Basic and clinical associations between bone and cancer

Abstract

Bone is one of the most common distant organs in which tumor cells tend to metastasize depending on complicated immune system and bone microenvironments. Clinical symptoms such as severe pain and bone fractures associated with bone metastases severely affect patients’ quality of life. According to the pathological types of bone destruction caused by the biological characteristics of different primary cancer cells, bone metastases are classified as osteolytic, osteoblastic and mixed types. Herein, we discuss the molecular mechanisms of bone metastasis and the therapeutic strategy with focus on bone metabolism.

Keywords:

• Bone metastases
• bisphosphonates
• denosumab

1. Introduction

Metastasis is a process in which malignant tumor cells grow at a site distant from the primary and it is associated with poor prognosis. Bone is one of the most common distant metastatic organs for tumor cells. In the first large-scale US study, the incidence of bone metastases of all solid tumors combined was estimated, and it was shown that prostate cancer patients are at the highest risk for bone metastasis (18–29%) followed by patients with lung, renal and breast cancer [1]. It was also shown that the cumulative incidence of bone metastasis increased with an increase in the clinical stage at the time of diagnosis and that 11% of cancer patients diagnosed as Stage IV had bone metastases [1]. In 2016, the group of the Shikoku Cancer Center in Japan reported that the incidences of bone metastasis in autopsy cases from 1959 to 1997 were 75% and 22% in patients with breast or prostate cancer and patients with gut cancer, respectively [2]. Patients with bone metastasis suffer from skeletal-related events including severe pain, bone fractures, spinal cord compression, hypercalcemia, anemia, spinal instability, and decreased mobility [3]. Bone metastases, associated with a reduction in the quality of life of patients, are caused by complicated immune system and bone microenvironments. In this review, we discuss the recently revealed molecular mechanisms of bone metastasis and the therapeutic strategy with focus on bone metabolism.

2. Classification of bone metastases

Bone is a highly dynamic organ that is always undergoing remodeling regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Disruption of this balance by disseminated tumor cells results in different types of bone metastases, which are classified as osteolytic, osteoblastic and mixed, depending on the biological characteristics of primary cancer cells. Breast cancer predominantly causes osteolytic bone metastasis with bone loss, while prostate cancer causes osteoblastic lesions with new bone formation [4].

3. Mechanisms of bone metastasis

Bone metastasis is a complex process in which many factors are involved. The mechanism of bone metastasis includes changes in the bone microenvironment before metastasis, homing of disseminated tumor cells and adaptation of these cells to bone.

3.1. Changes in the bone microenvironment before metastasis

According to the ‘seed and soil’ hypothesis proposed by Paget in 1889, tumor cells tend to metastasize to specific regions rather than be randomly transferred [5]. Cancer cells are more likely to grow in fertile soil as seeds. Bone is a storage site of growth factors, including insulin-like growth factors (IGF), transforming growth factor-β (TGF-β), fibroblast growth factors (FGFs), platelet-derived growth factors and bone morphogenetic proteins (BMPs), that are required for bone metastasis [6,7]. Additionally, the characteristics of bone cells are changed by tumor cells to provide a suitable microenvironment for the survival of metastatic cancer cells [8,9]. The extracellular matrix-modifying enzyme lysyl oxidase (LOX), which is only derived from estrogen receptor-negative breast cancer cells [10–12], decreases osteoblast proliferation while driving osteoclastogenesis that leads to disruption of bone homeostasis and subsequent formation of pre-metastatic osteolytic niches. Interleukin (IL)-6 [13], parathyroid hormone-related protein [14] and Dickkopf-1 [15] secreted by tumor cells also promote the formation of pre-metastatic niches.

3.2. Homing of disseminated tumor cells

After entering circulation, disseminated tumor cells home to the bone in a manner similar to that of hematopoietic stem cells (HSCs) [16]. C-X-C motif chemokine ligand 12 (CXCL12), which is highly expressed on osteoblasts and bone marrow stromal cells and is required for homing of HSCs to the bone, interacts with its receptor, C-X-C motif chemokine receptor 4 (CXCR4), on various cancer cells, leading to bone homing of these cells [16,17]. Shiozawa et al. [18] found by using a mouse model of metastasis that human prostate cancer cells directly compete with HSCs for occupancy of the mouse HSC niche. In addition to the CXCL12/CXCR4 axis, tumor cells express many chemokine receptors, cell adhesion molecules and integrin receptors α4β1 and α2β1, which enable them to adhere to the bone matrix [17]. Receptor activator of NF-κB ligand (RANKL) is a critical osteoclast differentiation factor that is highly expressed in the bone marrow environment. Multiple tumor cells express RANK, the receptor for RANKL, and RANKL can act as a tissue-specific factor for the migration of cancer cells through the interaction between RANK and RANKL [19,20].

