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Bone Metastasis Challenge: New Ideas and Future Perspectives
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Bone Metastasis Challenge: New Ideas and Future Perspectives

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 (31 March 2021) | Viewed by 17470

Special Issue Editors

Dr. Manuel Scimeca

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Guest Editor
Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: environmental pollution; oncology; cardiovascular diseases; electron microscopy; histology
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Orazio Schillaci

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Guest Editor
Division of Nuclear Medicine, Universita degli Studi di Roma Tor Vergata, Rome, Italy
Interests: molecular imaging; precision oncology; targeted therapy; theranostics
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Elena Bonanno

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Guest Editor
Department of Anatomic Pathology, University of Rome Tor Vergata, Rome, Italy
Interests: breast cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Nicoletta Urbano

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Guest Editor
Fondazione Policlinico Tor Vergata, Rome, Nuclear Medicine Unit, Rome, Italy
Special Issues, Collections and Topics in MDPI journals
Dr. Rita Bonfiglio

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Guest Editor
Università degli Studi di Roma Tor Vergata, Department of Experimental Medicine, Rome, Italy

Special Issue Information

Dear Colleagues,

Metastatization is a highly orchestrated process that involves several molecular mechanisms such as loss of intercellular cohesion, cell migration, angiogenesis, cell access to systemic circulation, cell survival in the circulation, evasion of local immune responses, and growth in distant organs. Bone represents the third most frequent site of metastasis; some types of cancer, including breast cancer and prostate cancer, are particularly likely to spread to bone.  The presence of bone metastatic lesions highly affects patients‘ quality of life. Indeed, bone metastases are a major cause of morbidity, characterized by severe pain, impaired mobility, pathologic fractures, spinal cord compression, and hypercalcemia. However, the molecular mechanisms of tumor osteotropism are not fully understood. Currently, neither biomarkers nor instrumental investigations are able to early identify lesions with high bone metastatic potential. In addition, no therapeutic perspectives are available for patients affected by bone metastatic lesions. Starting from these considerations, the aim of this Special Issue is to publish the latest discoveries and bring together researchers and clinicians working in the field of “Bone Metastases”. Topics will include (but are not limited to): 


-          Molecular mechanisms of cancer escape
-          Homing of cancer cells to bone sites
-          Epithelial-to-mesenchymal transition vs. mesenchymal-to-epithelial transition
-          Role of cancer stem cells in the development of bone metastases
-          Circulating tumor cells
-          Biomarkers of tumor osteotropism
-          Molecular imaging of bone metastases
-          Therapeutic and theragnostic perspectives 

Dr. Manuel Scimeca
Prof. Orazio Schillaci
Prof. Elena Bonanno
Dr. Nicoletta Urbano
Dr. Rita Bonfiglio
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 submissions that pass pre-check are 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 semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 metastasis
  • epithelial-to-mesenchymal transition
  • immuno-escape
  • cancer stem cells
  • tumor invasion
  • biomarkers
  • circulationg tumor cells

Published Papers (7 papers)

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Editorial

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2 pages, 169 KiB  
Editorial
Bone Metastasis Challenge: New Ideas and Future
by Manuel Scimeca
Int. J. Mol. Sci. 2023, 24(7), 6161; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076161 - 24 Mar 2023
Cited by 1 | Viewed by 816
Abstract
Bone metastasis is a complex and challenging clinical problem, affecting patients with advanced stages of cancer [...] Full article
(This article belongs to the Special Issue Bone Metastasis Challenge: New Ideas and Future Perspectives)

