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Bone Metastasis: Pathophysiology and Molecular Mechanisms

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 67104

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Prof. Dr. Ingunn Holen

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Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Interests: breast cancer; bone metastases; microenvironment; bone microvasculature; tumour cell dormancy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bone metastases, common features of advanced breast and prostate cancer, are increasingly also found in patients with other cancers (e.g., lung) due to improved treatment of the primary tumour and, hence, prolonged survival. However, once skeletal involvement is established, patient survival is limited and treatment often limited to palliation. The main current therapies are bone-targeted agents to prevent and/or reduce skeletal related events like fractures and spinal cord compression. However, no treatment specifically prevents the development of bone metastases. Novel therapeutic approaches to improve outcome for these poor prognosis patients require a better understanding of the molecular and cellular mechanisms that underpin tumour cell dissemination, colonisation and progression in bone. In particular, the role of the bone microenvironment in regulation of cancer cell dormancy, as well as identification of the signals that trigger escape from dormancy, remain to be elucidated. Another main area of interest is how tumour cell interactions with the bone microenvironment represents novel therapeutic targets, in particular in relation to new treatment modalities like immunotherapy.

This Special Issue will contain a collection of manuscripts that describe investigations into the different stages of bone metastasis, covering a range of model systems and tumour types, reflecting our current knowledge.

Prof. Dr. Ingunn Holen
Guest Editors

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Keywords

bone
bone microenvironment
bone metastases
breast cancer
disseminated tumour cells
extracellular matrix
lung cancer
prostate cancer
tumour cell dormancy

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Published Papers (11 papers)

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Research

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8 pages, 933 KiB

Open AccessArticle

Levels of Circulating Fibroblast Growth Factor 23 (FGF23) and Prognosis in Cancer Patients with Bone Metastases

by André Mansinho, Arlindo R. Ferreira, Sandra Casimiro, Irina Alho, Inês Vendrell, Ana Lúcia Costa, Rita Sousa, Catarina Abreu, Catarina Pulido, Daniela Macedo, Teresa R. Pacheco, Lurdes Correia and Luís Costa

Int. J. Mol. Sci. 2019, 20(3), 695; https://doi.org/10.3390/ijms20030695 - 6 Feb 2019

Cited by 22 | Viewed by 3649

Abstract

The fibroblast growth factor (FGF) signaling pathway plays a key role in tumorigenesis and is recognized as a potential therapeutic target. In this study, the authors aimed to assess the impact of serum FGF23 levels in the prognosis of patients with cancer and bone metastases from solid tumors. A cohort of 112 patients with cancer and metastatic bone disease were treated with bone-targeted agents (BTA). Serum baseline FGF23 was quantified by ELISA and dichotomized in FGF23^high and FGF23^low groups. Additionally, the association between FGF23 and overall survival (OS) and time to skeletal-related events (TTSRE) was investigated. Baseline characteristics were balanced between groups, except for the median urinary N-terminal telopeptide (uNTX) level. After a median follow-up of 26.0 months, a median OS of 34.4 and 12.2 months was found in the FGF23^low and FGF23^high groups, respectively (multivariate HR 0.18, 95% CI 0.07–0.44, p = 0.001; univariate HR 0.27, p = 0.001). Additionally, TTSRE was significantly longer for patients with FGF23^low (13.0 vs. 2.0 months, p = 0.04). Overall, this study found that patients with FGF23^low at baseline had longer OS and TTSRE. Further studies are warranted to define its role as a prognostic biomarker and in the use of drugs targeting the FGF axis. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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11 pages, 4907 KiB

Open AccessArticle

Dynamic Collision Behavior Between Osteoblasts and Tumor Cells Regulates the Disordered Arrangement of Collagen Fiber/Apatite Crystals in Metastasized Bone

by Aira Matsugaki, Tatsuki Harada, Yumi Kimura, Aiko Sekita and Takayoshi Nakano

Int. J. Mol. Sci. 2018, 19(11), 3474; https://doi.org/10.3390/ijms19113474 - 5 Nov 2018

