef Google Scholar
102. Yin JJ, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest. 1999;103(2):197–206.
     View this article via: JCI PubMed CrossRef Google Scholar
103. Guise TA, et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest. 1996;98(7):1544–1549.
     View this article via: JCI PubMed CrossRef Google Scholar
104. Kakonen SM, et al. Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J Biol Chem. 2002;277(27):24571–24578.
     View this article via: PubMed CrossRef Google Scholar
105. Sethi N, et al. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell. 2011;19(2):192–205.
     View this article via: PubMed CrossRef Google Scholar
106. Korpal M, et al. Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med. 2009;15(8):960–966.
     View this article via: PubMed CrossRef Google Scholar
107. Zhang XH, et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009;16(1):67–78.
     View this article via: PubMed CrossRef Google Scholar
108. Luo X, et al. Stromal-initiated changes in the bone promote metastatic niche development. Cell Rep. 2016;14(1):82–92.
     View this article via: PubMed CrossRef Google Scholar
109. Ross MH, et al. Bone-induced expression of integrin β3 enables targeted nanotherapy of breast cancer metastases. Cancer Res. 2017;77(22):6299–6312.
     View this article via: PubMed CrossRef Google Scholar
110. Andrade K, et al. RON kinase: a target for treatment of cancer-induced bone destruction and osteoporosis. Sci Transl Med. 2017;9(374):eaai9338.
     View this article via: PubMed CrossRef Google Scholar
111. Lu X, et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell. 2011;20(6):701–714.
     View this article via: PubMed CrossRef Google Scholar
112. Sharma P, et al. Prostate cancer with lytic bone metastases: 18F-fluorodeoxyglucose positron emission tomography-computed tomography for diagnosis and monitoring response to medical castration therapy. Indian J Nucl Med. 2013;28(3):178–179.
     View this article via: PubMed CrossRef Google Scholar
113. Wong SK, et al. Prostate cancer and bone metastases: the underlying mechanisms. Int J Mol Sci. 2019;20(10):2587.
     View this article via: PubMed CrossRef Google Scholar
114. Logothetis CJ, Lin SH. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer. 2005;5(1):21–28.
     View this article via: PubMed CrossRef Google Scholar
115. Guise TA, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006;12(20 pt 2):6213s–6216s.
     View this article via: PubMed Google Scholar
116. Quiroz-Munoz M, et al. Mechanisms of osteoblastic bone metastasis in prostate cancer: role of prostatic acid phosphatase. J Endocr Soc. 2019;3(3):655–664.
     View this article via: PubMed CrossRef Google Scholar
117. Sturge J, et al. Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat Rev Clin Oncol. 2011;8(6):357–368.
     View this article via: PubMed CrossRef Google Scholar
118. Nelson JB, et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med. 1995;1(9):944–999.
     View this article via: PubMed CrossRef Google Scholar
119. Li X, et al. Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. J Biol Chem. 2007;282(45):33098–33106.
     View this article via: PubMed CrossRef Google Scholar
120. Liao J, et al. Tumor expressed PTHrP facilitates prostate cancer-induced osteoblastic lesions. Int J Cancer. 2008;123(10):2267–2278.
     View this article via: PubMed CrossRef Google Scholar
121. Iwamura M, et al. Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen. Urology. 1996;48(2):317–325.
     View this article via: PubMed CrossRef Google Scholar
122. Scimeca M, et al. Osteoblast-like cells in human cancers: new cell type and reliable markers for bone metastasis. Future Oncol. 2018;14(1):9–11.
     View this article via: PubMed CrossRef Google Scholar
123. Kumar SK, et al. Multiple myeloma. Nat Rev Dis Primers. 2017;3:17046.
     View this article via: PubMed Google Scholar
124. Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2016;91(1):101–119.
     View this article via: PubMed CrossRef Google Scholar
125. Hameed A, et al. Bone disease in multiple myeloma: pathophysiology and management. Cancer Growth Metastasis. 2014;7:33–42.
