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Bone and Soft Tissue Sarcomas - Basic Research and Multimodal Treatment Concepts

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 (15 September 2023) | Viewed by 11996

Special Issue Editor

Dr. Birgit Lohberger

E-Mail Website
Guest Editor
Department of Orthopedics and Trauma, Medical University of Graz, Auenbrugggerplatz 5, 8036 Graz, Austria
Interests: basic cellular and molecular research in sarcomas and chordomas; influence of particle irradiation (proton and carbon ions) on physiology and signal transduction cascades of tumor cells; research into new compounds for the chemotherapy of sarcomas/chordomas; osteoarthritis research; material science of prosthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Sarcomas are heterogeneous and clinically challenging soft-tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. Through molecular profiling, more histological subtypes are still being characterized. Current interdisciplinary treatment concepts combine surgery, chemotherapy, irradiation, immunotherapy, or targeted therapeutics. Unfortunately, many entities are resistant to conventional chemotherapy and radiation therapies and therefore have a limited effect.

This Special Issue is intended to give the latest advances in the cellular and molecular biology of sarcomas and their implications for clinical oncology. Topics include basic cellular and molecular research, molecular diagnostics, clinical oncology and pathology, and new surgical methods that can improve the treatment of sarcomas. The articles aimed at a wide readership ranging from beginners to experts in the field of sarcomas.

Dr. Birgit Lohberger
Guest Editor

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 and soft tissue sarcomas
  • chemotherapy
  • irradiation
  • molecular diagnostics

Published Papers (6 papers)

