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Molecular and Translational Research on Bone Tumors

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 26488

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Dr. Andrea Del Fattore

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Guest Editor

Bone Physiopathology Group, Multifactorial Disease and Complex Phenotype Research Area, Bambino Gesù Children’s Hospital, 00146 Rome, Italy
Interests: bone cell biology; bone diseases; bone regeneration; mesenchymal stem cells; osteoclasts; osteoblasts; osteocytes; extracellular vesicles
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Dr. Michela Rossi

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Guest Editor

Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS Viale San Paolo, 1500146 Rome, Italy
Interests: bone cell biology; bone diseases; osteoclasts; osteoblasts; osteocytes; bone metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bone tumours can affect every part of the skeleton and can develop in any part of the bone, from the centre to the surface. Their growth can destroy healthy tissue and reduce bone strength, causing pathologic fractures. Primary bone tumours and metastases are characterized by the perturbation of physiological bone remodelling activity by osteoblasts and osteoclasts. The crosstalk between cancer and bone cells allows the growth and the spread of the tumour.

Due to the unknown aetiology, complexity and heterogeneity of most bone tumours, a better understanding of the mechanisms underlying the oncogenesis is still necessary.

This Special Issue will focus both on benign and malignant bone tumours, in particular on:

The analysis of the molecular and cellular mechanisms leading to the onset of these tumours;

The identification of new therapeutic approaches;

The detection of biomarkers for early diagnosis.

Both original research and review articles are welcome.

Dr. Andrea Del Fattore
Dr. Michela Rossi
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

Primary bone tumours
Metastatic bone tumour
Therapy
Biomarkers
Epigenetic factors
Immune-oncology

Published Papers (10 papers)

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Editorial

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3 pages, 194 KiB

Open AccessEditorial

Molecular and Translational Research on Bone Tumors

by Michela Rossi and Andrea Del Fattore

Int. J. Mol. Sci. 2023, 24(3), 1946; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031946 - 18 Jan 2023

Cited by 4 | Viewed by 937

Abstract

Primary bone tumors (PBTs) represent a huge variety of rare malignancies that originate in the skeletal system [...] Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

Research

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20 pages, 4300 KiB

Open AccessArticle

CD44 Contributes to the Regulation of MDR1 Protein and Doxorubicin Chemoresistance in Osteosarcoma

by Monserrat Gerardo-Ramírez, Friederike L. Keggenhoff, Vanessa Giam, Diana Becker, Marco Groth, Nils Hartmann, Beate K. Straub, Helen Morrison, Peter R. Galle, Jens U. Marquardt, Peter Herrlich and Monika Hartmann

Int. J. Mol. Sci. 2022, 23(15), 8616; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158616 - 03 Aug 2022

Cited by 16 | Viewed by 2406

Abstract

Osteosarcoma is the most common type of pediatric bone tumor. Despite great advances in chemotherapy during the past decades, the survival rates of osteosarcoma patients remain unsatisfactory. Drug resistance is one of the main reasons, leading to treatment failure and poor prognosis. Previous reports correlated expression of cluster of differentiation 44 (CD44) with drug resistance and poor survival of osteosarcoma patients, however the underlying mechanisms are poorly defined. Here, we investigated the role of CD44 in the regulation of drug chemoresistance, using osteosarcoma cells isolated from mice carrying a mutation of the tumor suppressor neurofibromatosis type 2 (Nf2) gene. CD44 expression was knocked-down in the cells using CRISPR/Cas9 approach. Subsequently, CD44 isoforms and mutants were re-introduced to investigate CD44-dependent processes. Sensitivity to doxorubicin was analyzed in the osteosarcoma cells with modified CD44 expression by immunoblot, colony formation- and WST-1 assay. To dissect the molecular alterations induced by deletion of Cd44, RNA sequencing was performed on Cd44-positive and Cd44-negative primary osteosarcoma tissues isolated from Nf2-mutant mice. Subsequently, expression of candidate genes was evaluated by quantitative reverse transcription PCR (qRT-PCR). Our results indicate that CD44 increases the resistance of osteosarcoma cells to doxorubicin by up-regulating the levels of multidrug resistance (MDR) 1 protein expression, and suggest the role of proteolytically released CD44 intracellular domain, and hyaluronan interactions in this process. Moreover, high throughput sequencing analysis identified differential regulation of several apoptosis-related genes in Cd44-positive and -negative primary osteosarcomas, including p53 apoptosis effector related to PMP-22 (Perp). Deletion of Cd44 in osteosarcoma cells led to doxorubicin-dependent p53 activation and a profound increase in Perp mRNA expression. Overall, our results suggest that CD44 might be an important regulator of drug resistance and suggest that targeting CD44 can sensitize osteosarcoma to standard chemotherapy. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