Cited by 15 | Viewed by 5596

Abstract

Bone metastasis is one of the most intractable bone diseases; it is accompanied with a severe mechanical dysfunction of bone tissue. We recently discovered that the disorganized collagen/apatite microstructure in cancer-bearing bone is a dominant determinant of the disruption of bone mechanical function; disordered osteoblast arrangement was found to be one of the principal determinants of the deteriorated collagen/apatite microstructure. However, the precise molecular mechanisms regulating the disordered osteoblast arrangement triggered by cancer invasion are not yet understood. Herein, we demonstrate a significant disorganization of bone tissue anisotropy in metastasized bone in our novel ex vivo metastasis model. Further, we propose a novel mechanism underlying the disorganization of a metastasized bone matrix: A dynamic collision behavior between tumor cells and osteoblasts disturbs the osteoblast arrangement along the collagen substrate. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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18 pages, 10595 KiB

Open AccessArticle

Parathyroid Hormone (PTH) Increases Skeletal Tumour Growth and Alters Tumour Distribution in an In Vivo Model of Breast Cancer

by Hannah K. Brown, Gloria Allocca, Penelope D. Ottewell, Ning Wang, Nicola J. Brown, Peter I. Croucher, Colby L. Eaton and Ingunn Holen

Int. J. Mol. Sci. 2018, 19(10), 2920; https://doi.org/10.3390/ijms19102920 - 26 Sep 2018

Cited by 11 | Viewed by 4519

Abstract

Breast cancer cells colonize the skeleton by homing to specific niches, but the involvement of osteoblasts in tumour cell seeding, colonization, and progression is unknown. We used an in vivo model to determine how increasing the number of cells of the osteoblast lineage with parathyroid hormone (PTH) modified subsequent skeletal colonization by breast cancer cells. BALB/c nude mice were injected for five consecutive days with PBS (control) or PTH and then injected with DiD-labelled breast cancer cells via the intra-cardiac route. Effects of PTH on the bone microenvironment and tumour cell colonization and growth was analyzed using bioluminescence imaging, two-photon microscopy, and histological analysis. PTH treatment caused a significant, transient increase in osteoblast numbers compared to control, whereas bone volume/structure in the tibia was unaffected. There were no differences in the number of tumour cells seeding to the tibias, or in the number of tumours in the hind legs, between the control and PTH group. However, animals pre-treated with PTH had a significantly higher number of tumour colonies distributed throughout skeletal sites outside the hind limbs. This is the first demonstration that PTH-induced stimulation of osteoblastic cells may result in alternative skeletal sites becoming available for breast cancer cell colonization. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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17 pages, 5556 KiB

Open AccessArticle

Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity

by Annika Nordstrand, Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, Sead Crnalic, Anders Widmark, Anders Bergh, Ulf H. Lerner and Pernilla Wikström

Int. J. Mol. Sci. 2018, 19(4), 1223; https://doi.org/10.3390/ijms19041223 - 18 Apr 2018

Cited by 26 | Viewed by 5252

Abstract

Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naïve (n = 11) and castration-resistant (n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-naïve and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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18 pages, 5036 KiB

Open AccessArticle

Therapeutic and Preventive Effects of Osteoclastogenesis Inhibitory Factor on Osteolysis, Proliferation of Mammary Tumor Cell and Induction of Cancer Stem Cells in the Bone Microenvironment

by Mitsuru Futakuchi, Takao Nitanda, Saeko Ando, Harutoshi Matsumoto, Eri Yoshimoto, Katsumi Fukamachi and Masumi Suzui

Int. J. Mol. Sci. 2018, 19(3), 888; https://doi.org/10.3390/ijms19030888 - 16 Mar 2018

Cited by 3 | Viewed by 4643

Abstract

Background: We examined the effects of recombinant human osteoclastogenesis inhibitory factor (hOCIF) on osteolysis, proliferation of mammary tumor cells, and induction of cancer stem cells (CSCs) in the tumor-bone and tumor-subcutaneous microenvironments (TB- and TS-microE). Methods: Mouse mammary tumor cells were transplanted onto the calvaria or into a subcutaneous lesion of female mice, creating a TB-microE and a TS-microE, and the mice were then treated with hOCIF. To investigate the preventive effects of hOCIF, mice were treated with hOCIF before tumor cell implantation onto the calvaria (Pre), after (Post), and both before and after (Whole). The number of CSCs and cytokine levels were evaluated by IHC and ELISA assay, respectively. Results: hOCIF suppressed osteolysis, and growth of mammary tumors in the TB-microE, but not in the TS-microE. In the Pre, Post, and Whole groups, hOCIF suppressed osteolysis, and cell proliferation. hOCIF increased mouse osteoprotegrin (mOPG) levels in vivo, which suppressed mammary tumor cell proliferation in vitro. These preventive effects were observed in the dose-dependent. hOCIF did not affect the induction of CSCs in either microenvironment. Conclusion: While receptor activator of NF-κB ligand (RANKL) targeting therapy may not affect the induction of CSCs, RANKL is a potential target for prevention as well as treatment of breast cancer bone metastasis. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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Review

