Synovial sarcoma: molecular and biological features, the role of tissue microenvironment elements and their prognostic significance

Purpose of the study. Analysis of the molecular and biological features of synovial sarcoma (SS), as well as its tissue microenvironment according to modern research.

Materials and methods. The analysis of literature sources was carried out mainly in the databases «Istina» and «PubMed», publication date limitations were set up from 2019 to 2023. The following keywords for the search were used: «synovial sarcoma», «chromosomal aberrations», «carcinogenesis».

Results. Understanding the molecular mechanisms and signaling pathways in the development of SS may lead to the development of more effective treatment strategies. The importance of further research in this area cannot be overestimated, as it can provide new data to create innovative approaches aimed at improving the prognosis and quality of patients’ lives. Chromosomal aberrations, such as translocations and deletions, can lead to the activation of oncogenes or inactivation of tumor suppressor genes, which, in turn, contributes to the malignant transformation of cells. Epigenetic changes such as DNA methylation and histone modifications also play an important role in the regulation of genes related to the growth and survival of tumor cells. Disorders in these processes can contribute to tumor progression by altering the expression of key genes involved in the cell cycle, apoptosis, and angiogenesis. Additionally, part of the review is devoted to the interaction of atypical cells against the background of chromosomal aberrations and epigenetic changes with the SS microenvironment. These factors may have a certain effect on the growth and progression of synovial sarcoma. In addition, the review discusses various aspects of the diagnosis of SS using modern molecular genetic methods. Examples of successful use of targeted therapy and immunotherapy are given, which open up new prospects in the treatment of this disease.

Conclusion. The importance of molecular biological and molecular genetic analysis of SS for the possibility of an interdisciplinary approach in the study and treatment of this aggressive malignant tumor has been revealed.

1. Hale R, Sandakly S, Shipley J, Walters Z. Epigenetic Targets in Synovial Sarcoma: A Mini-Review. Front Oncol. 2019 Oct 18;9:1078. doi: 10.3389/fonc.2019.01078

2. Blay JY, von Mehren M, Jones RL, Martin-Broto J, Stacchiotti S, Bauer S, et al. Synovial sarcoma: characteristics, challenges, and evolving therapeutic strategies. ESMO Open. 2023 Oct;8(5):101618. doi: 10.1016/j.esmoop.2023.101618

3. Nagy A, Somers GR. Round Cell Sarcomas: Newcomers and Diagnostic Approaches. Surg Pathol Clin. 2020 Dec;13(4):763–782. doi: 10.1016/j.path.2020.08.004

4. Gerarduzzi C, Hartmann U, Leask A, Drobetsky E. The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment. Cancer Res. 2020 Jul 1;80(13):2705–2717. doi: 10.1158/0008-5472.can-18-2098

5. Kling MJ, Chaturvedi NK, Kesherwani V, Coulter DW, McGuire TR, Sharp JG, Joshi SS. Exosomes secreted under hypoxia enhance stemness in Ewing's sarcoma through miR-210 delivery. Oncotarget. 2020 Oct 6;11(40):3633–3645. doi: 10.18632/oncotarget.27702

6. Ruscetti M, Morris JP 4^th , Mezzadra R, Russell J, Leibold J, Romesser PB, et al. Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer. Cell. 2020 Apr 16;181(2):424–441.e21. doi: 10.1016/j.cell.2020.03.008. Erratum in: Cell. 2021 Sep 2;184(18):4838–4839. doi: 10.1016/j.cell.2021.07.028

7. Black JO, Al-Ibraheemi A, Arnold MA, Coffin CM, Davis JL, Parham DM, et al. The Pathologic Diagnosis of Pediatric Soft Tissue Tumors in the Era of Molecular Medicine: The Sarcoma Pediatric Pathology Research Interest Group Perspective. Arch Pathol Lab Med. 2024 Jan 1;148(1):107–116. doi: 10.5858/arpa.2022-0364-ra

8. Scholl A, Chen J, Cardona D. Synovial Sarcoma Isn’t Supposed to To This! American Journal of Clinical Pathology. 2022;158:35–36. doi: 10.1093/ajcp/aqac126.065

9. Baranov E, McBride MJ, Bellizzi AM, Ligon AH, Fletcher CDM, Kadoch C, Hornick JL. A Novel SS18-SSX Fusion-specific Antibody for the Diagnosis of Synovial Sarcoma. Am J Surg Pathol. 2020 Jul;44(7):922–933.