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17 pages, 3898 KiB

Open AccessArticle

Analyzing BMP2, FGFR, and TGF Beta Expressions in High-Grade Osteosarcoma Untreated and Treated Autografts Using Proteomic Analysis

by Rashmi Madda, Chao-Ming Chen, Cheng-Fong Chen, Jir-You Wang, Hsin-Yi Wu, Po-Kuei Wu and Wei-Ming Chen

Int. J. Mol. Sci. 2022, 23(13), 7409; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137409 - 03 Jul 2022

Cited by 1 | Viewed by 2398

Abstract

In the last few decades, biological reconstruction techniques have improved greatly for treating high-grade osteosarcoma patients. To conserve the limb, and its function the affected tumor-bearing bones have been treated using liquid nitrogen and irradiation processes that enable the removal of entire tumors from the bone, and these treated autografts can be reconstructed for the patients. Here, we focus on the expressions of the growth factor family proteins from the untreated and treated autografts that play a crucial role in bone union, remodeling, and regeneration. In this proteomic study, we identify several important cytoskeletal, transcriptional, and growth factor family proteins that showed substantially low levels in untreated autografts. Interestingly, these protein expressions were elevated after treating the tumor-bearing bones using liquid nitrogen and irradiation. Therefore, from our preliminary findings, we chose to determine the expressions of BMP2, TGF-Beta, and FGFR proteins by the target proteomics approach. Using a newly recruited validation set, we successfully validate the expressions of the selected proteins. Furthermore, the increased growth factor protein expression after treatment with liquid nitrogen may contribute to bone regeneration healing, assist in faster recovery, and reduce local recurrence and metastatic spread in high-grade sarcoma patients. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

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24 pages, 5535 KiB

Open AccessArticle

New Borane-Protected Derivatives of α-Aminophosphonous Acid as Anti-Osteosarcoma Agents: ADME Analysis and Molecular Modeling, In Vitro Studies on Anti-Cancer Activities, and NEP Inhibition as a Possible Mechanism of Anti-Proliferative Activity

by Magdalena Mizerska-Kowalska, Sylwia Sowa, Beata Donarska, Wojciech Płaziński, Adrianna Sławińska-Brych, Aleksandra Tomasik, Anna Ziarkowska, Krzysztof Z. Łączkowski and Barbara Zdzisińska

Int. J. Mol. Sci. 2022, 23(12), 6716; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126716 - 16 Jun 2022

