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Cited by 319Sarcoma Diagnosis and TreatmentChromatin Remodeling and CancerLymphoma Diagnosis and Treatment

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Sarcoma treatment in the era of molecular medicine

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Grünewald, Thomas GP, Alonso, Marta, Avnet, Sofia, Banito, Ana, Burdach, Stefan, Cidre‐Aranaz, Florencia, Di Pompo, Gemma, Distel, Martin, Dorado‐Garcia, Heathcliff, Garcia‐Castro, Javier, González‐González, Laura, Grigoriadis, Agamemnon E, Kasan, Merve, Koelsche, Christian, Krumbholz, Manuela, Lecanda, Fernando, Lemma, Silvia, Longo, Dario L, Madrigal‐Esquivel, Claudia, Morales‐Molina, Álvaro, Musa, Julian, Ohmura, Shunya, Ory, Benjamin, Pereira‐Silva, Miguel, Perut, Francesca, Rodriguez, Rene, Seeling, Carolin, Al Shaaili, Nada, Shaabani, Shabnam, Shiavone, Kristina, Sinha, Snehadri, Tomazou, Eleni M, Trautmann, Marcel, Vela, Maria, Versleijen‐Jonkers, Yvonne MH, Visgauss, Julia, Zalacain, Marta, Schober, Sebastian J, Lissat, Andrej, English, William R, Baldini, Nicola, Heymann, Dominique·2020·EMBO Molecular Medicine
DOI 10.15252/emmm.201911131PMC PMC7645378
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Abstract

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. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult‐to‐treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.

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Figures

Figure 1 Diversity of sarcomas as highlighted by DNA methylation profiling t‐distributed stochastic neighbor embedding (t‐SNE) plot of n = 18 major sarcoma and soft tissue tumor subtypes based on genome‐wide DNA methylation profiling on Illumina EPIC arrays (Koelsche et al, 2018a,b). Web‐link to classifier: www.molecularsarcomapathology.org.
Figure 1 Diversity of sarcomas as highlighted by DNA methylation profiling t‐distributed stochastic neighbor embedding (t‐SNE) plot of n = 18 major sarcoma and soft tissue tumor subtypes based on genome‐wide DNA methylation profiling on Illumina EPIC arrays (Koelsche et al, 2018a,b). Web‐link to classifier: www.molecularsarcomapathology.org.CC BY · PubMed Central
Figure 2 Biological features of sarcomas and therapeutic approaches Sarcoma development results from a complex biological process. Their natural history combines the emergence of a first oncogenic hit followed by secondary oncogenic and epigenetic events with a conjuncture of a permissive microenvironment composed by cell types from mesodermal tissues, immune infiltrate, vascular, and extracellular matrix components. Sarcoma cells interact with their close environment through direct contact, enhanced cytokine/growth factors/miRNA signaling under a soluble form or encapsulated in extracellular vesicles. Sarcoma cells are characterized by a phenotypic and genetic heterogeneity coming from the successive oncogenic/epigenetic events occurring during tumor development and by cancer cells acquiring stemness properties that become progressively quiescent. Sarcomas are prone to induce distant metastatic foci spread by circulating tumor cells and invading after extravasation appropriate metastatic niches. Cancer cells installed in distant organs can spread again and enrich other metastatic sites increasing the tumor heterogeneity and potentially drug resistances. Persisting cells after resection of the primary tumor or dormant cancer cells located in distant organs characterize the minimal residual disease and are responsible of tumor recurrences. A selection of approved and experimental treatments aimed to prevent tumor growth and/or dissemination is shown.
Figure 2 Biological features of sarcomas and therapeutic approaches Sarcoma development results from a complex biological process. Their natural history combines the emergence of a first oncogenic hit followed by secondary oncogenic and epigenetic events with a conjuncture of a permissive microenvironment composed by cell types from mesodermal tissues, immune infiltrate, vascular, and extracellular matrix components. Sarcoma cells interact with their close environment through direct contact, enhanced cytokine/growth factors/miRNA signaling under a soluble form or encapsulated in extracellular vesicles. Sarcoma cells are characterized by a phenotypic and genetic heterogeneity coming from the successive oncogenic/epigenetic events occurring during tumor development and by cancer cells acquiring stemness properties that become progressively quiescent. Sarcomas are prone to induce distant metastatic foci spread by circulating tumor cells and invading after extravasation appropriate metastatic niches. Cancer cells installed in distant organs can spread again and enrich other metastatic sites increasing the tumor heterogeneity and potentially drug resistances. Persisting cells after resection of the primary tumor or dormant cancer cells located in distant organs characterize the minimal residual disease and are responsible of tumor recurrences. A selection of approved and experimental treatments aimed to prevent tumor growth and/or dissemination is shown.CC BY · PubMed Central
Figure 3 Sarcomas are characterized by an immune oasis Sarcomas are infiltrated by numerous immune cells, which are in some sarcoma subtypes deleterious by establishing an immune tolerant microenvironment that can be at the origin of innovative therapeutic approaches. In physiological condition, the adaptive immune system is activated by exogenous antigens leading to initiation of an effective immune response against the host at the origin of these antigens. Unfortunately, in most cases immune activation by tumor‐associated antigen is counterbalanced by inhibitory signals transmitted after the binding of immune checkpoint molecules (e.g., PD‐1) expressed by immune effectors to their ligands expressed by cancer cells such as PD‐L1. Macrophages also contribute to the immune surveillance in sarcomas with two main distinct subsets: M1 macrophages with pro‐tumor activities and M2 macrophages with anti‐tumor and immunosuppressive functions. This immune landscape has led to the development of immunotherapies including immune checkpoint inhibitors, activated NK cells, or genetically modified T lymphocytes (CAR T cells) in order to reactivate the tumor immune surveillance.
Figure 3 Sarcomas are characterized by an immune oasis Sarcomas are infiltrated by numerous immune cells, which are in some sarcoma subtypes deleterious by establishing an immune tolerant microenvironment that can be at the origin of innovative therapeutic approaches. In physiological condition, the adaptive immune system is activated by exogenous antigens leading to initiation of an effective immune response against the host at the origin of these antigens. Unfortunately, in most cases immune activation by tumor‐associated antigen is counterbalanced by inhibitory signals transmitted after the binding of immune checkpoint molecules (e.g., PD‐1) expressed by immune effectors to their ligands expressed by cancer cells such as PD‐L1. Macrophages also contribute to the immune surveillance in sarcomas with two main distinct subsets: M1 macrophages with pro‐tumor activities and M2 macrophages with anti‐tumor and immunosuppressive functions. This immune landscape has led to the development of immunotherapies including immune checkpoint inhibitors, activated NK cells, or genetically modified T lymphocytes (CAR T cells) in order to reactivate the tumor immune surveillance.CC BY · PubMed Central
Figure 4 Main features and functional aspects of oncolytic virus (A) Characteristics of oncolytic Adenoviruses Delta‐24-RGD and VCN‐01. These two Adenoviruses harbor different modifications (black for Delta‐24-RG (D24‐RGD) and dashed blue for VCN‐01) that render them with tumor specificity and enhanced infectivity. (B) Schematic representation of the virus’ mechanism of action. (1) The viruses are able to infect both normal and tumor cells. (2) However, due to their tumor specificity they only replicate and lyse the tumor cells. (3) They exert a potent cytolytic effect, and they are able to trigger an anti‐tumor immune response, which is crucial to successfully eliminate the tumors.
Figure 4 Main features and functional aspects of oncolytic virus (A) Characteristics of oncolytic Adenoviruses Delta‐24-RGD and VCN‐01. These two Adenoviruses harbor different modifications (black for Delta‐24-RG (D24‐RGD) and dashed blue for VCN‐01) that render them with tumor specificity and enhanced infectivity. (B) Schematic representation of the virus’ mechanism of action. (1) The viruses are able to infect both normal and tumor cells. (2) However, due to their tumor specificity they only replicate and lyse the tumor cells. (3) They exert a potent cytolytic effect, and they are able to trigger an anti‐tumor immune response, which is crucial to successfully eliminate the tumors.CC BY · PubMed Central

