Abstract
Bone metastases are a frequent and debilitating consequence for many tumors, of which breast, lung, prostate, and kidney cancer are the most common. The dialog among cancer cells, bone microenvironment, and immune system regulates bone metastasis formation. Indeed, bone and immune system are strictly linked to each other because bone regulates the hematopoietic stem cells from which all cells of the immune system derive. Many immunoregulatory cytokines influence the fate of bone cells and promote the growth of tumor cells in bone, contributing to sustain the vicious cycle of bone metastasis. Bone is an attractive soil for cancer cells, which can remain dormant for years or directly form bone lesions. The fate of cancer cells after their arrival to bone marrow depends on a complex cross-talk among cancer, bone, and immune cells in the microenvironment. This review provides an overview of the different steps occurring during bone metastatic process, with particular attention to the osteoimmunology field. Furthermore, we will revise the current available clinical approaches for the therapy of bone metastatic patients.
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Introduction
The metastatic process at all is inefficient; indeed, despite disseminated tumor cells (DTCs) that are found in the bone marrow (BM) of cancer patients, many of them do not develop overt metastatic disease [1]. Even though bone is conducive for tumor dissemination and survival of cancer cells, other processes need to sustain tumor progression. Indeed, the diffusion of cancer cells from the primary site to other organs is a complex process depending both on the invasive abilities of cancer cells and on the microenvironment of the target organ. Tissues are not prone to welcome metastatic cells since in a healthy organ there are active innate immune system and stroma that commonly do not support the growth of “foreign cells” [2]. Nonetheless, certain organs have a less hostile microenvironment than others, such as the bone, which seems to be the most attractive “soil” for many cancers. Bone metastases are particularly common complications for solid tumors, such as breast, prostate cancer, and to a lesser extent melanoma, lung, and kidney cancer [3]. Bone lesions cause morbidity due to the frequent occurrence of skeletal related events (SREs), such as pathological fracture, spinal cord compression, bone pain, and hypercalcemia [4]. Several reasons account for the “peculiar attraction” of cancer cells to bone, for instance the genetic component demonstrated in breast cancer, where cancer cells in the primary tumor acquire a bone tropism signature [5, 6]; the hematopoietic stem cell (HSC) niche is an appealing site for cancer cells because it induces HSC mobilization to occupy the niche [7] and activates myeloid subsets, which perform an immunosuppressive action in the bone microenvironment [8]. Nowadays, the role of the immune system in promoting bone metastases has become more and more evident. This review will focus on different aspects affecting the bone metastatic process and will revise the current available therapeutic options.
Bone is an Attractive Soil for Cancer Cells to Thrive on
BM is constituted by red and yellow marrow. The red marrow is highly vascularized and provides a fertile soil for homing, survival, and proliferation of disseminated tumor cells (DTCs), which often acquired characteristics of stem cells. The yellow marrow contains BM adipocytes, which promote the growth of metastatic tumor cells in the bone [9]. Moreover, BM provides both endosteal and vascular niches, which support HSCs and non-hematopoietic stem cells such as mesenchymal stem cells (MSCs) [10, 11]. Cancer cells recognize chemokine gradients toward BM, similar to the gradient followed by HSCs and leukocytes to migrate to the bone [12]. HSCs migrate to the BM after the activation of CXCL12/CXCR4 axis and osteoblasts (OBs) in BM constitutively express CXCL12, the ligand of CXCR4 [13]. The overexpression of CXCR4 and CXCR7 by breast and prostate cancer cells increases their ability to exit the vascular niche then to colonize bone in mice models [5, 14]. Other than tumor cells, cancer-associated fibroblasts in the tumor microenvironment can also produce CXCL12, which stimulates the release of pro-angiogenic hematopoietic progenitor cells into the circulation [15]. In both breast and non-small cell lung cancer, the CXCR4 inhibition by neutralizing antibodies or pharmacological agents decreases metastatization to bone and lung [16, 17]. Moreover, CXCR4 stimulates the CCL20 production by different tumor cells, further promoting tumor growth and invasion [18, 19]. In particular, CCL20 serum levels were higher in renal cancer patients with bone metastases compared to the non-bone metastatic ones [20], and in multiple myeloma patients, CCL20 overexpression contributes to the increased OC formation and osteolysis [21]. Osteocytes express CXCL16 [22], the ligand of CXCR6, promoting the migration of cancer cells, such as prostate cancer cells, which express this chemokine receptor [23]. Differentiating osteoclasts (OCs) release CCL22 that links CCR4 expressed on breast cancer cells [24], and again OBs express CCL12, which stimulates the tropism of cells expressing CCR7, such as breast cancer cells [12].
