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Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas - Series...
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Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas - Series 2

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 October 2021) | Viewed by 28968

Special Issue Editors

Prof. Katia Scotlandi

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Guest Editor
CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Institute, Bologna, Italy
Interests: experimental oncology; sarcomas
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Enrique de Alava

E-Mail Website
Guest Editor
Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, 41013 Seville, Spain
Interests: cancer biology; immunohistochemistry; cell signaling; histopathology; surgical pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bone sarcomas are still enigmatic tumors. They are mesenchymal tumors deriving from the transformation of stem cells that are blocked in their differentiation processes, and give raise to very aggresssive tumors. The natural history of bone sarcomas is mostly unknown, and they are genetically very different, ranging from tumors with defined molecular events and simple karyotypes, such as Ewing sarcoma, to tumors with variable genetic changes and complex unbalanced karyotypes, such as osteosarcoma. Despite these differences, bone-affecting tumors share a very grave clinical history, some fundamental biological features, and similar unresolved problems. This Special Issue seeks reviews and original papers covering a wide range of topics related to bone sarcoma molecular biology and therapy, such as the role of epigenetic regulators in tumor pathogenesis and progression, biomarkers of risk and response to conventional chemotherapy, mechanisms of drug resistance, and interactions of tumors with normal stromal and immune cells, in the hope of offering novel insights for therapeutic developments.

Prof. Katia Scotlandi
Prof. Enrique de Alava
Guest Editors

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Published Papers (6 papers)

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Research

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17 pages, 6867 KiB  
Article
EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma
by Giorgia Giordano, Alessandra Merlini, Giulio Ferrero, Giulia Mesiano, Erika Fiorino, Silvia Brusco, Maria Laura Centomo, Valeria Leuci, Lorenzo D’Ambrosio, Massimo Aglietta, Dario Sangiolo, Giovanni Grignani and Ymera Pignochino
Cells 2021, 10(11), 2893; https://doi.org/10.3390/cells10112893 - 26 Oct 2021
Cited by 15 | Viewed by 3642
Abstract
Bone sarcomas are a group of heterogeneous malignant mesenchymal tumors. Complete surgical resection is still the cornerstone of treatment, but, in the advanced/unresectable setting, their management remains challenging and not significantly improved by target- and immuno-therapies. We focused on the tyrosine kinase Eph [...] Read more.
Bone sarcomas are a group of heterogeneous malignant mesenchymal tumors. Complete surgical resection is still the cornerstone of treatment, but, in the advanced/unresectable setting, their management remains challenging and not significantly improved by target- and immuno-therapies. We focused on the tyrosine kinase Eph type-A receptor-2 (EphA2), a key oncoprotein implicated in self-renewal, angiogenesis, and metastasis, in several solid tumors and thus representing a novel potential therapeutic target. Aiming at better characterizing its expression throughout the main bone sarcoma histotypes, we investigated EPHA2 expression in the Cancer Cell Lines Encyclopedia and in public datasets with clinical annotations. looking for correlations with molecular, histopathological and patients’ features and clinical outcomes in a total of 232 osteosarcomas, 197 Ewing’s sarcomas, and 102 chondrosarcomas. We observed EPHA2 expression in bone sarcoma cell lines. We demonstrated higher EPHA2 expression in tumor tissues when compared to normal counterparts. A significant correlation was found between EPHA2 expression and Huvos grade (osteosarcoma) and with worse overall survival (dedifferentiated chondrosarcoma). Next, we characterized EPHA2 expression and activation in bone sarcoma primary tissues and in patient-derived xenografts generated in our laboratory to verify their reliability as in vivo models of osteosarcoma, Ewing’s sarcoma and chondrosarcoma. Furthermore, for the first time, we demonstrated EPHA2 expression in chondrosarcoma, suggesting its potential key role in this histotype. Indeed, we observed a significant dose-dependent antitumor effect of the EphA2-inhibitor ALW-II-41-27 in patient-derived in vitro models. In conclusion, EphA2 targeting represents a promising novel therapeutic strategy against bone sarcomas. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas - Series 2)
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15 pages, 2333 KiB  
Article
Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619
by Mélanie Lavaud, Mathilde Mullard, Robel Tesfaye, Jérôme Amiaud, Mélanie Legrand, Geoffroy Danieau, Régis Brion, Sarah Morice, Laura Regnier, Maryne Dupuy, Bénédicte Brounais-Le Royer, François Lamoureux, Benjamin Ory, Françoise Rédini and Franck Verrecchia
Cells 2021, 10(9), 2268; https://doi.org/10.3390/cells10092268 - 31 Aug 2021
Cited by 21 | Viewed by 3732
Abstract
Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and [...] Read more.
Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and more studies are emerging on the role of Ubiquitin-Specific Proteases (USPs) in the development of many cancers, few data exist regarding OS. In this context, RNA-sequencing analysis of OS cells and mesenchymal stem cells differentiated or not differentiated into osteoblasts reveals increased expression of four USPs in OS tumor cells: USP6, USP27x, USP41 and USP43. Tissue microarray analysis of patient biopsies demonstrates the nucleic and/or cytoplasmic expression of these four USPs at the protein level. Interestingly, Kaplan–Meyer analysis shows that the expression of two USPs, USP6 and USP41, is correlated with patient survival. In vivo experiments using a preclinical OS model, finally demonstrate that PR619, a USP inhibitor able to enhance protein ubiquitination in OS cell lines, reduces primary OS tumor growth and the development of lung metastases. In this context, in vitro experiments show that PR619 decreases the viability of OS cells, mainly by inducing a caspase3/7-dependent cell apoptosis. Overall, these results demonstrate the relevance of targeting USPs in OS. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas - Series 2)
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33 pages, 2479 KiB  
Article
Investigating Optimal Chemotherapy Options for Osteosarcoma Patients through a Mathematical Model
by Trang Le, Sumeyye Su and Leili Shahriyari
Cells 2021, 10(8), 2009; https://doi.org/10.3390/cells10082009 - 6 Aug 2021
Cited by 13 | Viewed by 3622
Abstract
Since all tumors are unique, they may respond differently to the same treatments. Therefore, it is necessary to study their characteristics individually to find their best treatment options. We built a mathematical model for the interactions between the most common chemotherapy drugs and [...] Read more.
Since all tumors are unique, they may respond differently to the same treatments. Therefore, it is necessary to study their characteristics individually to find their best treatment options. We built a mathematical model for the interactions between the most common chemotherapy drugs and the osteosarcoma microenvironments of three clusters of tumors with unique immune profiles. We then investigated the effects of chemotherapy with different treatment regimens and various treatment start times on the behaviors of immune and cancer cells in each cluster. Saliently, we suggest the optimal drug dosages for the tumors in each cluster. The results show that abundances of dendritic cells and HMGB1 increase when drugs are given and decrease when drugs are absent. Populations of helper T cells, cytotoxic cells, and IFN-γ grow, and populations of cancer cells and other immune cells shrink during treatment. According to the model, the MAP regimen does a good job at killing cancer, and is more effective than doxorubicin and cisplatin combined or methotrexate alone. The results also indicate that it is important to consider the tumor’s unique growth rate when deciding the treatment details, as fast growing tumors need early treatment start times and high dosages. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas - Series 2)
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Review