Research

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21 pages, 22804 KiB  
Article
Expression Profile of New Marker Genes Involved in Differentiation of Canine Adipose-Derived Stem Cells into Osteoblasts
by Maurycy Jankowski, Mariusz Kaczmarek, Grzegorz Wąsiatycz, Claudia Dompe, Paul Mozdziak, Jędrzej M. Jaśkowski, Hanna Piotrowska-Kempisty and Bartosz Kempisty
Int. J. Mol. Sci. 2021, 22(13), 6663; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136663 - 22 Jun 2021
Cited by 2 | Viewed by 2582
Abstract
Next-generation sequencing (RNAseq) analysis of gene expression changes during the long-term in vitro culture and osteogenic differentiation of ASCs remains to be important, as the analysis provides important clues toward employing stem cells as a therapeutic intervention. In this study, the cells were [...] Read more.
Next-generation sequencing (RNAseq) analysis of gene expression changes during the long-term in vitro culture and osteogenic differentiation of ASCs remains to be important, as the analysis provides important clues toward employing stem cells as a therapeutic intervention. In this study, the cells were isolated from adipose tissue obtained during routine surgical procedures and subjected to 14-day in vitro culture and differentiation. The mRNA transcript levels were evaluated using the Illumina platform, resulting in the detection of 19,856 gene transcripts. The most differentially expressed genes (fold change >|2|, adjusted p value < 0.05), between day 1, day 14 and differentiated cell cultures were extracted and subjected to bioinformatical analysis based on the R programming language. The results of this study provide molecular insight into the processes that occur during long-term in vitro culture and osteogenic differentiation of ASCs, allowing the re-evaluation of the roles of some genes in MSC progression towards a range of lineages. The results improve the knowledge of the molecular mechanisms associated with long-term in vitro culture and differentiation of ASCs, as well as providing a point of reference for potential in vivo and clinical studies regarding these cells’ application in regenerative medicine. Full article
(This article belongs to the Special Issue Bone Metastasis Challenge: New Ideas and Future Perspectives)
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15 pages, 2403 KiB  
Article
Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model
by Mari I. Suominen, Jenni Mäki-Jouppila, Anna Huhtinen, Birgitta Sjöholm, Jukka P. Rissanen, Anniina Luostarinen, Katja M. Fagerlund, Esa Alhoniemi, Gerhard Siemeister, Dominik Mumberg, Sanna-Maria Käkönen and Arne Scholz
Int. J. Mol. Sci. 2021, 22(11), 5570; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115570 - 25 May 2021
Cited by 4 | Viewed by 3054
Abstract
Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha [...] Read more.
Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor–bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease. Full article
(This article belongs to the Special Issue Bone Metastasis Challenge: New Ideas and Future Perspectives)
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14 pages, 2641 KiB  
Article
Cold Atmospheric Plasma Promotes Regeneration-Associated Cell Functions of Murine Cementoblasts In Vitro
by Benedikt Eggers, Jana Marciniak, James Deschner, Matthias Bernhard Stope, Alexander Mustea, Franz-Josef Kramer and Marjan Nokhbehsaim
Int. J. Mol. Sci. 2021, 22(10), 5280; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105280 - 17 May 2021
Cited by 16 | Viewed by 2597
Abstract
The aim of the study was to examine the efficacy of cold atmospheric plasma (CAP) on the mineralization and cell proliferation of murine dental cementoblasts. Cells were treated with CAP and enamel matrix derivates (EMD). Gene expression of alkaline phosphatase (ALP), bone gamma-carboxyglutamate [...] Read more.
The aim of the study was to examine the efficacy of cold atmospheric plasma (CAP) on the mineralization and cell proliferation of murine dental cementoblasts. Cells were treated with CAP and enamel matrix derivates (EMD). Gene expression of alkaline phosphatase (ALP), bone gamma-carboxyglutamate protein (BGLAP), periostin (POSTN), osteopontin (OPN), osterix (OSX), collagen type I alpha 1 chain (COL1A1), dentin matrix acidic phosphoprotein (DMP)1, RUNX family transcription factor (RUNX)2, and marker of proliferation Ki-67 (KI67) was quantified by real-time PCR. Protein expression was analyzed by immunocytochemistry and ELISA. ALP activity was determined by ALP assay. Von Kossa and alizarin red staining were used to display mineralization. Cell viability was analyzed by XTT assay, and morphological characterization was performed by DAPI/phalloidin staining. Cell migration was quantified with an established scratch assay. CAP and EMD upregulated both mRNA and protein synthesis of ALP, POSTN, and OPN. Additionally, DMP1 and COL1A1 were upregulated at both gene and protein levels. In addition to upregulated RUNX2 mRNA levels, treated cells mineralized more intensively. Moreover, CAP treatment resulted in an upregulation of KI67, higher cell viability, and improved cell migration. Our study shows that CAP appears to have stimulatory effects on regeneration-associated cell functions in cementoblasts. Full article
(This article belongs to the Special Issue Bone Metastasis Challenge: New Ideas and Future Perspectives)
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11 pages, 2797 KiB  
Article
Osteoprotective Effects of Loganic Acid on Osteoblastic and Osteoclastic Cells and Osteoporosis-Induced Mice
by Eunkuk Park, Chang Gun Lee, Eunguk Lim, Seokjin Hwang, Seung Hee Yun, Jeonghyun Kim, Hyesoo Jeong, Yoonjoong Yong, Seong-Hoon Yun, Chun Whan Choi, Hyun-Seok Jin and Seon-Yong Jeong
Int. J. Mol. Sci. 2021, 22(1), 233; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010233 - 28 Dec 2020
Cited by 21 | Viewed by 2606
Abstract
Osteoporosis is a common disease caused by an imbalance of processes between bone resorption by osteoclasts and bone formation by osteoblasts in postmenopausal women. The roots of Gentiana lutea L. (GL) are reported to have beneficial effects on various human diseases related to [...] Read more.
Osteoporosis is a common disease caused by an imbalance of processes between bone resorption by osteoclasts and bone formation by osteoblasts in postmenopausal women. The roots of Gentiana lutea L. (GL) are reported to have beneficial effects on various human diseases related to liver functions and gastrointestinal motility, as well as on arthritis. Here, we fractionated and isolated bioactive constituent(s) responsible for anti-osteoporotic effects of GL root extract. A single phytochemical compound, loganic acid, was identified as a candidate osteoprotective agent. Its anti-osteoporotic effects were examined in vitro and in vivo. Treatment with loganic acid significantly increased osteoblastic differentiation in preosteoblast MC3T3-E1 cells by promoting alkaline phosphatase activity and increasing mRNA expression levels of bone metabolic markers such as Alpl, Bglap, and Sp7. However, loganic acid inhibited osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. For in vivo experiments, the effect of loganic acid on ovariectomized (OVX) mice was examined for 12 weeks. Loganic acid prevented OVX-induced bone mineral density loss and improved bone structural properties in osteoporotic model mice. These results suggest that loganic acid may be a potential therapeutic candidate for treatment of osteoporosis. Full article
(This article belongs to the Special Issue Bone Metastasis Challenge: New Ideas and Future Perspectives)
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11 pages, 1251 KiB  
Article
TGF-β in the Secretome of Irradiated Peripheral Blood Mononuclear Cells Supports In Vitro Osteoclastogenesis
by Layla Panahipour, Zahra Kargarpour, Maria Laggner, Michael Mildner, Hendrik J. Ankersmit and Reinhard Gruber
Int. J. Mol. Sci. 2020, 21(22), 8569; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228569 - 13 Nov 2020
Cited by 5 | Viewed by 1864
Abstract
Osteoclastogenesis required for bone remodeling is also a key pathologic mechanism of inflammatory osteolysis being controlled by paracrine factors released from dying cells. The secretome of irradiated, dying peripheral blood mononuclear cells (PBMCs) has a major impact on the differentiation of myeloid cells [...] Read more.
Osteoclastogenesis required for bone remodeling is also a key pathologic mechanism of inflammatory osteolysis being controlled by paracrine factors released from dying cells. The secretome of irradiated, dying peripheral blood mononuclear cells (PBMCs) has a major impact on the differentiation of myeloid cells into dendritic cells, and macrophage polarization. The impact on osteoclastogenesis, however, has not been reported. For this aim, we used murine bone marrow macrophages exposed to RANKL and M-CSF to initiate osteoclastogenesis, with and without the secretome obtained from γ-irradiated PBMCs. We reported that the secretome significantly enhanced in vitro osteoclastogenesis as determined by means of histochemical staining of the tartrate-resistant acid phosphatase (TRAP), as well as the expression of the respective target genes, including TRAP and cathepsin K. Considering that TGF-β enhanced osteoclastogenesis, we confirmed the TGF-β activity in the secretome with a bioassay that was based on the increased expression of IL11 in fibroblasts. Neutralizing TGF-β by an antibody decreased the ability of the secretome to support osteoclastogenesis. These findings suggested that TGF-β released by irradiated PBMCs could enhance the process of osteoclastogenesis in vitro. Full article
(This article belongs to the Special Issue Bone Metastasis Challenge: New Ideas and Future Perspectives)
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Review