Living in the Bone Marrow
Once in the BM, DTCs can die, remain dormant, or proliferate according to the signals received by the local microenvironment [25]. Dormancy signals derive from both endosteal and vascular niches. In endosteal niches, OBs secrete factors such as growth arrest specific 6, a receptor for annexin II [26] and osteopontin, whereas vascular niches release thrombospondin-1 and Notch1 [27], which maintain tumor cells in quiescence. Recently, also the expression of interleukin-6 (IL-6) cytokine leukemia inhibitory factor has been associated to the dormancy phenotype in breast DTCs disseminated to the BM [28]. Conversely, the release in the bone microenvironment of fibronectin, type I collagen, and periostin repress dormancy [29]. After their arrival in BM, HSCs and DTCs compete to endosteal niche since they express cadherins, which allow bonds with OBs residing in these niches [30] and with bone matrix [31, 32]. Indeed, tumor cells express adhesion molecules, able to bind BM stromal cells, releasing angiogenic and bone-resorbing factors that disrupt the normal homeostasis of BM microenvironment leading to bone metastasis [33, 34]. αvβ3 is an integrin expressed by breast and prostate cancer cells, which is particularly important for OC adhesion to bone. Indeed, treatment with non-peptide antagonists of αvβ3 blocked bone colonization [35, 36]. In breast cancer, the vascular-endothelial molecule-1 (VCAM-1) binds α4β7 and α4β1 (VLA-4) integrins on OC precursors with high affinity, causing osteoclastogenesis. α4 or VCAM-1 blocking antibodies effectively inhibit bone metastasis [37]. Further, CD44 is a molecule highly expressed by breast cancer cells, which promotes invasion and adhesion to BM [38]. Breast CSCs express CD44; they can lie in a dormant state in the BM [39] and then directly induce bone metastases [6]. Annexin II is expressed by prostate cancer cells and can link its receptor on OBs promoting the homing in bone [40]. Thus, OBs and OCs both affect the HSC maintenance and mobilization [32].
Dynamic interactions between DTCs and stromal cells in bone cause the release of different molecules which provide a fertile soil for tumor cells, such as transforming growth factor-β (TGF-β), insulin-like growth factors I and II, platelet-derived growth factor, fibroblast growth factor, and bone morphogenetic proteins [41, 42]. Also, the physiological bone remodeling, which is a tightly regulated activity of bone-resorbing OCs and bone-forming OBs, determines the release from the bone matrix of different factors, promoting the growth of cancer cells and/or the outgrowth from dormancy of DTCs [37]. Moreover, physical factors such as acid pH, hypoxia, and high extracellular calcium concentration contribute to tumor cell growth [43]. For instance, the high extracellular Ca2+ concentration present in bone (due to the physiological bone remodeling) can bind to calcium-sensing receptor and stimulate PTH-related peptide in cancer cells, promoting tumor cell proliferation and survival [44, 45]. In breast cancer, it has been shown that tumor cells activate OC precursors, which in turn stimulate dormant DTCs [37]. Tumor cells can secrete prostaglandins, PTH, activated vitamin D, interleukin-6 (IL-6), and tumor necrosis factor (TNF), leading to an increase in receptor activator of nuclear factor NF-kB ligand (RANKL) expression on OBs and BM stromal cells [42], which stimulates the OC number, survival, and activity. Jagged1, a ligand of Notch, is a downstream mediator of the pro-metastatic TGF-β that directly activates OC differentiation and promotes tumor growth stimulating IL-6 production by OBs [46]. Moreover, tumor-derived microvesicles such as exosomes are involved in metastasis formation because they can transfer oncogenic proteins and nucleic acids that modulate the fate of tumor cells and target organs [47,48,49,50].