     View this article via: PubMed Google Scholar
126. Dimopoulos MA, et al. Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol. 2015;33(6):657–664.
     View this article via: PubMed CrossRef Google Scholar
127. Giuliani N, et al. New insight in the mechanism of osteoclast activation and formation in multiple myeloma: focus on the receptor activator of NF-κB ligand (RANKL). Exp Hematol. 2004;32(8):685–691.
     View this article via: PubMed CrossRef Google Scholar
128. Roodman GD. Pathogenesis of myeloma bone disease. J Cell Biochem. 2010;109(2):283–291.
     View this article via: PubMed Google Scholar
129. Roodman GD. Novel targets for myeloma bone disease. Expert Opin Ther Targets. 2008;12(11):1377–1387.
     View this article via: PubMed CrossRef Google Scholar
130. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23(1):3–9.
     View this article via: PubMed CrossRef Google Scholar
131. Macedo F, et al. Bone metastases: an overview. Oncol Rev. 2017;11(1):321.
     View this article via: PubMed Google Scholar
132. Bidwell BN, et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat Med. 2012;18(8):1224–1231.
     View this article via: PubMed CrossRef Google Scholar
133. Zou L, et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res. 2004;64(22):8451–8455.
     View this article via: PubMed CrossRef Google Scholar
134. Jarnicki AG, et al. Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol. 2006;177(2):896–904.
     View this article via: PubMed CrossRef Google Scholar
135. Collison LW, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566–569.
     View this article via: PubMed CrossRef Google Scholar
136. Fujisaki J, et al. In vivo imaging of T reg cells providing immune privilege to the haematopoietic stem-cell niche. Nature. 2011;474(7350):216–220.
     View this article via: PubMed CrossRef Google Scholar
137. Zhao E, et al. Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer. Oncoimmunology. 2012;1(2):152–161.
     View this article via: PubMed CrossRef Google Scholar
138. Tan W, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature. 2011;470(7335):548–553.
     View this article via: PubMed CrossRef Google Scholar
139. Bronte V, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7(1):12150.
     View this article via: PubMed CrossRef Google Scholar
140. Almand B, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166(1):678–689.
     View this article via: PubMed CrossRef Google Scholar
141. Mittal D, et al. New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16–25.
     View this article via: PubMed CrossRef Google Scholar
142. Esen E, Long F. Aerobic glycolysis in osteoblasts. Curr Osteoporos Rep. 2014;12(4):433–438.
     View this article via: PubMed CrossRef Google Scholar
143. Le A, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A. 2010;107(5):2037–2042.
     View this article via: PubMed CrossRef Google Scholar
144. Leithner K, et al. PCK2 activation mediates an adaptive response to glucose depletion in lung cancer. Oncogene. 2015;34(8):1044–1050.
     View this article via: PubMed CrossRef Google Scholar
145. Park S, et al. ERRα-regulated lactate metabolism contributes to resistance to targeted therapies in breast cancer. Cell Rep. 2016;15(2):323–335.
     View this article via: PubMed CrossRef Google Scholar
146. Angelin A, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017;25(6):1282–1293.
     View this article via: PubMed CrossRef Google Scholar
147. Quarta G, et al. Determining 14C content in different human tissues: implications for application of 14C bomb-spike dating in forensic medicine. Radiocarbon. 2013;55(2–3):1845–1849.
     View this article via: CrossRef Google Scholar
148. Siddiqui JA, Partridge NC. Physiological bone remodeling: systemic regulation and growth factor involvement. Physiology (Bethesda). 2016;31(3):233–245.
     View this article via: PubMed Google Scholar
149. Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci. 2006;1092:385–396.
     View this article via: PubMed CrossRef Google Scholar
150. Veldurthy V, et al. Vitamin D, calcium homeostasis and aging. Bone Res. 2016;4:16041.
     View this article via: PubMed Google Scholar
151. Wu M, et al. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009.
     View this article via: PubMed Google Scholar
152. Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015;11(1):45–54.