Cited by 5 | Viewed by 1751

Abstract

Many organophosphorus compounds (OPs), especially various α-aminophosphonates, exhibit anti-cancer activities. They act, among others, as inhibitors of the proteases implicated in cancerogenesis. Thesetypes of inhibitors weredescribed, e.g., for neutral endopeptidase (NEP) expressed in different cancer cells, including osteosarcoma (OS). The aim of the present study isto evaluate new borane-protected derivatives of phosphonous acid (compounds 1–7) in terms of their drug-likeness properties, anti-osteosarcoma activities in vitro (against HOS and Saos-2 cells), and use as potential NEP inhibitors. The results revealed that all tested compounds exhibited the physicochemical and ADME properties typical for small-molecule drugs. However, compound 4 did not show capability of blood–brain barrier penetration (Lipiński and Veber rules;SwissAdme tool). Moreover, the α-aminophosphonite-boranes (compounds 4–7) exhibited stronger anti-proliferative activity against OS cells than the other phosphonous acid-borane derivatives (compounds 1–3),especially regarding HOS cells (MTT assay). The most promising compounds 4 and 6 induced apoptosis through the activation of caspase 3 and/or cell cycle arrest at the G₂ phase (flow cytometry). Compound 4 inhibited the migration and invasiveness of highly aggressive HOS cells (wound/transwell and BME-coated transwell assays, respectively). Additionally, compound 4 and, to a lesser extent, compound 6 inhibited NEP activity (fluorometric assay). This activity of compound 4 was involved in its anti-proliferative potential (BrdU assay). The present study shows that compound 4 can be considered a potential anti-osteosarcoma agent and a scaffold for the development of new NEP inhibitors. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

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25 pages, 4403 KiB

Open AccessArticle

Proteomic Assessment of Extracellular Vesicles from Canine Tissue Explants as a Pipeline to Identify Molecular Targets in Osteosarcoma: PSMD14/Rpn11 as a Proof of Principle

by Anita K. Luu, Mia Cadieux, Mackenzie Wong, Rachel Macdonald, Robert Jones, Dongsic Choi, Michelle Oblak, Brigitte Brisson, Scott Sauer, James Chafitz, David Warshawsky, Geoffrey A. Wood and Alicia M. Viloria-Petit

Int. J. Mol. Sci. 2022, 23(6), 3256; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063256 - 17 Mar 2022

Cited by 6 | Viewed by 2582

Abstract

Osteosarcoma (OS) is a highly malignant bone tumour that has seen little improvement in treatment modalities in the past 30 years. Understanding what molecules contribute to OS biology could aid in the discovery of novel therapies. Extracellular vesicles (EVs) serve as a mode of cell-to-cell communication and have the potential to uncover novel protein signatures. In our research, we developed a novel pipeline to isolate, characterize, and profile EVs from normal bone and osteosarcoma tissue explants from canine OS patients. Proteomic analysis of vesicle preparations revealed a protein signature related to protein metabolism. One molecule of interest, PSMD14/Rpn11, was explored further given its prognostic potential in human and canine OS, and its targetability with the drug capzimin. In vitro experiments demonstrated that capzimin induces apoptosis and reduces clonogenic survival, proliferation, and migration in two metastatic canine OS cell lines. Capzimin also reduces the viability of metastatic human OS cells cultured under 3D conditions that mimic the growth of OS cells at secondary sites. This unique pipeline can improve our understanding of OS biology and identify new prognostic markers and molecular targets for both canine and human OS patients. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

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18 pages, 28060 KiB

Open AccessArticle

15d-PGJ₂ Promotes ROS-Dependent Activation of MAPK-Induced Early Apoptosis in Osteosarcoma Cell In Vitro and in an Ex Ovo CAM Assay

by Mateja Mikulčić, Nassim Ghaffari Tabrizi-Wizsy, Eva M. Bernhart, Martin Asslaber, Christopher Trummer, Werner Windischhofer, Wolfgang Sattler, Ernst Malle and Andelko Hrzenjak

Int. J. Mol. Sci. 2021, 22(21), 11760; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111760 - 29 Oct 2021

