Synovial Sarcoma Is a Stem Cell Malignancy

Abstract

Synovial sarcoma (SS) is a malignant soft tissue tumor characterized by its unique t(X;18)(p11;q11) chromosomal translocation leading to the formation of the SS18-SSX fusion gene. The resulting fusion protein product is considered to play as an aberrant transcription factor and transform target cells by perturbing their gene expression program. However, the cellular origin of SS is highly debated. We herein established two novel human SS cell lines, named Yamato-SS and Aska-SS, and investigated their biological properties. We found the self-renewal ability of these cells to generate sarcospheres, to form tumors in serial xenotransplantation and reconstitute the tumor phenotypes without fractionation by any surface markers. Both SS cells as well as clinical tissue specimens from 15 patients expressed the marker genes-associated stem cell identity, Oct3/4, Nanog, and Sox2. We also found that both SS cells displayed limited differentiation potentials for mesenchymal lineages into osteocytes and chondrocytes albeit with the expression of early mesenchymal and hematopoietic lineage genes. Upon SS18-SSX silencing with sequence-specific siRNAs, these SS cells exhibited morphological transition from spherical growth in suspension to adherent growth in monolayer, additional expression of later mesenchymal and hematopoietic lineage genes, and broader differentiation potentials into osteocytes, chondrocytes, adipocytes, and macrophages in appropriate differentiation cocktails. Collectively, these data suggest that a human multipotent mesenchymal stem cell can serve as a cell of origin for SS and SS is a stem cell malignancy resulting from dysregulation of self-renewal and differentiation capacities driven by SS18-SSX fusion protein.

Modeling sarcomagenesis using multipotent mesenchymal stem cells

“…Interestingly, SS tumor is reproduced when the SYT-SSX2 fusion is expressed in immature myoblasts (MYF5+) but not in more differentiated cells (MYF6+), highlighting how the same genetic alteration may lead to different outcomes/tumor phenotype in different cell populations down the lineage hierarchy. Human MSCs In the human setting, silencing of the fusion gene expression with specific shRNA in primary SS cells induces the expression of mesenchymal markers and enhances their ability to differentiate into osteocytes, chondrocytes and adipocytes, suggesting that MSCs could be at the origin of this disease [79]. Similarly, the expression of SYT-SSX1 in hMSCs induces a transcriptional profile very similar to the SS expression signature [80].…”

“…CSCs that display tumor re-initiating properties have been recently identified in osteosarcoma [81][82][83], chondrosarcoma [82], Ewing's sarcoma [61] and synovial sarcoma [79]. The identification of these sarcoma-initiating cells was based on both their ability to form spherical, clonal expanding colonies (called sarcospheres) in anchorage-independent and serum-starved conditions and the expression of stem cell markers [61,79,[81][82][83][84].…”

“…All of these CSCs are characterized by the expression of the pluripotent stem cell markers OCT3/4, NANOG and SOX2 and are able to self-renew and to sustain the tumor in serial transplantation experiments. More importantly, many of these sarcoma-initiating cells express MSC markers [79,[81][82][83] and retain MSC in vitro differentiation properties, giving rise to adipogenic, chondrogenic and osteogenic lineages [61,79,82]. In addition, these MSC-like CSCs are associated with drug resistance and metastasis [81,84] and therefore, they may be responsible for the frequent relapses observed in sarcomas [85].…”

“…The second model is supported by many studies reporting sarcoma formation from spontaneous or mutation-induced transformation of human or mouse primitive MSCs. Likewise, several types of CSCs presenting MSC properties have been reported [61,79,82] and moreover, sarcoma cells of certain subtypes can also differentiate into multiple mesenchymal lineages in vitro [30,31,42]. Existing sarcoma mouse models also provide arguments in favor of this theory.…”

50 Years Ago in CORR®: Synovial Sarcoma Kirk J. Anderson, MD and Orliss Wildermuth, MD CORR 1961;29:55-70

“…Evidence during the past two decades suggests synovial sarcoma has a genetic basis [6,7,9,10,12], related to specific fusion proteins. Naka et al [8] noted synovial sarcoma was characterized by a unique t(X;18)(p11;q11) chromosomal translocation, and suggested this unique sarcoma may arise from mesenchymal stem cells driven to dysregulation by the SS18-SSX fusion protein. There is little doubt our view of synovial sarcoma will continue to evolve as new methods of observation become available.…”