10. Zaborowski M, Vargas AC, Pulvers J, Clarkson A, de Guzman D, Sioson L, et al. When used together SS18-SSX fusion-specific and SSX C-terminus immunohistochemistry are highly specific and sensitive for the diagnosis of synovial sarcoma and can replace FISH or molecular testing in most cases. Histopathology. 2020 Oct;77(4):588–600. doi: 10.1111/his.14190

11. Ferrari A, De Salvo GL, Brennan B, van Noesel MM, De Paoli A, Casanova M, et al. Synovial sarcoma in children and adolescents: the European Pediatric Soft Tissue Sarcoma Study Group prospective trial (EpSSG NRSTS 2005). Ann Oncol. 2015 Mar;26(3):567–572. doi: 10.1093/annonc/mdu562

12. Gutiérrez-Jimeno M, Alba-Pavón P, Astigarraga I, Imízcoz T, Panizo-Morgado E, García-Obregón S, et al. Clinical Value of NGS Genomic Studies for Clinical Management of Pediatric and Young Adult Bone Sarcomas. Cancers (Basel). 2021 Oct 29;13(21):5436. doi: 10.3390/cancers13215436

13. Vyse S, Thway K, Huang PH, Jones RL. Next-generation sequencing for the management of sarcomas with no known driver mutations. Curr Opin Oncol. 2021 Jul 1;33(4):315–322. doi: 10.1097/cco.0000000000000741

14. Zhuyan J, Chen M, Zhu T, Bao X, Zhen T, Xing K, et al. Critical steps to tumor metastasis: alterations of tumor microenvironment and extracellular matrix in the formation of pre-metastatic and metastatic niche. Cell Biosci. 2020 Jul 28;10:89. doi: 10.1186/s13578-020-00453-9

15. Seligson ND, Maradiaga RD, Stets CM, Katzenstein HM, Millis SZ, Rogers A, et al. Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target. NPJ Precis Oncol. 2021 May 21;5(1):43. doi: 10.1038/s41698-021-00177-0

16. Huang Y, Li Q, Feng Z, Zheng L. STIM1 controls calcineurin/Akt/mTOR/NFATC2-mediated osteoclastogenesis induced by RANKL/M-CSF. Exp Ther Med. 2020 Aug;20(2):736–747. doi: 10.3892/etm.2020.8774

17. Sigafoos AN, Paradise BD, Fernandez-Zapico ME. Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease. Cancers (Basel). 2021 Jul 7;13(14):3410. doi: 10.3390/cancers13143410

18. Nikolopoulou PA, Koufaki MA, Kostourou V. The Adhesome Network: Key Components Shaping the Tumour Stroma. Cancers (Basel). 2021 Jan 30;13(3):525. doi: 10.3390/cancers13030525

19. Zhang DX, Vu LT, Ismail NN, Le MTN, Grimson A. Landscape of extracellular vesicles in the tumour microenvironment: Interactions with stromal cells and with non-cell components, and impacts on metabolic reprogramming, horizontal transfer of neoplastic traits, and the emergence of therapeutic resistance. Semin Cancer Biol. 2021 Sep;74:24–44. doi: 10.1016/j.semcancer.2021.01.007

20. Henke E, Nandigama R, Ergün S. Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy. Front Mol Biosci. 2020 Jan 31;6:160. doi: 10.3389/fmolb.2019.00160

21. Gerarduzzi C, Hartmann U, Leask A, Drobetsky E. The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment. Cancer Res. 2020 Jul 1;80(13):2705–2717. doi: 10.1158/0008-5472.can-18-2098

22. Eble JA, Niland S. The extracellular matrix in tumor progression and metastasis. Clin Exp Metastasis. 2019 Jun;36(3):171-198. doi: 10.1007/s10585-019-09966-1

23. Mazumdar A, Urdinez J, Boro A, Migliavacca J, Arlt MJE, Muff R, et al. Osteosarcoma-Derived Extracellular Vesicles Induce Lung Fibroblast Reprogramming. Int J Mol Sci. 2020 Jul 30;21(15):5451. doi: 10.3390/ijms21155451

24. Samuel G, Crow J, Klein JB, Merchant ML, Nissen E, Koestler DC, et al. Ewing sarcoma family of tumors-derived small extracellular vesicle proteomics identify potential clinical biomarkers. Oncotarget. 2020 Aug 4;11(31):2995–3012. doi: 10.18632/oncotarget.27678

25. Hsu YL, Huang MS, Hung JY, Chang WA, Tsai YM, Pan YC, et al. Bone-marrow-derived cell-released extracellular vesicle miR-92a regulates hepatic pre-metastatic niche in lung cancer. Oncogene. 2020 Jan;39(4):739–753. doi: 10.1038/s41388-019-1024-y

26. Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol. 2021 Dec;18(12):792–804. doi: 10.1038/s41571-021-00546-5

27. Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020 Mar;20(3):174–186. doi: 10.1038/s41568-019-0238-1

28. Ahn YH, Kim JS. Long Non-Coding RNAs as Regulators of Interactions between Cancer-Associated Fibroblasts and Cancer Cells in the Tumor Microenvironment. Int J Mol Sci. 2020 Oct 11;21(20):7484. doi: 10.3390/ijms21207484