Interaction Between Immune System and Bone Cells
A basic link between immune system and bone is represented by the axis including the receptor activator of nuclear factor NF-kB ligand (RANKL), its receptor RANK, and the natural decoy receptor osteoprotegerin (OPG). The membrane RANKL is expressed by OBs/stromal cells, whereas the soluble RANKL is secreted by activated T cells [51, 52], whereas the receptor RANK is expressed on OC precursors on tumor cells as well [53]. The serum RANKL to OPG ratio is a critical factor in determining OC activation at bone level, with a high serum RANKL to OPG ratio reflecting up-regulation of osteoclastogenesis [54]. OC precursors, circulating in peripheral blood, derive from the monocyte-macrophage lineage, and they can be recruited in response to pathological or healthy conditions. In patients affected by breast, prostate, and lung cancer with bone metastases, we demonstrated an increase in circulating OC precursors compared to patients without bone metastases and healthy controls [55, 56]. Moreover, in bone metastatic patients, OC precursors differentiate into mature OCs in vitro in the presence of T cells without the addition of M-CSF and RANKL, whereas T-cell depletion results in the absence of OC formation without exogenous stimulation [55]. Literature data from our group and others showed that T cells can directly carry on a modulatory action on OCs, thus regulating bone resorption in bone metastasis [55, 57].
IL-7, a cytokine produced by stromal and T cells at inflammatory sites, is an important mediator of the interactions between T lymphocytes and bone cells [58] other than being the main regulator of B and T lymphopoiesis [59]. IL-7 displays either a positive or negative effect on OCs [60, 61], thus it contributes to the maintenance of a correct bone homeostasis [61, 62]. T cells release IL-7 that in turn promotes osteoclastogenesis by up-regulating T-cell release of RANKL and TNFα [63,64,65]. We demonstrated that in bone metastatic patients, IL-7 serum levels were significantly higher than in non-bone metastatic ones and healthy controls [56, 65, 66]. We also showed in a human-in-mice model of bone metastasis by lung cancer that tumor cells release IL-7, thus they are responsible at least in part for the increased IL-7 serum levels [67]. T cells can also mediate a negative regulation of osteoclastogenesis by inducing CD137, a co-stimulatory member of the TNF receptor [68]. CD137 ligand is expressed on OC precursors and its link to CD137 causes an osteoclastogenesis suppression through the inhibition of OC precursor fusion [68].
Bone Shows a Dampened Immune System Response that Favor Tumor Cells
A relevant factor influencing tumor cell dormancy or growth in bone is represented by the reduced immunoreactivity of bone, likely depending on its function as protector of HSC niches [69, 70]. MSCs support HSCs and interact with bone microenvironment maintaining a correct bone remodeling. MSCs can help the entrance of tumor cells in the bone microenvironment through the production of chemoattractant factors, such as stromal derived factor 1α (SDF-1α/CXCL12) [71, 72]. Thus, tumor cells refuge in bone with mechanisms of quiescence similar to HSCs [25], and they often show a more immunoevasive phenotype than cells in the primary tumor [73], easily escaping immunosurveillance. Bone is characterized by a dampened immune system response, with the failure of both innate and adaptive immune system leading to bone metastasis formation [74, 75].
Commonly, the percentage of activated CD4 and CD8 T cells is low in BM, but these populations have been reported in BM of untreated breast cancer patients, suggesting their protective role against tumor growth in bone [76]. At least in an early phase, T cells try to counteract tumor cell diffusion, for instance by releasing IFNγ after their activation. Indeed, the lack of IFNγ has been related to the increase of bone metastases [77]. Furthermore, the importance of T cells in controlling bone metastases has been shown in a mouse model, where T-cell deficiency reduced the anti-tumor effect of zoledronic acid, which is commonly utilized to treat bone lesions. Indeed the anti-resorptive therapy blocked the bone loss due to tumor, but was ineffective to reduce tumor burden, suggesting that impairment or reduction of T cells affects the efficacy of zoledronic acid [78]. In the era of the immune checkpoint inhibitors, it has been shown in a melanoma mice model that ipilimumab (an antibody blocking the inhibitor signal CTLA4 on T cells) suppressed bone metastases [78], and it has been introduced in clinical practice for the treatment of metastatic melanoma.
