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Osteosarcoma: Current Advances from Molecular and Cellular Mechanisms to Therapy

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: 20 January 2025 | Viewed by 6497

Special Issue Editors


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Guest Editor
Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland
Interests: cancer; molecular genetics; osteosarcoma; cancer biomarkers

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Guest Editor
Biomedical Science and Technologies and Nanobiotechnology Lab, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy
Interests: bone cell biology and oncology; bone tissue engineering and regenerative medicine; exosome-mediated communication in bone pathophysiology

Special Issue Information

Dear Colleagues,

Osteosarcoma is a rare aggressive primary bone cancer with the highest incidence in children and young adults between 10 and 30 years of age. Standard treatment for osteosarcoma is surgery and neoadjuvant/adjuvant chemotherapy, which is quite effective in localized disease. The prognosis for recurrent or metastatic osteosarcoma is poor and treatment may include targeted therapies with kinase inhibitors or mTOR inhibitors.

Osteosarcoma arises from mesenchymal-stem-cell-derived osteoblast precursor cells. The tumors are highly heterogeneous with complex genomic landscape involving numerous structural and copy number alterations. Alterations in TP53 are the most frequently somatic changes, while pathogenic germline mutations in RB1, TP53, RECQL4, BLM, and WRN are associated with an increased risk of osteosarcoma. Tumor heterogeneity and a lack of recurrent driver mutations make it difficult to identify effective molecularly targeted therapies. Recent multi-omics studies have enhanced our understanding of the molecular pathways in osteosarcoma pathogenesis and are opening up new opportunities for biomarker-driven precision therapies based on molecular subtypes or altered genomic or cellular pathways such as PI3K-ATK-mTOR signaling, homologous recombination repair pathway, or therapies based on the immune profile/response of tumors. This Special Issue will compile recent research on various cellular and molecular processes involved in osteosarcoma growth, progression, and drug sensitivity/resistance, which could lead to the identification of new drug targets or therapies and improvements in osteosarcoma treatment.

Dr. Virinder Kaur Sarhadi
Dr. Francesca Perut
Guest Editors

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Keywords

  • osteosarcoma
  • cell signalling
  • molecular pathways
  • transcriptome
  • epigenetics
  • genomics
  • drug targets
  • therapy
  • drug resistance
  • targeted therapy

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Published Papers (4 papers)