Cited by 6 | Viewed by 2194

Abstract

Osteosarcoma (OS) is the most common type of bone tumor, and has limited therapy options. 15-Deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) has striking anti-tumor effects in various tumors. Here, we investigated molecular mechanisms that mediate anti-tumor effects of 15d-PGJ₂ in different OS cell lines. Human U2-OS and Saos-2 cells were treated with 15d-PGJ₂ and cell survival was measured by MTT assay. Cell proliferation and motility were investigated by scratch assay, the tumorigenic capacity by colony forming assay. Intracellular ROS was estimated by H₂DCFDA. Activation of MAPKs and cytoprotective proteins was detected by immunoblotting. Apoptosis was detected by immunoblotting and Annexin V/PI staining. The ex ovo CAM model was used to study growth capability of grafted 15d-PGJ₂-treated OS cells, followed by immunohistochemistry with hematoxylin/eosin and Ki-67. 15d-PGJ₂ substantially decreased cell viability, colony formation and wound closure capability of OS cells. Non-malignant human osteoblast was less affected by 15d-PGJ₂. 15d-PGJ₂ induced rapid intracellular ROS production and time-dependent activation of MAPKs (pERK1/2, pJNK and pp38). Tempol efficiently inhibited 15d-PGJ₂-induced ERK1/2 activation, while N-acetylcystein and pyrrolidine dithiocarbamate were less effective. Early but weak activation of cytoprotective proteins was overrun by induction of apoptosis. A structural analogue, 9,10-dihydro-15d-PGJ₂, did not show toxic effects in OS cells. In the CAM model, we grafted OS tumors with U2-OS, Saos-2 and MG-63 cells. 15d-PGJ₂ treatment resulted in significant growth inhibition, diminished tumor tissue density, and reduced tumor cell proliferation for all cell lines. Our in vitro and CAM data suggest 15d-PGJ₂ as a promising natural compound to interfere with OS tumor growth. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

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14 pages, 4172 KiB

Open AccessArticle

Suppression of Estrogen Receptor Alpha Inhibits Cell Proliferation, Differentiation and Enhances the Chemosensitivity of P53-Positive U2OS Osteosarcoma Cell

by Jir-You Wang, Chao-Ming Chen, Cheng-Fong Chen, Po-Kuei Wu and Wei-Ming Chen

Int. J. Mol. Sci. 2021, 22(20), 11238; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011238 - 18 Oct 2021

Cited by 4 | Viewed by 1998

Abstract

Osteosarcoma is a highly malignant musculoskeletal tumor that is commonly noticed in adolescent children, young children, and elderly adults. Due to advances in surgery, chemotherapy and imaging technology, survival rates have improved to 70–80%, but chemical treatments do not enhance patient survival; in addition, the survival rate after chemical treatments is still low. The most obvious clinical feature of osteosarcoma is new bone formation, which is called “sun burst”. Estrogen receptor alpha (ERα) is an essential feature of osteogenesis and regulates cell growth in various tumors, including osteosarcoma. In this study, we sought to investigate the role of ERα in osteosarcoma and to determine if ERα can be used as a target to facilitate the chemosensitivity of osteosarcoma to current treatments. The growth rate of each cell clone was assayed by MTT and trypan blue cell counting, and cell cycle analysis was conducted by flow cytometry. Osteogenic differentiation was induced by osteogenic induction medium and quantified by ARS staining. The effects of ERα on the chemoresponse of OS cells treated with doxorubicin were evaluated by colony formation assay. Mechanistic studies were conducted by examining the levels of proteins by Western blot. The role of ERα on OS prognosis was investigated by an immunohistochemical analysis of OS tissue array. The results showed an impaired growth rate and a decreased osteogenesis ability in the ERα-silenced P53(+) OS cell line U2OS, but not in P53(−) SAOS2 cells, compared with the parental cell line. Cotreatment with tamoxifen, an estrogen receptor inhibitor, increased the sensitivity to doxorubicin, which decreased the colony formation of P53(+) U2OS cells. Cell cycle arrest in the S phase was observed in P53(+) U2OS cells cotreated with low doses of doxorubicin and tamoxifen, while increased levels of apoptosis factors indicated cell death. Moreover, patients with ER−/P53(+) U2OS showed better chemoresponse rates (necrosis rate > 90%) and impaired tumor sizes, which were compatible with the findings of basic research. Taken together, ERα may be a potential target of the current treatments for osteosarcoma that can control tumor growth and improve chemosensitivity. In addition, the expression of ERα in osteosarcoma can be a prognostic factor to predict the response to chemotherapy. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