Moreover, bone has a large number of immature and suppressor immune cell types, such as T regulatory cells, which have to maintain a balanced immunoreactivity [79], and the immunosuppressive myeloid derived suppressor cells (MDSCs) that stimulate osteoclastogenesis [80]. In breast cancer, infiltrating T reg produce RANKL, promoting OC differentiation, activity, and subsequent bone lesions [81]. On the other side, OCs affect T-cell activity, inducing the activation of CD8 T regulatory cells, which regulate an inappropriate activation of the immune response [82].
Another subset of CD4 T cells promoting bone damage is represented by T helper type 17 (Th17) cells, which are linked to an increased osteoclastogenesis and bone lesions in inflammatory arthritis [83]. Th17 cells release IL-17 and RANKL production [84], which stimulate OC activity. IL-17 is also produced by BM-derived stem cells, promoting tumor growth in the bone [85].
Cancer patients show an increased level of circulating myeloid populations, which help tumor growth and metastatization suppressing innate and adaptive immune response. MDSC expansion is due to the production of different factors, such as granulocyte colony-stimulating factor (G-CSF), TGF-β, and interleukin-1β (IL-1β) by tumor cells. After mobilization, MDSCs move from the BM into the circulation, where they show a strong suppressive function on T-cell-mediated immune response, particularly on CD8+ T cells [86, 87] but also CD4 T and NK cells [78]. In turn, MDSCs stimulate T regs [88] and release many cytokines and angiogenic factors which promote tumor growth in bone, inhibiting T-cell response [78, 89]. In cancer patients and mostly in advanced cancer ones, MDSCs are largely increased, particularly in the circulation of bone metastatic patients. Indeed, MDSCs can rise from 2% up to 25% [80, 90]. Moreover, it has been demonstrated that MDSCs derived from bone metastatic microenvironment can differentiate into mature and functional OCs in vitro [91], and in multiple myeloma they act as OC precursors [92].
Clinical Approach for Treatment of Bone Metastases
Treatment of patients with bone metastases showed a progressive improvement in the last 15 years. Indeed, the survival rate of the patients with bone localizations of solid tumors increased dramatically. Second therapeutic lines on gastrointestinal, prostate, kidney, and lately lung tumors raised the problem to preserve the quality of life of these patients for longer periods of time.
The paramount clinical condition of bone metastasis is pain, and reversibly, bone cancer pain is the most common form of distress for a patient with cancer. Thus, pain reduction and functional preservation remain the mail goal of therapy which, due to the increase life expectancy, must be modified accordingly. The issue of pain control was addressed showing that 45% of patients with cancer accompanied by pain could not be effectively controlled [93]. These observations led to the development of a rat mouse model of femoral cancer pain, and a good animal foundation has been developed for the investigation of the mechanisms of cancer pain in animal models [94]. On clinical grounds, pain from bone metastasis can be controlled by radiotherapy or radioisotopes, pharmacologic therapy (mainly opioids), surgery, bone cement, and novel approaches.
The use of external beam radiotherapy in a single fraction of 8 Gy to treat patients with bone metastases and pain is strongly recommended and still represents the gold standard for local control of bone lesions. Further techniques include an increased radiation dose in order to achieve a radical radiation treatment on oligometastatic patients and the more sophisticated imaging-mediated stereotactic body radiation therapy [95]. It offers the patient a short course of outpatient, non-invasive ablative therapy [96].
The efficacy of radioisotopes for relieving pain has been proven, looking at the reduction of patients’ needs for conventional painkillers, improvements in quality of life, and increased survival. Indeed, there is some evidence that radioisotopes may give pain relief over 1 to 6 months, although the treatment also seems to be associated with adverse effects, notably reduction of leukocytes [97].
Currently, opioids are one of the most effective drugs for cancer pain. More than 80% of patients with bone metastasis need to use opioids to improve or control pain. However, the associated side effects of opioid drugs (tolerance, addiction, excitement, drowsiness, constipation, nausea, vomiting, and respiratory depression) limit further application [98].
High dose of bisphosphonates, such as zoledronic acid, was introduced as a treatment for bone metastasis and prevention of its complications. Decreased progression of the disease in the bone was proven, and eventually, according to various studies, nesting of tumor cells in the bone was prevented [99].