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30 pages, 1336 KiB  
Review
Mechanisms, Diagnosis and Treatment of Bone Metastases
by Jozef Ban, Valerie Fock, Dave N. T. Aryee and Heinrich Kovar
Cells 2021, 10(11), 2944; https://doi.org/10.3390/cells10112944 - 29 Oct 2021
Cited by 52 | Viewed by 9021
Abstract
Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, [...] Read more.
Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients’ quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas - Series 2)
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22 pages, 1781 KiB  
Review
Impact of ABC Transporters in Osteosarcoma and Ewing’s Sarcoma: Which Are Involved in Chemoresistance and Which Are Not?
by Massimo Serra, Claudia Maria Hattinger, Michela Pasello, Chiara Casotti, Leonardo Fantoni, Chiara Riganti and Maria Cristina Manara
Cells 2021, 10(9), 2461; https://doi.org/10.3390/cells10092461 - 17 Sep 2021
Cited by 10 | Viewed by 3548
Abstract
The ATP-binding cassette (ABC) transporter superfamily consists of several proteins with a wide repertoire of functions. Under physiological conditions, ABC transporters are involved in cellular trafficking of hormones, lipids, ions, xenobiotics, and several other molecules, including a broad spectrum of chemical substrates and [...] Read more.
The ATP-binding cassette (ABC) transporter superfamily consists of several proteins with a wide repertoire of functions. Under physiological conditions, ABC transporters are involved in cellular trafficking of hormones, lipids, ions, xenobiotics, and several other molecules, including a broad spectrum of chemical substrates and chemotherapeutic drugs. In cancers, ABC transporters have been intensely studied over the past decades, mostly for their involvement in the multidrug resistance (MDR) phenotype. This review provides an overview of ABC transporters, both related and unrelated to MDR, which have been studied in osteosarcoma and Ewing’s sarcoma. Since different backbone drugs used in first-line or rescue chemotherapy for these two rare bone sarcomas are substrates of ABC transporters, this review particularly focused on studies that have provided findings that have been either translated to clinical practice or have indicated new candidate therapeutic targets; however, findings obtained from ABC transporters that were not directly involved in drug resistance were also discussed, in order to provide a more complete overview of the biological impacts of these molecules in osteosarcoma and Ewing’s sarcoma. Finally, therapeutic strategies and agents aimed to circumvent ABC-mediated chemoresistance were discussed to provide future perspectives about possible treatment improvements of these neoplasms. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas - Series 2)
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13 pages, 1502 KiB  
Review
The Immune Landscape of Osteosarcoma: Implications for Prognosis and Treatment Response
by Caterina Cascini and Claudia Chiodoni
Cells 2021, 10(7), 1668; https://doi.org/10.3390/cells10071668 - 2 Jul 2021
Cited by 35 | Viewed by 4372
Abstract
Osteosarcoma (OS) is a high-grade malignant stromal tumor composed of mesenchymal cells producing osteoid and immature bone, with a peak of incidence in the second decade of life. Hence, although relatively rare, the social impact of this neoplasm is particularly relevant. Differently from [...] Read more.
Osteosarcoma (OS) is a high-grade malignant stromal tumor composed of mesenchymal cells producing osteoid and immature bone, with a peak of incidence in the second decade of life. Hence, although relatively rare, the social impact of this neoplasm is particularly relevant. Differently from carcinomas, molecular genetics and the role of the tumor microenvironment in the development and progression of OS are mainly unknown. Indeed, while the tumor microenvironment has been widely studied in other solid tumor types and its contribution to tumor progression has been definitely established, tumor–stroma interaction in OS has been quite neglected for years. Only recently have new insights been gained, also thanks to the availability of new technologies and bioinformatics tools. A better understanding of the cross-talk between the bone microenvironment, including immune and stromal cells, and OS will be key not only for a deeper knowledge of osteosarcoma pathophysiology, but also for the development of novel therapeutic strategies. In this review, we summarize the current knowledge about the tumor microenvironment in OS, mainly focusing on immune cells, discussing their role and implication for disease prognosis and treatment response. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas - Series 2)
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