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21 pages, 1932 KiB

Open AccessReview

Bone Metastasis Pain, from the Bench to the Bedside

by Federica Aielli, Marco Ponzetti and Nadia Rucci

Int. J. Mol. Sci. 2019, 20(2), 280; https://doi.org/10.3390/ijms20020280 - 11 Jan 2019

Cited by 60 | Viewed by 7750

Abstract

Bone is the most frequent site of metastasis of the most common cancers in men and women. Bone metastasis incidence has been steadily increasing over the years, mainly because of higher life expectancy in oncologic patients. Although bone metastases are sometimes asymptomatic, their consequences are most often devastating, impairing both life quality and expectancy, due to the occurrence of the skeletal-related events, including bone fractures, hypercalcemia and spinal cord compression. Up to 75% of patients endure crippling cancer-induced bone pain (CIBP), against which we have very few weapons. This review’s purpose is to discuss the molecular and cellular mechanisms that lead to CIBP, including how cancer cells convert the bone “virtuous cycle” into a cancer-fuelling “vicious cycle”, and how this leads to the release of molecular mediators of pain, including protons, neurotrophins, interleukins, chemokines and ATP. Preclinical tests and assays to evaluate CIBP, including the incapacitance tester (in vivo), and neuron/glial activation in the dorsal root ganglia/spinal cord (ex vivo) will also be presented. Furthermore, current therapeutic options for CIBP are quite limited and nonspecific and they will also be discussed, along with up-and-coming options that may render CIBP easier to treat and let patients forget they are patients. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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12 pages, 228 KiB

Open AccessReview

Cellular and Molecular Mediators of Bone Metastatic Lesions

by Giulia Battafarano, Michela Rossi, Francesco Marampon and Andrea Del Fattore

Int. J. Mol. Sci. 2018, 19(6), 1709; https://doi.org/10.3390/ijms19061709 - 8 Jun 2018

Cited by 16 | Viewed by 4526

Abstract

Bone is the preferential site of metastasis for breast and prostate tumor. Cancer cells establish a tight relationship with the host tissue, secreting factors that stimulate or inhibit bone cells, receiving signals generated from the bone remodeling activity, and displaying some features of bone cells. This interplay between tumor and bone cells alters the physiological bone remodeling, leading to the generation of a vicious cycle that promotes bone metastasis growth. To prevent the skeletal-related events (SRE) associated with bone metastasis, approaches to inhibit osteoclast bone resorption are reported. The bisphosphonates and Denosumab are currently used in the treatment of patients affected by bone lesions. They act to prevent or counteract the SRE, including pathologic fractures, spinal cord compression, and pain associated with bone metastasis. However, their primary effects on tumor cells still remain controversial. In this review, a description of the mechanisms leading to the onset of bone metastasis and clinical approaches to treat them are described. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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13 pages, 3114 KiB

Open AccessReview

The Role of Extracellular Vesicles in Bone Metastasis

by Michela Rossi, Giulia Battafarano, Matteo D’Agostini and Andrea Del Fattore

Int. J. Mol. Sci. 2018, 19(4), 1136; https://doi.org/10.3390/ijms19041136 - 10 Apr 2018