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Review

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25 pages, 919 KiB

Open AccessReview

Recent and Ongoing Research into Metastatic Osteosarcoma Treatments

by Michael A. Harris and Christine J. Hawkins

Int. J. Mol. Sci. 2022, 23(7), 3817; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073817 - 30 Mar 2022

Cited by 44 | Viewed by 6215

Abstract

The survival rate for metastatic osteosarcoma has not improved for several decades, since the introduction and refinement of chemotherapy as a treatment in addition to surgery. Over two thirds of metastatic osteosarcoma patients, many of whom are children or adolescents, fail to exhibit durable responses and succumb to their disease. Concerted efforts have been made to increase survival rates through identification of candidate therapies via animal studies and early phase trials of novel treatments, but unfortunately, this work has produced negligible improvements to the survival rate for metastatic osteosarcoma patients. This review summarizes data from clinical trials of metastatic osteosarcoma therapies as well as pre-clinical studies that report efficacy of novel drugs against metastatic osteosarcoma in vivo. Considerations regarding the design of animal studies and clinical trials to improve survival outcomes for metastatic osteosarcoma patients are also discussed. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

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14 pages, 314 KiB

Open AccessReview

Challenges of Systemic Therapy Investigations for Bone Sarcomas

by Kenji Nakano

Int. J. Mol. Sci. 2022, 23(7), 3540; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073540 - 24 Mar 2022

Cited by 10 | Viewed by 2352

Abstract

Bone sarcoma is a rare component of malignant solid tumors that accounts for only ~0.2% of malignancies. Bone sarcomas present various histological types, and genomic mutations differ markedly by the histological types. Although there are vast mutations in various bone sarcomas, most of them are non-actionable, and even potential targetable mutations that are actionable targets in other malignancies have not shown the appropriate responses in clinical trials for bone sarcomas. Investigations of new systemic therapy, including molecular targeted therapies for bone sarcomas, have thus not progressed like those for other solid tumors. Another problem is that high rates of pediatric/adolescent and young adult patients have bone sarcomas such as osteosarcoma, and patient recruitment for clinical trials (especially randomized trials) is challenging. For pediatric patients, evaluations of tolerability and appropriate dose modifications of new drugs are needed, as their findings could provide the threshold for investigating new drugs for bone sarcomas. To solve these problems, improvements in registry systems, real world data, and pediatric extrapolation have been attempted. We review the issues regarding targeted drug investigations for bone sarcomas, focusing on the current clinical evidence and efforts to resolve these issues. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

16 pages, 1318 KiB

Open AccessReview

Extracellular Vesicles in Osteosarcoma: Antagonists or Therapeutic Agents?

by Viviana De Martino, Michela Rossi, Giulia Battafarano, Jessica Pepe, Salvatore Minisola and Andrea Del Fattore

Int. J. Mol. Sci. 2021, 22(22), 12586; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212586 - 22 Nov 2021

Cited by 12 | Viewed by 2432

Abstract

Osteosarcoma (OS) is a skeletal tumor affecting mainly children and adolescents. The presence of distance metastasis is frequent and it is localized preferentially to the lung, representing the main reason for death among patients. The therapeutic approaches are based on surgery and chemotherapeutics. However, the drug resistance and the side effects associated with the chemotherapy require the identification of new therapeutic approaches. The understanding of the complex biological scenario of the osteosarcoma will open the way for the identification of new targets for its treatment. Recently, a great interest of scientific community is for extracellular vesicles (EVs), that are released in the tumor microenvironment and are important regulators of tumor proliferation and the metastatic process. At the same time, circulating extracellular vesicles can be exploited as diagnostic and prognostic biomarkers, and they can be loaded with drugs as a new therapeutic approach for osteosarcoma patients. Thus, the characterization of OS-related EVs could represent a way to convert these vesicles from antagonists for human health into therapeutic and/or diagnostic agents. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Bone Tumors)

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