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Bone Metastasis Challenge: New Ideas and Future Perspectives

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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 (31 March 2021) | Viewed by 21633

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Special Issue Editors

Dr. Manuel Scimeca

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Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: environmental pollution; oncology; cardiovascular diseases; electron microscopy; histology
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Prof. Dr. Orazio Schillaci

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Division of Nuclear Medicine, Universita degli Studi di Roma Tor Vergata, Rome, Italy
Interests: molecular imaging; precision oncology; targeted therapy; theranostics
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Prof. Dr. Elena Bonanno

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Department of Anatomic Pathology, University of Rome Tor Vergata, Rome, Italy
Interests: breast cancer
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Dr. Nicoletta Urbano

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Fondazione Policlinico Tor Vergata, Rome, Nuclear Medicine Unit, Rome, Italy
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Dr. Rita Bonfiglio

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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

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Keywords

bone metastasis
epithelial-to-mesenchymal transition
immuno-escape
cancer stem cells
tumor invasion
biomarkers
circulationg tumor cells

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

2 pages, 169 KiB

Open AccessEditorial

Bone Metastasis Challenge: New Ideas and Future

by Manuel Scimeca

Int. J. Mol. Sci. 2023, 24(7), 6161; https://doi.org/10.3390/ijms24076161 - 24 Mar 2023

Cited by 2 | Viewed by 1141

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

Open AccessArticle

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://doi.org/10.3390/ijms22136663 - 22 Jun 2021

Cited by 3 | Viewed by 3117

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 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

Open AccessArticle

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://doi.org/10.3390/ijms22115570 - 25 May 2021

Cited by 4 | Viewed by 3558

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 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

Open AccessArticle

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://doi.org/10.3390/ijms22105280 - 17 May 2021

Cited by 16 | Viewed by 3204

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 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

Open AccessArticle

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://doi.org/10.3390/ijms22010233 - 28 Dec 2020

Cited by 28 | Viewed by 3234

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 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

Open AccessArticle

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://doi.org/10.3390/ijms21228569 - 13 Nov 2020

Cited by 5 | Viewed by 2295

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 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

Open AccessReview

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://doi.org/10.3390/ijms22136869 - 26 Jun 2021

Cited by 31 | Viewed by 4052

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 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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