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Research

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15 pages, 1143 KiB  
Article
Curcumin and Methotrexate: A Promising Combination for Osteosarcoma Treatment via Hedgehog Pathway Inhibition
by Giulia Giliberti, Maria Maddalena Marrapodi, Giuseppe Di Feo, Elvira Pota, Martina Di Martino, Daniela Di Pinto, Francesca Rossi and Alessandra Di Paola
Int. J. Mol. Sci. 2024, 25(20), 11300; https://doi.org/10.3390/ijms252011300 - 21 Oct 2024
Viewed by 528
Abstract
Osteosarcoma (OS) is the most severe bone tumor in children. A chemotherapy regimen includes a combination of high-dose Methotrexate (MTX), doxorubicin, and cisplatin. These drugs cause acute and chronic side effects, such as infections, thrombocytopenia, neutropenia, DNA damage, and inflammation. Therefore, to identify [...] Read more.
Osteosarcoma (OS) is the most severe bone tumor in children. A chemotherapy regimen includes a combination of high-dose Methotrexate (MTX), doxorubicin, and cisplatin. These drugs cause acute and chronic side effects, such as infections, thrombocytopenia, neutropenia, DNA damage, and inflammation. Therefore, to identify new therapeutic strategies, effective and with a safety profile, is necessary. The Hedgehog (Hh) signaling pathway involved in tumorigenesis is active in OS. Hh components Patched receptor 1 (PTCH1), Smoothened (SMO), and glioma-associated oncogene homolog transcription factors (GLI1 and GLI2) are overexpressed in OS cell lines and patient samples. Curcumin (CUR)—with antioxidant and anti-cancer properties—downregulates Hh components in cancer, inhibiting progression. This study investigates CUR effects on the MG-63 OS cell line, alone and combined with MTX, to propose a novel therapeutic approach. Our study suggests CUR as a novel therapeutic agent in OS, particularly when combined with MTX. Targeting the Hh signaling pathway, CUR and MTX showed significant pro-apoptotic effects, increasing the BAX/Bcl-2 ratio and total apoptotic cell percentage. They reduced the expression of Hh pathway components (PTCH1, SMO, GLI1, and GLI2), inhibiting OS cell proliferation, survival, and invasion. CUR and MTX combined determined a β-Catenin decrease and a trend toward reducing NF-kB and matrix metalloproteinases (MMP-2 and MMP-9). Our findings suggest CUR as a support to OS treatment, improving outcomes and reducing the adverse effects of current therapies. Full article
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13 pages, 2716 KiB  
Article
The Role of FAS Receptor Methylation in Osteosarcoma Metastasis
by Jiayi M. Sun, Wing-Yuk Chow, Gufeng Xu, M. John Hicks, Manjula Nakka, Jianhe Shen, Patrick Kwok Shing Ng, Aaron M. Taylor, Alexander Yu, Jason E. Farrar, Donald A. Barkauskas, Richard Gorlick, Jaime M. Guidry Auvil, Daniela Gerhard, Paul Meltzer, Rudy Guerra, Tsz-Kwong Man, Ching C. Lau and on behalf of the TARGET Osteosarcoma Consortium
Int. J. Mol. Sci. 2023, 24(15), 12155; https://doi.org/10.3390/ijms241512155 - 29 Jul 2023
Cited by 1 | Viewed by 1511
Abstract
Osteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, [...] Read more.
Osteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, FAS, triggers apoptosis in normal cells; however, this function is altered in cancer cells. DNA methylation has previously been explored as a mechanism for altering FAS expression, but no variability was identified in the CpG island (CGI) overlapping the promoter. Analysis of an expanded region, including CGI shores and shelves, revealed high variability in the methylation of certain CpG sites that correlated significantly with FAS mRNA expression in a negative manner. Bisulfite sequencing revealed additional CpG sites, which were highly methylated in the metastatic LM7 cell line but unmethylated in its parental non-metastatic SaOS-2 cell line. Treatment with the demethylating agent, 5-azacytidine, resulted in a loss of methylation in CpG sites located within the FAS promoter and restored FAS protein expression in LM7 cells, resulting in reduced migration. Orthotopic implantation of 5-azacytidine treated LM7 cells into severe combined immunodeficient mice led to decreased lung metastases. These results suggest that DNA methylation of CGI shore sites may regulate FAS expression and constitute a potential target for osteosarcoma therapy, utilizing demethylating agents currently approved for the treatment of other cancers. Full article
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19 pages, 9639 KiB  
Article
Gold Nanoparticles Inhibit Extravasation of Canine Osteosarcoma Cells in the Ex Ovo Chicken Embryo Chorioallantoic Membrane Model
by Anna Małek, Marek Wojnicki, Aleksandra Borkowska, Michał Wójcik, Gabriela Ziółek, Roman Lechowski and Katarzyna Zabielska-Koczywąs
Int. J. Mol. Sci. 2023, 24(12), 9858; https://doi.org/10.3390/ijms24129858 - 7 Jun 2023
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Abstract
Canine osteosarcoma (OS) is an aggressive bone tumor with high metastatic potential and poor prognosis, mainly due to metastatic disease. Nanomedicine-based agents can be used to improve both primary and metastatic tumor treatment. Recently, gold nanoparticles were shown to inhibit different stages of [...] Read more.
Canine osteosarcoma (OS) is an aggressive bone tumor with high metastatic potential and poor prognosis, mainly due to metastatic disease. Nanomedicine-based agents can be used to improve both primary and metastatic tumor treatment. Recently, gold nanoparticles were shown to inhibit different stages of the metastatic cascade in various human cancers. Here, we assessed the potential inhibitory effect of the glutathione-stabilized gold nanoparticles (Au-GSH NPs) on canine OS cells extravasation, utilizing the ex ovo chick embryo chorioallantoic membrane (CAM) model. The calculation of cells extravasation rates was performed using wide-field fluorescent microscopy. Transmission electron microscopy and Microwave Plasma Atomic Emission Spectroscopy revealed Au-GSH NPs absorption by OS cells. We demonstrated that Au-GSH NPs are non-toxic and significantly inhibit canine OS cells extravasation rates, regardless of their aggressiveness phenotype. The results indicate that Au-GSH NPs can act as a possible anti metastatic agent for OS treatment. Furthermore, the implemented CAM model may be used as a valuable preclinical platform in veterinary medicine, such as testing anti-metastatic agents. Full article
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Review

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29 pages, 1205 KiB  
Review
Lipid Peroxidation-Related Redox Signaling in Osteosarcoma
by Suzana Borović Šunjić, Morana Jaganjac, Josipa Vlainić, Mirna Halasz and Neven Žarković
Int. J. Mol. Sci. 2024, 25(8), 4559; https://doi.org/10.3390/ijms25084559 - 22 Apr 2024
Cited by 2 | Viewed by 1427
Abstract
Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including [...] Read more.
Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including osteosarcoma, express altered redox signaling pathways. Such redox signaling pathways protect cancer cells from the cytotoxic effects of oxidative stress, thus supporting malignant transformation, and eventually from cytotoxic anticancer therapies associated with oxidative stress. In this review, we aim to explore the status of lipid peroxidation in osteosarcoma and highlight the involvement of lipid peroxidation products in redox signaling pathways, including the involvement of lipid peroxidation in osteosarcoma therapies. Full article
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