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Special Issue "Bone Metastasis: Pathophysiology and Molecular Mechanisms"

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)

Special Issue Editor

Guest Editor
Prof. Dr. Ingunn Holen

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Website | E-Mail
Interests: breast cancer; bone metastases; microenvironment; bone microvasculature; tumour cell dormancy

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (9 papers)

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Research

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Open AccessArticle Dynamic Collision Behavior Between Osteoblasts and Tumor Cells Regulates the Disordered Arrangement of Collagen Fiber/Apatite Crystals in Metastasized Bone
Int. J. Mol. Sci. 2018, 19(11), 3474; https://doi.org/10.3390/ijms19113474
Received: 29 September 2018 / Revised: 25 October 2018 / Accepted: 2 November 2018 / Published: 5 November 2018
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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;
[...] Read more.
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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Open AccessArticle Parathyroid Hormone (PTH) Increases Skeletal Tumour Growth and Alters Tumour Distribution in an In Vivo Model of Breast Cancer
Int. J. Mol. Sci. 2018, 19(10), 2920; https://doi.org/10.3390/ijms19102920
Received: 2 August 2018 / Revised: 5 September 2018 / Accepted: 12 September 2018 / Published: 26 September 2018
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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
[...] Read more.
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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Open AccessArticle Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity
Int. J. Mol. Sci. 2018, 19(4), 1223; https://doi.org/10.3390/ijms19041223
Received: 26 March 2018 / Revised: 14 April 2018 / Accepted: 14 April 2018 / Published: 18 April 2018
Cited by 2 | PDF Full-text (5556 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
[...] Read more.
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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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
Int. J. Mol. Sci. 2018, 19(3), 888; https://doi.org/10.3390/ijms19030888
Received: 29 January 2018 / Revised: 2 March 2018 / Accepted: 14 March 2018 / Published: 16 March 2018
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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
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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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Open AccessReview Cellular and Molecular Mediators of Bone Metastatic Lesions
Int. J. Mol. Sci. 2018, 19(6), 1709; https://doi.org/10.3390/ijms19061709
Received: 7 May 2018 / Revised: 1 June 2018 / Accepted: 6 June 2018 / Published: 8 June 2018
Cited by 1 | PDF Full-text (228 KB) | HTML Full-text | XML Full-text
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
[...] Read more.
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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Open AccessReview The Role of Extracellular Vesicles in Bone Metastasis
Int. J. Mol. Sci. 2018, 19(4), 1136; https://doi.org/10.3390/ijms19041136
Received: 28 February 2018 / Revised: 5 April 2018 / Accepted: 5 April 2018 / Published: 10 April 2018
Cited by 2 | PDF Full-text (3114 KB) | HTML Full-text | XML Full-text
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
[...] Read more.
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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Open AccessReview Mesenchymal Stromal Cells: Emerging Roles in Bone Metastasis
Int. J. Mol. Sci. 2018, 19(4), 1121; https://doi.org/10.3390/ijms19041121
Received: 9 February 2018 / Revised: 25 March 2018 / Accepted: 29 March 2018 / Published: 9 April 2018
Cited by 2 | PDF Full-text (15302 KB) | HTML Full-text | XML Full-text
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
[...] Read more.
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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Open AccessReview Understanding the Progression of Bone Metastases to Identify Novel Therapeutic Targets
Int. J. Mol. Sci. 2018, 19(1), 148; https://doi.org/10.3390/ijms19010148
Received: 21 November 2017 / Revised: 22 December 2017 / Accepted: 2 January 2018 / Published: 4 January 2018
PDF Full-text (913 KB) | HTML Full-text | XML Full-text
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
[...] Read more.
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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Open AccessReview Targeted α Therapies for the Treatment of Bone Metastases
Int. J. Mol. Sci. 2018, 19(1), 74; https://doi.org/10.3390/ijms19010074
Received: 14 November 2017 / Revised: 27 November 2017 / Accepted: 6 December 2017 / Published: 28 December 2017
Cited by 2 | PDF Full-text (620 KB) | HTML Full-text | XML Full-text
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
[...] Read more.
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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