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Research

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14 pages, 3486 KiB  
Article
The ATR Inhibitor VE-821 Enhances the Radiosensitivity and Suppresses DNA Repair Mechanisms of Human Chondrosarcoma Cells
by Birgit Lohberger, Dietmar Glänzer, Nicole Eck, Katharina Stasny, Anna Falkner, Andreas Leithner and Dietmar Georg
Int. J. Mol. Sci. 2023, 24(3), 2315; https://doi.org/10.3390/ijms24032315 - 24 Jan 2023
Cited by 3 | Viewed by 1895
Abstract
To overcome the resistance to radiotherapy in chondrosarcomas, the prevention of efficient DNA repair with an additional treatment was explored for particle beams as well as reference X-ray irradiation. The combined treatment with DNA repair inhibitors—with a focus on ATRi VE-821—and proton or [...] Read more.
To overcome the resistance to radiotherapy in chondrosarcomas, the prevention of efficient DNA repair with an additional treatment was explored for particle beams as well as reference X-ray irradiation. The combined treatment with DNA repair inhibitors—with a focus on ATRi VE-821—and proton or carbon ions irradiation was investigated regarding cell viability, proliferation, cell cycle distribution, MAPK phosphorylation, and the expression of key DNA repair genes in two human chondrosarcoma cell lines. Pre-treatment with the PARPis Olaparib or Veliparib, the ATMi Ku-55933, and the ATRi VE-821 resulted in a dose-dependent reduction in viability, whereas VE-821 has the most efficient response. Quantification of γH2AX phosphorylation and protein expression of the DNA repair pathways showed a reduced regenerative capacity after irradiation. Furthermore, combined treatment with VE-821 and particle irradiation increased MAPK phosphorylation and the expression of apoptosis markers. At the gene expression and at the protein expression/phosphorylation level, we were able to demonstrate the preservation of DNA damage after combined treatment. The present data showed that the combined treatment with ATMi VE-821 increases the radiosensitivity of human chondrosarcoma cells in vitro and significantly suppresses efficient DNA repair mechanisms, thus improving the efficiency of radiotherapy. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Sarcomas - Basic Research and Multimodal Treatment Concepts)
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12 pages, 5651 KiB  
Article
Implementation of Copy Number Variations-Based Diagnostics in Morphologically Challenging EWSR1/FUS::NFATC2 Neoplasms of the Bone and Soft Tissue
by Iva Brcic, Susanne Scheipl, Marko Bergovec, Andreas Leithner, Joanna Szkandera, Karl Sotlar, Arnold J. Suda, Maria Anna Smolle, Tanja Kraus, Andrew Eric Rosenberg, Bernadette Liegl-Atzwanger and Jasminka Igrec
Int. J. Mol. Sci. 2022, 23(24), 16196; https://doi.org/10.3390/ijms232416196 - 19 Dec 2022
Cited by 6 | Viewed by 1401
Abstract
In the last decade, new tumor entities have been described, including EWSR1/FUS::NFATC2-rearranged neoplasms of different biologic behavior. To gain further insights into the behavior of these tumors, we analyzed a spectrum of EWSR1/FUS::NFATC2-rearranged neoplasms and discuss their key diagnostic and molecular [...] Read more.
In the last decade, new tumor entities have been described, including EWSR1/FUS::NFATC2-rearranged neoplasms of different biologic behavior. To gain further insights into the behavior of these tumors, we analyzed a spectrum of EWSR1/FUS::NFATC2-rearranged neoplasms and discuss their key diagnostic and molecular features in relation to their prognosis. We report five patients with EWSR1/FUS::NFATC2-rearranged neoplasms, including one simple bone cyst (SBC), two complex cystic bone lesions lacking morphological characteristics of SBC, and two sarcomas. In three cases, fluorescence in situ hybridization (FISH) and in all cases copy number variation (CNV) profiling and fusion analyses were performed. All patients were male, three cystic lesions occurred in children (aged 10, 14, and 17 years), and two sarcomas in adults (69 and 39 years). Fusion analysis revealed two FUS::NFATC2 rearrangements in two cystic lesions and three EWSR1::NFATC2 rearrangements in one complex cystic lesion and two sarcomas. EWSR1 FISH revealed tumor cells with break-apart signal without amplification in one complex cystic lesion and EWSR1 amplification in both sarcomas was documented. CNV analysis showed simple karyotypes in all cystic lesions, while more complex karyotypes were found in NFATC2-rearranged sarcomas. Our study supports and expands previously reported molecular findings of EWSR1/FUS::NFATC2-rearranged neoplasms. The study highlights the importance of combining radiology and morphologic features with molecular aberrations. The use of additional molecular methods, such as CNV and FISH in the routine diagnostic workup, can be crucial in providing a correct diagnosis and avoiding overtreatment. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Sarcomas - Basic Research and Multimodal Treatment Concepts)
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14 pages, 5778 KiB  
Article
Cellular and Molecular Biological Alterations after Photon, Proton, and Carbon Ions Irradiation in Human Chondrosarcoma Cells Linked with High-Quality Physics Data
by Birgit Lohberger, Sandra Barna, Dietmar Glänzer, Nicole Eck, Sylvia Kerschbaum-Gruber, Katharina Stasny, Andreas Leithner and Dietmar Georg
Int. J. Mol. Sci. 2022, 23(19), 11464; https://doi.org/10.3390/ijms231911464 - 28 Sep 2022
Cited by 5 | Viewed by 1392
Abstract
Chondrosarcomas are particularly difficult to treat due to their resistance to chemotherapy and radiotherapy. However, particle therapy can enhance local control and patient survival rates. To improve our understanding of the basic cellular radiation response, as a function of dose and linear energy [...] Read more.
Chondrosarcomas are particularly difficult to treat due to their resistance to chemotherapy and radiotherapy. However, particle therapy can enhance local control and patient survival rates. To improve our understanding of the basic cellular radiation response, as a function of dose and linear energy transfer (LET), we developed a novel water phantom-based setup for cell culture experiments and characterized it dosimetrically. In a direct comparison, human chondrosarcoma cell lines were analyzed with regard to their viability, cell proliferation, cell cycle, and DNA repair behavior after irradiation with X-ray, proton, and carbon ions. Our results clearly showed that cell viability and proliferation were inhibited according to the increasing ionization density, i.e., LET, of the irradiation modes. Furthermore, a prominent G2/M arrest was shown. Gene expression profiling proved the upregulation of the senescence genes CDKN1A (p21), CDKN2A (p16NK4a), BMI1, and FOXO4 after particle irradiation. Both proton or C-ion irradiation caused a positive regulation of the repair genes ATM, NBN, ATXR, and XPC, and a highly significant increase in XRCC1/2/3, ERCC1, XPC, and PCNA expression, with C-ions appearing to activate DNA repair mechanisms more effectively. The link between the physical data and the cellular responses is an important contribution to the improvement of the treatment system. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Sarcomas - Basic Research and Multimodal Treatment Concepts)
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12 pages, 1573 KiB  
Article
Individualized Mini-Panel Sequencing of ctDNA Allows Tumor Monitoring in Complex Karyotype Sarcomas
by David Braig, Alexander Runkel, Anja E. Eisenhardt, Adrian Schmid, Johannes Zeller, Thomas Pauli, Ute Lausch, Julius Wehrle, Peter Bronsert, Matthias Jung, Jurij Kiefer, Melanie Boerries and Steffen U. Eisenhardt
Int. J. Mol. Sci. 2022, 23(18), 10215; https://doi.org/10.3390/ijms231810215 - 6 Sep 2022
Cited by 1 | Viewed by 1584
Abstract
Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For [...] Read more.
Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For metastasized STS, only limited inferences can be drawn from imaging data regarding therapy response. To date there are no established and evidence-based diagnostic biomarkers for STS due to their rarity and diversity. In a proof-of-concept study, circulating tumor DNA (ctDNA) was quantified in (n = 25) plasma samples obtained from (n = 3) patients with complex karyotype STS collected over three years. Genotyping of tumor tissue was performed by exome sequencing. Patient-individual mini-panels for targeted next-generation sequencing were designed encompassing up to 30 mutated regions of interest. Circulating free DNA (cfDNA) was purified from plasma and ctDNA quantified therein. ctDNA values were correlated with clinical parameters. ctDNA concentrations correlated with the tumor burden. In case of full remission, no ctDNA was detectable. Patients with a recurrence at a later stage showed low levels of ctDNA during clinical remission, indicating minimal residual disease. In active disease (primary tumor or metastatic disease), ctDNA was highly elevated. We observed direct response to treatment, with a ctDNA decline after tumor resections, radiotherapy, and chemotherapy. Quantification of ctDNA allows for the early detection of recurrence or metastases and can be used to monitor treatment response in STS. Therapeutic decisions can be made earlier, such as the continuation of a targeted adjuvant therapy or the implementation of extended imaging to detect recurrences. In metastatic disease, therapy can be adjusted promptly in case of no response. These advantages may lead to a survival benefit for patients in the future. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Sarcomas - Basic Research and Multimodal Treatment Concepts)
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Review