     View this article via: PubMed CrossRef Google Scholar
153. Schell H, et al. The haematoma and its role in bone healing. J Exp Orthop. 2017;4(1):5.
     View this article via: PubMed CrossRef Google Scholar
154. Holmes D. Closing the gap. Nature. 2017;550(7677):S194–S195.
     View this article via: PubMed CrossRef Google Scholar
155. Koga T, et al. In vitro hypertrophy and calcification of human fracture haematoma-derived cells in chondrogenic differentiation. Int Orthop. 2013;37(5):961–967.
     View this article via: PubMed CrossRef Google Scholar
156. Ford JL, et al. The fate of soft callus chondrocytes during long bone fracture repair. J Orthop Res. 2003;21(1):54–61.
     View this article via: PubMed CrossRef Google Scholar
157. Zhou BO, et al. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell. 2014;15(2):154–168.
     View this article via: PubMed CrossRef Google Scholar
158. Iwaki A, et al. Localization and quantification of proliferating cells during rat fracture repair: detection of proliferating cell nuclear antigen by immunohistochemistry. J Bone Miner Res. 1997;12(1):96–102.
     View this article via: PubMed CrossRef Google Scholar
159. Zhu W, et al. Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol. 2006;80(3):267–274.
     View this article via: PubMed CrossRef Google Scholar
160. Lim PK, et al. Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Res. 2011;71(5):1550–1560.
     View this article via: PubMed CrossRef Google Scholar
161. Bartosh TJ, et al. Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs). Proc Natl Acad Sci U S A. 2016;113(42):E6447–E6456.
     View this article via: PubMed CrossRef Google Scholar
162. Yan XL, et al. Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. Breast Cancer Res Treat. 2012;132(1):153–164.
     View this article via: PubMed CrossRef Google Scholar
163. Schindeler A, et al. Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol. 2008;19(5):459–466.
     View this article via: PubMed CrossRef Google Scholar
164. Muscarella AM. Unique cellular protrusions mediate breast cancer cell migration by tethering to osteogenic cells. NPJ Breast Cancer. 2020;6:42.
     View this article via: PubMed Google Scholar
165. Coleman R, et al. Bone health in cancer patients: ESMO clinical practice guidelines. Ann Oncol. 2014;25(suppl 3):iii124–iii137.
     View this article via: PubMed Google Scholar
166. Whitaker M, et al. Bisphosphonates for osteoporosis—where do we go from here? N Engl J Med. 2012;366(22):2048–2051.
     View this article via: PubMed CrossRef Google Scholar
167. Ebetino FH, et al. The relationship between the chemistry and biological activity of the bisphosphonates. Bone. 2011;49(1):20–33.
     View this article via: PubMed CrossRef Google Scholar
168. Sato M, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest. 1991;88(6):2095–2105.
     View this article via: JCI PubMed CrossRef Google Scholar
169. Dunford JE, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001;296(2):235–242.
     View this article via: PubMed Google Scholar
170. Hughes DE, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res. 1995;10(10):1478–1487.
     View this article via: PubMed Google Scholar
171. Cremers S, Papapoulos S. Pharmacology of bisphosphonates. Bone. 2011;49(1):42–49.
     View this article via: PubMed CrossRef Google Scholar
172. Triffitt JT, et al. From Nuclear Physics to bone cell biology – Maureen Owen – 1927–2011. Bone. 2011;49(6):1121–1124.
     View this article via: PubMed CrossRef Google Scholar
173. Rennert G, et al. Oral bisphosphonates and improved survival of breast cancer. Clin Cancer Res. 2017;23(7):1684–1689.
     View this article via: PubMed CrossRef Google Scholar
174. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386(10001):1353–1361.
     View this article via: PubMed CrossRef Google Scholar
175. Allen MR, Burr DB. Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: what we think we know and what we know that we don’t know. Bone. 2011;49(1):56–65.
