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Molecular Research of Osteosarcoma Pathology and the Latest Therapies

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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: 15 August 2024 | Viewed by 5850

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Special Issue Editor

Dr. Claudio Di Cristofano

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Guest Editor

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
Interests: neuroscience; pharmacology, toxicology and pharmaceutics; metabolic diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Osteosarcoma is a rare tumour but it’s a most common non-hematological primary malignant tumour of the bone. It arises mainly in the long bones of the extremities and the main feature is the detection of osteoid matrix produced by neoplastic mesenchymal cells. The aetiology of osteosarcoma remains poorly understood due to the rarity of this highly aggressive cancer and the difficulty of obtaining an adequate number of samples with high tumour content for further analyses.

The therapeutic protocols include neoadjuvant conventional chemotherapy, surgical resection of the primary tumour and eventually post-operative chemotherapy. The prognosis depends on several factors: histological features of the tumor, tumor grading, radiological characteristics, presence or absence of pathological fractures, tumor size, age and sex of the patient, tumor localization, metastasis and response to therapy. Between them, the metastatic spread and the response to neoadjuvant chemotherapy, assessed as a percentage of tissue necrosis observed by histological examination after surgery, are recognized as particularly significant.

The survival rate has improved considerably after the introduction of neoadjuvant chemotherapy and surgery, metastatic or recurrent disease still occurs, and the survival rate of patients is mainly linked to the resistance to therapy. To date, clinical-pathological parameters and molecular markers that could be used as predictors of response to chemotherapy or to be able to identify patients with elevated risk of developing metastasis, have not yet been identified.

Metastasis and response to therapy are the main problem of osteosarcoma patients affecting their prognosis and survival and the molecular events underlying this process remain largely unclear; for these reasons it is necessary to identify new targets to develop new therapies that could prevent metastasis development in osteosarcoma.

Dr. Claudio Di Cristofano
Guest Editor

Manuscript Submission Information

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Keywords

osteosarcoma
cancer biomarker
evidence-based medicine
molecular diagnostics
genomics
epigenomics
proteomics
metabolomics
microarray
next generation sequencing
molecular target therapy
precision medicine
personalized treatment
metastasis
neoadjuvant chemotherapy

Published Papers (4 papers)

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Research

Jump to: Review

16 pages, 4814 KiB

Open AccessArticle

Proteomic Analyses Reveal the Role of Alpha-2-Macroglobulin in Canine Osteosarcoma Cell Migration

by Sylwia S. Wilk, Katarzyna Michalak, Ewelina P. Owczarek, Stanisław Winiarczyk and Katarzyna A. Zabielska-Koczywąs

Int. J. Mol. Sci. 2024, 25(7), 3989; https://doi.org/10.3390/ijms25073989 - 03 Apr 2024

Viewed by 673

Abstract

Canine osteosarcoma (OSA) is an aggressive bone neoplasia with high metastatic potential. Metastasis is the main cause of death associated with OSA, and there is no current treatment available for metastatic disease. Proteomic analyses, including matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI TOF/TOF MS), are widely used to select molecular targets and identify proteins that may play a key role in primary tumours and at various steps of the metastatic cascade. The main aim of this study was to identify proteins differently expressed in canine OSA cell lines with different malignancy phenotypes (OSCA-8 and OSCA-32) compared to canine osteoblasts (CnOb). The intermediate aim of the study was to compare canine OSA cell migration capacity and assess its correlation with the malignancy phenotypes of each cell line. Using MALDI-TOF/TOF MS analyses, we identified eight proteins that were significantly differentially expressed (p ≤ 0.05) in canine OSA cell lines compared to CnOb: cilia- and flagella-associated protein 298 (CFAP298), general transcription factor II-I (GTF2I), mirror-image polydactyly gene 1 protein (MIPOL1), alpha-2 macroglobulin (A2M), phosphoglycerate mutase 1 (PGAM1), ubiquitin (UB2L6), ectodysplasin-A receptor-associated adapter protein (EDARADD), and leucine-rich-repeat-containing protein 72 (LRRC72). Using the Simple Western technique, we confirmed high A2M expression in CnOb compared to OSCA-8 and OSCA-32 cell lines (with intermediate and low A2M expression, respectively). Then, we confirmed the role of A2M in cancer cell migration by demonstrating significantly inhibited OSA cell migration by treatment with A2M (both at 10 and 30 mM concentrations after 12 and 24 h) in a wound-healing assay. This study may be the first report indicating A2M’s role in OSA cell metastasis; however, further in vitro and in vivo studies are needed to confirm its possible role as an anti-metastatic agent in this malignancy. Full article

(This article belongs to the Special Issue Molecular Research of Osteosarcoma Pathology and the Latest Therapies)

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11 pages, 4497 KiB

Open AccessArticle

Paradox: Curcumin, a Natural Antioxidant, Suppresses Osteosarcoma Cells via Excessive Reactive Oxygen Species

by Chunfeng Xu, Mingjie Wang, Behrouz Zandieh Doulabi, Yuanyuan Sun and Yuelian Liu