Cited by 36 | Viewed by 6924

Abstract

Multiple types of cancer have the specific ability to home to the bone microenvironment and cause metastatic lesions. Despite being the focus of intense investigation, the molecular and cellular mechanisms that regulate the metastasis of disseminated tumor cells still remain largely unknown. Bone metastases severely impact quality of life since they are associated with pain, fractures, and bone marrow aplasia. In this review, we will summarize the recent discoveries on the role of extracellular vesicles (EV) in the regulation of bone remodeling activity and bone metastasis occurrence. Indeed, it was shown that extracellular vesicles, including exosomes and microvesicles, released from tumor cells can modify the bone microenvironment, allowing the formation of osteolytic, osteosclerotic, and mixed mestastases. In turn, bone-derived EV can stimulate the proliferation of tumor cells. The inhibition of EV-mediated crosstalk between cancer and bone cells could represent a new therapeutic target for bone metastasis. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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34 pages, 15302 KiB

Open AccessReview

Mesenchymal Stromal Cells: Emerging Roles in Bone Metastasis

by Nicola Graham and Bin-Zhi Qian

Int. J. Mol. Sci. 2018, 19(4), 1121; https://doi.org/10.3390/ijms19041121 - 9 Apr 2018

Cited by 36 | Viewed by 7276

Abstract

Bone metastasis is the most advanced stage of many cancers and indicates a poor prognosis for patients due to resistance to anti-tumor therapies. The establishment of metastasis within the bone is a multistep process. To ensure survival within the bone marrow, tumor cells must initially colonize a niche in which they can enter dormancy. Subsequently, reactivation permits the proliferation and growth of the tumor cells, giving rise to a macro-metastasis displayed clinically as a bone metastatic lesion. Here, we review the evidences that suggest mesenchymal stromal cells play an important role in each of these steps throughout the development of bone metastasis. Similarities between the molecular mechanisms implicated in these processes and those involved in the homeostasis of the bone indicate that the metastatic cells may exploit the homeostatic processes to their own advantage. Identifying the molecular interactions between the mesenchymal stromal cells and tumor cells that promote tumor development may offer insight into potential therapeutic targets that could be utilized to treat bone metastasis. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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20 pages, 913 KiB

Open AccessReview

Understanding the Progression of Bone Metastases to Identify Novel Therapeutic Targets

by Annie Schmid-Alliana, Heidy Schmid-Antomarchi, Rasha Al-Sahlanee, Patricia Lagadec, Jean-Claude Scimeca and Elise Verron

Int. J. Mol. Sci. 2018, 19(1), 148; https://doi.org/10.3390/ijms19010148 - 4 Jan 2018

Cited by 36 | Viewed by 10731

Abstract

Bone is one of the most preferential target site for cancer metastases, particularly for prostate, breast, kidney, lung and thyroid primary tumours. Indeed, numerous chemical signals and growth factors produced by the bone microenvironment constitute factors promoting cancer cell invasion and aggression. After reviewing the different theories proposed to provide mechanism for metastatic progression, we report on the gene expression profile of bone-seeking cancer cells. We also discuss the cross-talk between the bone microenvironment and invading cells, which impacts on the tumour actions on surrounding bone tissue. Lastly, we detail therapies for bone metastases. Due to poor prognosis for patients, the strategies mainly aim at reducing the impact of skeletal-related events on patients’ quality of life. However, recent advances have led to a better understanding of molecular mechanisms underlying bone metastases progression, and therefore of novel therapeutic targets. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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620 KiB

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Targeted α Therapies for the Treatment of Bone Metastases

by Fable Zustovich and Roberto Barsanti

Int. J. Mol. Sci. 2018, 19(1), 74; https://doi.org/10.3390/ijms19010074 - 28 Dec 2017

Cited by 23 | Viewed by 5363

Abstract

The skeleton is the target tissue for many types of tumors, and, recently, the survival of patients with prostate cancer metastasis has been increased using α-emitting drugs known as targeted α therapies. The use of α-radiopharmaceuticals in medicine was hypothesized at the beginning of the nineteenth century after the observation that α-radionuclides were associated with high cell-killing energy and low tissue penetration in healthy tissues. In the prostate cancer (PC) scenario, current research suggests that this class of radiopharmaceuticals has limited toxicity, and that the mechanism of action does not overlap with pre-existing drugs, allowing us to extend therapeutic armaments and address medical oncology towards personalized and precision medicine. Ongoing studies may extend these benefits also to bone metastases deriving from other neoplasms. The aim of this review is to summarize the current research on targeted α therapies and try to identify the right patient to be treated in the right time in order to integrate in these medications in the every-day clinical practice. Full article

(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)

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