     View this article via: PubMed CrossRef Google Scholar
176. Body JJ, et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res. 2006;12(4):1221–1228.
     View this article via: PubMed CrossRef Google Scholar
177. Stopeck AT, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132–5139.
     View this article via: PubMed CrossRef Google Scholar
178. Smith MR, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013;31(30):3800–3806.
     View this article via: PubMed CrossRef Google Scholar
179. Lipton A, et al. Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics. Eur J Cancer. 2016;53:75–83.
     View this article via: PubMed CrossRef Google Scholar
180. Lutz S, et al. Palliative radiation therapy for bone metastases: update of an ASTRO evidence-based guideline. Pract Radiat Oncol. 2017;7(1):4–12.
     View this article via: PubMed CrossRef Google Scholar
181. Johnstone C, Lutz ST. External beam radiotherapy and bone metastases. Ann Palliat Med. 2014;3(2):114–122.
     View this article via: PubMed Google Scholar
182. Goblirsch M, et al. Radiation treatment decreases bone cancer pain through direct effect on tumor cells. Radiat Res. 2005;164(4 pt 1):400–408.
     View this article via: PubMed Google Scholar
183. Hoskin PJ, et al. Effect of local radiotherapy for bone pain on urinary markers of osteoclast activity. Lancet. 2000;355(9213):1428–1429.
     View this article via: PubMed CrossRef Google Scholar
184. Bruland OS, et al. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res. 2006;12(20 pt 2):6250s–6257s.
     View this article via: PubMed Google Scholar
185. Parker C, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–223.
     View this article via: PubMed CrossRef Google Scholar
186. Sartor O, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014;15(7):738–746.
     View this article via: PubMed CrossRef Google Scholar
187. Goyal J, Antonarakis ES. Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases. Cancer Lett. 2012;323(2):135–146.
     View this article via: PubMed CrossRef Google Scholar
188. Furubayashi N, et al. Palliative effects and adverse events of strontium-89 for prostate cancer patients with bone metastasis. Mol Clin Oncol. 2015;3(1):257–263.
     View this article via: PubMed CrossRef Google Scholar
189. Gallicchio R, et al. Palliative treatment of bone metastases with samarium-153 EDTMP at onset of pain. J Bone Miner Metab. 2014;32(4):434–440.
     View this article via: PubMed CrossRef Google Scholar
190. Nilsson S, et al. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016;27(5):868–874.
     View this article via: PubMed CrossRef Google Scholar
191. Paindelli C, et al. Engineered bone for probing organotypic growth and therapy response of prostate cancer tumoroids in vitro. Biomaterials. 2019;197:296–304.
     View this article via: PubMed CrossRef Google Scholar
192. Dondossola E, et al. Radium 223-mediated zonal cytotoxicity of prostate cancer in bone. J Natl Cancer Inst. 2019;111(10):1042–1050.
     View this article via: PubMed CrossRef Google Scholar
193. Schmid P, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–2121.
     View this article via: PubMed CrossRef Google Scholar
194. Mariathasan S, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544–548.
     View this article via: PubMed CrossRef Google Scholar
195. Sivasubramaniyan K, et al. Phenotypic and functional heterogeneity of human bone marrow- and amnion-derived MSC subsets. Ann N Y Acad Sci. 2012;1266:94–106.
     View this article via: PubMed CrossRef Google Scholar
196. Pevsner-Fischer M, et al. The origins of mesenchymal stromal cell heterogeneity. Stem Cell Rev Rep. 2011;7(3):560–568.
     View this article via: PubMed CrossRef Google Scholar
197. Kopp HG, et al. Functional heterogeneity of the bone marrow vascular niche. Ann N Y Acad Sci. 2009;1176:47–54.
     View this article via: PubMed CrossRef Google Scholar
198. Mendez-Ferrer S, et al. Bone marrow niches in haematological malignancies. Nat Rev Cancer. 2020;20(5):285–298.
     View this article via: PubMed CrossRef Google Scholar