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  1. Heymann D (2014) Bone Cancer. Academic Press, San Diego, California, USA

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Metadata

Authors
Grünewald, T. G., Alonso, M., Avnet, S., Banito, A., Burdach, S., Cidre‐Aranaz, F., Di Pompo, G., Distel, M., Dorado‐Garcia, H., Garcia‐Castro, J., González‐González, L., Grigoriadis, A. E., Kasan, M., Koelsche, C., Krumbholz, M., Lecanda, F., Lemma, S., Longo, D. L., Madrigal‐Esquivel, C., Morales‐Molina, Á., Musa, J., Ohmura, S., Ory, B., Pereira‐Silva, M., Perut, F., Rodriguez, R., Seeling, C., Al Shaaili, N., Shaabani, S., Shiavone, K., Sinha, S., Tomazou, E. M., Trautmann, M., Vela, M., Versleijen‐Jonkers, Y. M., Visgauss, J., Zalacain, M., Schober, S. J., Lissat, A., English, W. R., Baldini, N., & Heymann, D.
Affiliations
  • German Cancer Research Center (DE)
  • Universidad de Navarra (ES)
  • Istituto Ortopedico Rizzoli (IT)
  • Technical University of Munich (DE)
  • Pathologisches Institut (DE)
  • Instituto de Salud Carlos III (ES)
  • King's College London (GB)
  • University Hospital Heidelberg (DE)
  • Universitätsklinikum Erlangen (DE)
  • Centro de Investigación Médica Aplicada (ES)
  • Institute of Biostructure and Bioimaging (IT)
  • University of Sheffield (GB)
  • Heidelberg University (DE)
  • Inserm (FR)
  • University of Coimbra (PT)
  • Universität Ulm (DE)
  • University of Groningen (NL)
  • University of Helsinki (FI)
  • University of Münster (DE)
  • Radboud University Medical Center (NL)
  • Duke University (US)
  • University Children's Hospital Zurich (CH)
  • Institut de Cancérologie de l'Ouest (FR)
Corresponding author
  • Grünewald, Thomas GP
  • Baldini, Nicola
  • Heymann, Dominique
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2020-10-13
Volume
12
Issue
11
Pages
e11131-e11131
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.15252/emmm.201911131
PMC
PMC7645378
OpenAlex
W3092176105
Cited by
319
References
457
Citations by year
2026: 40 · 2025: 50 · 2024: 55 · 2023: 66 · 2022: 50 · 2021: 53 · 2020: 5
FWCI
6.10
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Deposito Adademico Digital Universidad De Navarra (University of Navarra) (submittedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion, other-oa)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
Agence Nationale de la Recherche (ANR-16-IDEX-0007)
Topics
  • Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Keywords
sarcoma, soft tissue sarcoma, bone sarcoma, sarcoma subtypes, multimodal therapy, combination chemotherapy, hyperthermia, immunotherapy, targeted therapy, prognostic factors, predictive biomarkers, pediatric sarcoma, secondary malignancies, therapeutic target
MeSH terms
Adolescent, Bone Neoplasms, Child, Humans, Sarcoma, Osteosarcoma, Soft Tissue Neoplasms, Molecular Medicine

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