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21 pages, 3894 KiB  
Review
Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer
by Zintle Mbese and Blessing A. Aderibigbe
Int. J. Mol. Sci. 2021, 22(13), 6869; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136869 - 26 Jun 2021
Cited by 23 | Viewed by 3036
Abstract
Metastatic bone cancer occurs in every type of cancer but is prevalent in lung, breast, and prostate cancers. These metastases can cause extensive morbidity, including a range of skeletal-related events, often painful and linked with substantial hospital resource usage. The treatment used is [...] Read more.
Metastatic bone cancer occurs in every type of cancer but is prevalent in lung, breast, and prostate cancers. These metastases can cause extensive morbidity, including a range of skeletal-related events, often painful and linked with substantial hospital resource usage. The treatment used is a combination of chemotherapy and surgery. However, anticancer drugs are still limited due to severe side effects, drug resistance, poor blood supply, and non-specific drug uptake, necessitating high toxic doses. Bisphosphonates are the main class of drugs utilized to inhibit metastatic bone cancer. It is also used for the treatment of osteoporosis and other bone diseases. However, bisphosphonate also suffers from serious side effects. Thus, there is a serious need to develop bisphosphonate conjugates with promising therapeutic outcomes for treating metastatic bone cancer and osteoporosis. This review article focuses on the biological outcomes of designed bisphosphonate-based conjugates for the treatment of metastatic bone cancer and osteoporosis. Full article
(This article belongs to the Special Issue Bone Metastasis Challenge: New Ideas and Future Perspectives)
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