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Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas

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

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 62621

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Prof. Katia Scotlandi

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CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Institute, Bologna, Italy
Interests: experimental oncology; sarcomas
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Prof. Dr. Enrique de Alava

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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
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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 (10 papers)

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22 pages, 4422 KiB

Open AccessArticle

Inhibiting Monocyte Recruitment to Prevent the Pro-Tumoral Activity of Tumor-Associated Macrophages in Chondrosarcoma

by Michele Minopoli, Sabrina Sarno, Gioconda Di Carluccio, Rosa Azzaro, Susan Costantini, Flavio Fazioli, Michele Gallo, Gaetano Apice, Lucia Cannella, Domenica Rea, Maria Patrizia Stoppelli, Diana Boraschi, Alfredo Budillon, Katia Scotlandi, Annarosaria De Chiara and Maria Vincenza Carriero

Cells 2020, 9(4), 1062; https://doi.org/10.3390/cells9041062 - 24 Apr 2020

Cited by 11 | Viewed by 3495

Abstract

Chondrosarcomas (CHS) are malignant cartilaginous neoplasms with diverse morphological features, characterized by resistance to chemo- and radiation therapies. In this study, we investigated the role of tumor-associated macrophages (TAM)s in tumor tissues from CHS patients by immunohistochemistry. Three-dimensional organotypic co-cultures were set up in order to evaluate the contribution of primary human CHS cells in driving an M2-like phenotype in monocyte-derived primary macrophages, and the capability of macrophages to promote growth and/or invasiveness of CHS cells. Finally, with an in vivo model of primary CHS cells engrafted in nude mice, we tested the ability of a potent peptide inhibitor of cell migration (Ac-d-Tyr-d-Arg-Aib-d-Arg-NH₂, denoted RI-3) to reduce recruitment and infiltration of monocytes into CHS neoplastic lesions. We found a significant correlation between alternatively activated M2 macrophages and intratumor microvessel density in both conventional and dedifferentiated CHS human tissues, suggesting a link between TAM abundance and vascularization in CHS. In 3D and non-contact cu-culture models, soluble factors produced by CHS induced a M2-like phenotype in macrophages that, in turn, increased motility, invasion and matrix spreading of CHS cells. Finally, we present evidence that RI-3 successfully prevent both recruitment and infiltration of monocytes into CHS tissues, in nude mice. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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19 pages, 3035 KiB

Open AccessArticle

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

by Dimas Carolina Belisario, Muhlis Akman, Martina Godel, Virginia Campani, Maria Pia Patrizio, Lorena Scotti, Claudia Maria Hattinger, Giuseppe De Rosa, Massimo Donadelli, Massimo Serra, Joanna Kopecka and Chiara Riganti

Cells 2020, 9(3), 647; https://doi.org/10.3390/cells9030647 - 06 Mar 2020

Cited by 29 | Viewed by 3319

Abstract

The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1^highABCA1^low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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Review

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25 pages, 1950 KiB

Open AccessReview

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

by Isabelle Corre, Franck Verrecchia, Vincent Crenn, Francoise Redini and Valérie Trichet

Cells 2020, 9(4), 976; https://doi.org/10.3390/cells9040976 - 15 Apr 2020

Cited by 237 | Viewed by 11338

Abstract

Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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34 pages, 3072 KiB

Open AccessReview

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

by Heinrich Kovar, Lisa Bierbaumer and Branka Radic-Sarikas

Cells 2020, 9(4), 972; https://doi.org/10.3390/cells9040972 - 15 Apr 2020

Cited by 66 | Viewed by 13153

Abstract

YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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28 pages, 1214 KiB

Open AccessReview

Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors

by Katia Scotlandi, Claudia Maria Hattinger, Evelin Pellegrini, Marco Gambarotti and Massimo Serra

Cells 2020, 9(4), 968; https://doi.org/10.3390/cells9040968 - 14 Apr 2020

Cited by 19 | Viewed by 3831

Abstract

Osteosarcoma, Ewing sarcoma and chondrosarcoma are rare diseases but the most common primary tumors of bone. The genes directly involved in the sarcomagenesis, tumor progression and treatment responsiveness are not completely defined for these tumors, and the powerful discovery of genetic analysis is highly warranted in the view of improving the therapy and cure of patients. The review summarizes recent advances concerning the molecular and genetic background of these three neoplasms and, of their most common variants, highlights the putative therapeutic targets and the clinical trials that are presently active, and notes the fundamental issues that remain unanswered. In the era of personalized medicine, the rarity of sarcomas may not be the major obstacle, provided that each patient is studied extensively according to a road map that combines emerging genomic and functional approaches toward the selection of novel therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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37 pages, 2933 KiB

Open AccessReview

Implication of the p53-Related miR-34c, -125b, and -203 in the Osteoblastic Differentiation and the Malignant Transformation of Bone Sarcomas

by Camille Jacques, Robel Tesfaye, Melanie Lavaud, Steven Georges, Marc Baud’huin, François Lamoureux and Benjamin Ory