3.3. Disseminated tumor cells adapting to the bone

After arriving at the bone marrow, disseminated tumor cells can persist in a dormant state characterized by cell cycle arrest at the G0 phase and a lack of proliferating markers for many years until they progress to metastatic lesions [21,22]. This dormancy is probably due to delayed adaption of the tumor cells to the foreign microenvironment. Yu-Lee et al. [23] found that osteoblast-secreted factors including growth differentiation factor-10 and TGF-β2 induce tumor dormancy through activation of the TGF-βRIII-p38MAPK-pS249/T252RB signaling pathway. Other factors such as BMPs [24], WNT family [25], and growth arrest specific-6 [26] are also associated with the regulation of tumor dormancy, leading to protection of tumor cells from immune surveillance and chemotherapeutics [27].

Bone cells in the bone microenvironment affect the status switching of tumor cells from dormancy to proliferation. In bone, osteoblasts are activated by parathyroid hormone-related peptide), tumor necrosis factor-α (TNF-α), IL-1, IL-6, IL-8, and IL-11 derived from cancer cells [28], and active osteoblasts further enhance osteoclastogenesis through expression of RANKL [28]. Then osteoclasts cause bone resorption, which results in the release of TGF-β, BMPs, IGFs and FGFs and subsequent activation of tumor growth and survival known as the ‘vicious cycle’ [9,29].

4. Therapeutic strategy based on mechanisms

The current therapeutic strategy for bone metastasis is treatment with bisphosphonates and denosumab (a RANKL inhibitor), which suppress osteoclastogenesis. Bisphosphonates have been updated for three generations. The first generation is non-nitrogen-containing bisphosphonates such as etidronate, clodronate, and tiludronate, and the second generation is nitrogen-containing bisphosphonates such as pamidronate, alendronate, and ibandronate. The third generation is nitrogen-containing bisphosphonates with a heterocyclic structure such as risedronate and zoledronic acid. A third-generation bisphosphonate has a stronger anti-bone resorption property and smaller side effects. Zoledronic acid sodium is a representative third-generation bisphosphonate. It has clarified that zoledronic acid sodium can specifically bind to hydroxyapatite in bone and then it is internalized by osteoclasts. Zoledronic acid inside osteoclasts inhibits farnesyl-diphosphate synthase, a rate-limiting enzyme of the mevalonate pathway, preventing prenylation of the GTPase activity of signaling proteins such as Ras, Rho, and Rab. Zoledronic acid inhibits bone resorption through disturbing specific biochemical processes of osteoclasts [30]. Guenther et al. [31] first provided evidence that nitrogen‐containing bisphosphonates have direct anti-tumor effects in plasma cell tumors in vivo and that these effects are executed by a molecular mechanism similar to that observed in osteoclasts. A randomized, placebo-controlled trial in Japan has shown the efficacy and safety of zoledronic acid for treatment of bone metastases from breast cancer. Zoledronic acid not only reduced the incidence of skeletal-related events (SREs) by 39% compared with that in a placebo group but was also well tolerated with a safety profile similar to that of the placebo [32]. In case of therapeutic failure by other bisphosphonates, switching to zoledronic acid may be effective for bone pain in cancer patients [33]. The standard dosing interval of bisphosphonates is usually every four weeks clinically. In a randomized, open-label clinical trial, treatment with zoledronic acid every four weeks showed efficacy and safety without an increased risk of SREs over a period of two years [34].

Denosumab is a fully human monoclonal antibody to RANKL that inhibits osteoclast-mediated bone destruction and blocks the cancer-mediated vicious cycle through preventing RANK/RANKL interaction. Denosumab may also be effective for directly targeting subtypes of cancers expressing RANKL [35]. The effectives of denosumab was compared with the effectiveness of zoledronic acid for delaying or preventing SREs in cancer patients with bone metastases in several studies. It was shown that tolerance to denosumab was better than that to zoledronic acid [36–39]. However, no significant difference was observed between denosumab and zoledronic acid regarding overall survival [40].

5. Conclusion

The presence of bone metastases heralds a decline in patient survival and quality of life. From the molecular mechanism, the interaction between primary cancer cells and the bone microenvironment plays a critical role in bone metastases. Bisphosphonates and denosumab are currently the first-line therapies for bone metastases. Further studies are needed to investigate the molecular mechanism and develop a new therapeutic strategy for bone metastases.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

YM has received research grants from Daiichi Sankyo.