Int. J. Mol. Sci. 2023, 24(15), 11975; https://doi.org/10.3390/ijms241511975 - 26 Jul 2023

Cited by 1 | Viewed by 1545

Abstract

Osteosarcoma (OS) is an aggressive tumor with a rare incidence. Extended surgical resections are the prevalent treatment for OS, which may cause critical-size bone defects. These bone defects lead to dysfunction, weakening the post-surgical quality of patients’ life. Hence, an ideal therapeutic agent for OS should simultaneously possess anti-cancer and bone repair capacities. Curcumin (CUR) has been reported in OS therapy and bone regeneration. However, it is not clear how CUR suppresses OS development. Conventionally, CUR is considered a natural antioxidant in line with its capacity to promote the nuclear translocation of a nuclear transcription factor, nuclear factor erythroid 2 (NRF2). After nuclear translocation, NRF2 can activate the transcription of some antioxidases, thereby circumventing excess reactive oxygen species (ROS) that are deleterious to cells. Intriguingly, this research demonstrated that, in vitro, 10 and 20 μM CUR increased the intracellular ROS in MG-63 cells, damaged cells’ DNA, and finally caused apoptosis of MG-63 cells, although increased NRF2 protein level and the expression of NRF2-regulated antioxidase genes were identified in those two groups. Full article

(This article belongs to the Special Issue Molecular Research of Osteosarcoma Pathology and the Latest Therapies)

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16 pages, 3971 KiB

Open AccessArticle

Identification of New Potential Prognostic and Predictive Markers in High-Grade Osteosarcoma Using Whole Exome Sequencing

by Raffaele Gaeta, Mariangela Morelli, Francesca Lessi, Chiara Maria Mazzanti, Michele Menicagli, Rodolfo Capanna, Lorenzo Andreani, Luca Coccoli, Paolo Aretini and Alessandro Franchi

Int. J. Mol. Sci. 2023, 24(12), 10086; https://doi.org/10.3390/ijms241210086 - 13 Jun 2023

Viewed by 1317

Abstract

Conventional high-grade osteosarcoma (OS) is the most common primary cancer of bone and it typically affects the extremities of adolescents. OS has a complex karyotype, and molecular mechanisms related to carcinogenesis, progression and resistance to therapy are still largely unknown. For this reason, the current standard of care is associated with considerable adverse effects. In this study, our aim was to identify gene alterations in OS patients using whole exome sequencing (WES) to find new potential prognostic biomarkers and therapeutic targets. We performed WES on formalin-fixed paraffin-embedded (FFPE) biopsy materials collected from 19 patients affected by conventional high-grade OS. The clinical and genetic data were analyzed according to response to therapy, presence of metastasis and disease status. By comparing good and poor responders to neoadjuvant therapy, we detected a clear prevalence of mutations in the ARID1A, CREBBP, BRCA2 and RAD50 genes in poor responders that negatively influence the progression-free survival time. Moreover, higher tumor mutational burden values correlated with worse prognosis. The identification of mutations in ARID1A, CREBBP, BRCA2 and RAD50 may support the use of a more specific therapy for tumors harboring these alterations. In particular, BRCA2 and RAD50 are involved in homologous recombination repair, and could thus be used as specific therapy targets of inhibitors of the enzyme Poly ADP Ribose Polymerase (PARP). Finally, tumor mutational burden is found to be a potential prognostic marker for OS. Full article

(This article belongs to the Special Issue Molecular Research of Osteosarcoma Pathology and the Latest Therapies)

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Review

Jump to: Research

12 pages, 981 KiB

Open AccessReview

The Future of HER2-Targeted Treatment for Osteosarcoma: Lessons from the Negative Trastuzumab Deruxtecan Results

by Kenji Nakano

Int. J. Mol. Sci. 2023, 24(23), 16823; https://doi.org/10.3390/ijms242316823 - 27 Nov 2023

Viewed by 1752

Abstract

Human epidermal growth factor receptor 2 (HER2), coded by the proto-oncogene ERBB, is known to be mutated or amplified in various malignant diseases, and many HER2-targeted therapies (including monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors) have been investigated. HER2 overexpression is observed in ~30% of patients with osteosarcoma, and HER2-targeted therapy for osteosarcoma has also been investigated, along with the prognostic and/or predictive value of HER2. An effective HER2-targeted therapy for osteosarcoma has not been established, however. An antibody–drug conjugate (ADC), i.e., trastuzumab deruxtecan (T-DXd), has been approved for the treatment of HER2-positive malignant diseases such as breast cancer and gastric cancer. T-DXd showed promising efficacy in a tumor-agnostic clinical trial, but even T-DXd did not demonstrate sufficient efficacy against HER2-positive osteosarcoma. In this review, the underlying reasons/mechanisms for the failure of HER2-targeted treatments for osteosarcoma (including T-DXd) are discussed, and the potential and future direction of HER2-targeted therapy is described. Full article

(This article belongs to the Special Issue Molecular Research of Osteosarcoma Pathology and the Latest Therapies)

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