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18 pages, 794 KiB  
Review
Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis
by Bikesh K. Nirala, Taku Yamamichi and Jason T. Yustein
Int. J. Mol. Sci. 2023, 24(14), 11367; https://doi.org/10.3390/ijms241411367 - 12 Jul 2023
Cited by 5 | Viewed by 2651
Abstract
Osteosarcoma (OS) is the predominant primary bone tumor in the pediatric and adolescent populations. It has high metastatic potential, with the lungs being the most common site of metastasis. In contrast to many other sarcomas, OS lacks conserved translocations or genetic mutations; instead, [...] Read more.
Osteosarcoma (OS) is the predominant primary bone tumor in the pediatric and adolescent populations. It has high metastatic potential, with the lungs being the most common site of metastasis. In contrast to many other sarcomas, OS lacks conserved translocations or genetic mutations; instead, it has heterogeneous abnormalities, including somatic DNA copy number alteration, ploidy, chromosomal amplification, and chromosomal loss and gain. Unfortunately, clinical outcomes have not significantly improved in over 30 years. Currently, no effective molecularly targeted therapies are available for this disease. Several genomic studies showed inactivation in the tumor suppressor genes, including p53, RB, and ATRX, and hyperactivation of the tumor promoter genes, including MYC and MDM2, in OS. Alterations in the major signaling pathways, including the PI3K/AKT/mTOR, JAK/STAT, Wnt/β-catenin, NOTCH, Hedgehog/Gli, TGF-β, RTKs, RANK/RANKL, and NF-κB signaling pathways, have been identified in OS development and metastasis. Although OS treatment is currently based on surgical excision and systematic multiagent therapies, several potential targeted therapies are in development. This review focuses on the major signaling pathways of OS, and we propose a biological rationale to consider novel and targeted therapies in the future. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Sarcomas - Basic Research and Multimodal Treatment Concepts)
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Other

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17 pages, 3379 KiB  
Case Report
Malignant Transformation of Giant Cell Tumour of Bone: A Review of Literature and the Experience of a Referral Centre
by Sabrina Vari, Federica Riva, Concetta Elisa Onesti, Antonella Cosimati, Davide Renna, Roberto Biagini, Jacopo Baldi, Carmine Zoccali, Vincenzo Anelli, Alessio Annovazzi, Renato Covello, Andrea Ascione, Beatrice Casini and Virginia Ferraresi
Int. J. Mol. Sci. 2022, 23(18), 10721; https://doi.org/10.3390/ijms231810721 - 14 Sep 2022
Cited by 5 | Viewed by 2350
Abstract
Giant cell tumour of bone (GCTB) is a benign, locally aggressive primary bone neoplasm that represents 5% of all bone tumours. The principal treatment approach is surgery. Although generally GCTB is considered only a locally aggressive disease, it can metastasise, and lung metastases [...] Read more.
Giant cell tumour of bone (GCTB) is a benign, locally aggressive primary bone neoplasm that represents 5% of all bone tumours. The principal treatment approach is surgery. Although generally GCTB is considered only a locally aggressive disease, it can metastasise, and lung metastases occur in 1–9% of patients. To date, only the use of denosumab has been approved as medical treatment for GCTB. Even more rarely, GCTB undergoes sarcomatous transformation into a malignant tumour (4% of all GCTB), but history of this malignant transformation is unclear and unpredictable. Considering the rarity of the event, the data in the literature are few. In this review, we summarise published data of GCTB malignant transformation and we analyse three cases of malignant transformation of GCTB, evaluating histopathology, genetics, and radiological aspects. Despite the rarity of this event, we conclude that a strict follow up is recommended to detect early malignant transformation. Full article
(This article belongs to the Special Issue Bone and Soft Tissue Sarcomas - Basic Research and Multimodal Treatment Concepts)
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