Cells 2020, 9(4), 810; https://doi.org/10.3390/cells9040810 - 27 Mar 2020

Cited by 14 | Viewed by 4578

Abstract

The formation of the skeleton occurs throughout the lives of vertebrates and is achieved through the balanced activities of two kinds of specialized bone cells: the bone-forming osteoblasts and the bone-resorbing osteoclasts. Impairment in the remodeling processes dramatically hampers the proper healing of fractures and can also result in malignant bone diseases such as osteosarcoma. MicroRNAs (miRNAs) are a class of small non-coding single-strand RNAs implicated in the control of various cellular activities such as proliferation, differentiation, and apoptosis. Their post-transcriptional regulatory role confers on them inhibitory functions toward specific target mRNAs. As miRNAs are involved in the differentiation program of precursor cells, it is now well established that this class of molecules also influences bone formation by affecting osteoblastic differentiation and the fate of osteoblasts. In response to various cell signals, the tumor-suppressor protein p53 activates a huge range of genes, whose miRNAs promote genomic-integrity maintenance, cell-cycle arrest, cell senescence, and apoptosis. Here, we review the role of three p53-related miRNAs, miR-34c, -125b, and -203, in the bone-remodeling context and, in particular, in osteoblastic differentiation. The second aim of this study is to deal with the potential implication of these miRNAs in osteosarcoma development and progression. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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16 pages, 1649 KiB

Open AccessReview

Breakthrough Technologies Reshape the Ewing Sarcoma Molecular Landscape

by Carmen Salguero-Aranda, Ana Teresa Amaral, Joaquín Olmedo-Pelayo, Juan Diaz-Martin and Enrique de Álava

Cells 2020, 9(4), 804; https://doi.org/10.3390/cells9040804 - 26 Mar 2020

Cited by 8 | Viewed by 4879

Abstract

Ewing sarcoma is a highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. At the molecular level, it is characterized by the presence of recurrent chromosomal translocations. In the last years, next-generation technologies have contributed to a more accurate diagnosis and a refined classification. Moreover, the application of these novel technologies has highlighted the relevance of intertumoral and intratumoral molecular heterogeneity and secondary genetic alterations. Furthermore, they have shown evidence that genomic features can change as the tumor disseminates and are influenced by treatment as well. Similarly, next-generation technologies applied to liquid biopsies will significantly impact patient management by allowing the early detection of relapse and monitoring response to treatment. Finally, the use of these novel technologies has provided data of great value in order to discover new druggable pathways. Thus, this review provides concise updates on the latest progress of these breakthrough technologies, underscoring their importance in the generation of key knowledge, prognosis, and potential treatment of Ewing Sarcoma. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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17 pages, 2129 KiB

Open AccessReview

SHH Signaling Pathway Drives Pediatric Bone Sarcoma Progression

by Frédéric Lézot, Isabelle Corre, Sarah Morice, Françoise Rédini and Franck Verrecchia

Cells 2020, 9(3), 536; https://doi.org/10.3390/cells9030536 - 26 Feb 2020

Cited by 16 | Viewed by 8488

Abstract

Primary bone tumors can be divided into two classes, benign and malignant. Among the latter group, osteosarcoma and Ewing sarcoma are the most prevalent malignant primary bone tumors in children and adolescents. Despite intensive efforts to improve treatments, almost 40% of patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma or Ewing sarcoma remains poor; less than 30% of patients who present metastases will survive 5 years after initial diagnosis. One common and specific point of these bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Over the past years, considerable interest in the Sonic Hedgehog (SHH) pathway has taken place within the cancer research community. The activation of this SHH cascade can be done through different ways and, schematically, two pathways can be described, the canonical and the non-canonical. This review discusses the current knowledge about the involvement of the SHH signaling pathway in skeletal development, pediatric bone sarcoma progression and the related therapeutic options that may be possible for these tumors. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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23 pages, 1606 KiB

Open AccessReview

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

by Maria Letizia Taddei, Laura Pietrovito, Angela Leo and Paola Chiarugi

Cells 2020, 9(2), 510; https://doi.org/10.3390/cells9020510 - 24 Feb 2020

Cited by 23 | Viewed by 4071

Abstract

Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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22 pages, 1343 KiB

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Exosomes in Bone Sarcomas: Key Players in Metastasis

by Mariona Chicón-Bosch and Oscar M. Tirado

Cells 2020, 9(1), 241; https://doi.org/10.3390/cells9010241 - 17 Jan 2020

Cited by 27 | Viewed by 4704

Abstract

Bone sarcomas are rare cancers which often present with metastatic disease and are still associated with poor survival rates. Studies in the last decade have identified that exosomes, a type of extracellular vesicle released by cells, play an important role in tumour progression and dissemination. Through the transfer of their cargo (RNAs, proteins, and lipids) across cells, they are involved in cellular cross-talk and can induce changes in cellular behaviour. Exosomes have been shown to be important in metastasis organotropism, induction of angiogenesis and vascular permeability, the education of cells towards a pro-metastatic phenotype or the interaction between stromal and tumour cells. Due to the importance exosomes have in disease progression and the high incidence of metastasis in bone sarcomas, recent studies have evaluated the implications of these extracellular vesicles in bone sarcomas. In this review, we discuss the studies that evaluate the role of exosomes in osteosarcoma, Ewing sarcoma, and preliminary data on chondrosarcoma. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Bone Sarcomas)

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