Bone-targeting therapy reduces skeletal-related events associated to bone metastases in patients with solid tumors and multiple myeloma [100,101,102]. In particular, the introduction of denosumab, a fully human antibody that specifically binds to RANKL in a reversible way, without interfering with other TNF ligands, resulted effective in preventing the homing of RANK-expressing tumor cells to bone and inhibiting the formation of bone lesions [103, 104]. Denosumab inhibited bone resorption in patients refractory to bisphosphonate therapy [105] and was superior to zoledronic acid in preventing SREs in patients with bone metastases from advanced cancer [103, 106].
The orthopedic surgeon has a leading role in pain control and in the prevention of SREs, consisting primarily in fracture of the affected bone, spinal cord compression, and hypercalcemia, all of which may profoundly impair the quality of life of patients [107]. All patients at risk of a long bone fracture should therefore be assessed to consider prophylactic surgery. Orthopedic surgeons had learned that solitary bone metastases, when surgically removable, had to be treated with oncologic rigor, preserving margins, considering that the surgical treatment needed a longer half life and had to provide function and durability for patients that could heal from cancer. Next, they further learned how to treat multiple metastatic patients keeping in mind that pathologic fractures never heal and therefore the surgical treatment had to provide stability for as long as the life expectancy of the patients. The surgical orthopedic solutions had to be modified according to the increased survival rate of metastatic patients. For instance, wide resection prostheses started to be used in upper and lower limbs, nail quality increased for intramedullary nailing of long bone metastases, and carbon fiber composite nails were recently introduced allowing better imaging after nailing and lack of electron scattering during post-surgical radiotherapy [108]. Particularly new light polymerized nails were recently introduced for upper limbs and are on trials on lower limb metastases [109]. Their peculiar characteristics allow mini-invasive surgery and immediate control of the stability of the bone especially in rotational motion due to the on-site polymerization of the nail itself. They also offer a perfect visibility of the bone after nailing, being RX translucent and MRI compatible. They also represent a perfect fixation system for further radiotherapy. The increased life expectancy of bone metastatic patients represented a new challenge for spine surgeons as well. Indeed, the indications for surgical stabilization of vertebral lesions increased and, in selected cases, partial or complete vertebrectomy of the affected vertebral body was performed [110]. In bone metastasis of the spine, the radiotherapy continues to be the most reliable treatment, but vertebroplasty became a new and rapidly growing method for stabilization of lytic lesions that could be performed on outpatients and on multiple sites, avoiding corsets, allowing pain control, preservation of function, and therefore quality of life [111]. Another option of imaging guided non-invasive treatment for bone localization of tumor cells is thermal ablation, which has been used for oncologic patients for over 20 years with limited but effective results, especially in non-weight-bearing segments [112]. Electrochemotherapy is under evaluation in many multicenter studies. It consists of electroporation of the affected bone segment using electrodes driven into bone under imaging control. The electroporated bone segment, together with the tumor tissue, then becomes susceptible to bleomycin i.v. infusion. Preliminary results are promising for palliation treatment [113].
Conclusions
A relentless research effort to explain the biological insights of the interaction between DTCs and bone has led to a clearer view of the bone metastatic process. We believe we are active spectators of a turning point in metastatic patients’ treatment from basic knowledge to patients’ bed. Examples of this transition are represented by many novel agents able to prevent or block bone metastases. One is denosumab, which is currently in clinical practice for bone metastases in solid tumors, and another is anti-DKK1 antibody, which is in clinical trials. On clinical grounds, the awareness of novel concepts and the availability of new treatments lead to a new philosophy of care for bone metastases which is more effective, decreases SREs, and improves the life quality of these patients.
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This work was supported by Cassa di Risparmio di Torino (CRT) and Compagnia di San Paolo Foundations and by Fondazione Ricerca Molinette ONLUS.
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Roato, I., Massè, A., Piana, R. et al. Bone Metastasis from Solid Tumors: Biologic and Clinical State of the Art. Clinic Rev Bone Miner Metab 15, 115–122 (2017). https://doi.org/10.1007/s12018-017-9233-9
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DOI: https://doi.org/10.1007/s12018-017-9233-9