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J Clin Invest. 2018 Jan 2;128(1):207-218. doi: 10.1172/JCI94955. Epub 2017 Nov 20.

Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cells.

Author information

1
Departments of Orthopaedics and Oncological Sciences, and.
2
Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
3
Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA.
4
Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
5
Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Abstract

Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma that is often discovered during adolescence and young adulthood. Despite the name, synovial sarcoma does not typically arise from a synoviocyte but instead arises in close proximity to bones. Previous work demonstrated that mice expressing the characteristic SS18-SSX fusion oncogene in myogenic factor 5-expressing (Myf5-expressing) cells develop fully penetrant sarcomagenesis, suggesting skeletal muscle progenitor cell origin. However, Myf5 is not restricted to committed myoblasts in embryos but is also expressed in multipotent mesenchymal progenitors. Here, we demonstrated that human SS and mouse tumors arising from SS18-SSX expression in the embryonic, but not postnatal, Myf5 lineage share an anatomic location that is frequently adjacent to bone. Additionally, we showed that SS can originate from periosteal cells expressing SS18-SSX alone and from preosteoblasts expressing the fusion oncogene accompanied by the added stabilization of β-catenin, which is a common secondary change in SS. Expression and secretion of the osteoclastogenesis inhibitory factor osteoprotegerin enabled early growth of SS18-SSX2-transformed cells, indicating a paracrine link between the bone and synovial sarcomagenesis. These findings explain the skeletal contact frequently observed in human SS and may provide alternate means of enabling SS18-SSX-driven oncogenesis in cells as differentiated as preosteoblasts.

KEYWORDS:

Bone development; Cancer; Development; Mouse models; Oncology

PMID:
29202462
PMCID:
PMC5749548
DOI:
10.1172/JCI94955
[Indexed for MEDLINE]
Free PMC Article

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