The SYT-SSX fusion protein and histological epithelial differentiation in synovial sarcoma: relationship with extracellular matrix remodeling

Abstract

Synovial sarcoma (SS) tumor cells, which have the chromosomal translocation t(X;18)(p11.2;q11.2), have an inherently greater propensity for epithelial differentiation than other mesenchymal tumors, especially spindle cell sarcomas. This is caused by de-repression of the transcription of E-cadherin by SYT-SSX1 and SYT-SSX2, which dissociate Snail or Slug, respectively, from the E-cadherin promoter. However, a subset of SS with SYT-SSX1 loses E-cadherin expression despite adequate de-repression because of mutations in E-cadherin, resulting in monophasic histology. The ratio of the expression levels of SYT-SSX1 and Snail is also associated with E-cadherin expression: the lower the SYT-SSX1/Snail ratio, the lower the level of E-cadherin expression, and vice versa, thus affecting tumor histology. In addition, Wnt signal activation caused by mutation of β-catenin, APC, or Axin 1 and 2 is associated with monophasic histology. Remodeling of the extracellular matrix is also important. Only cells that survive all of these steps can finally exhibit biphasic histology. On the other hand, the SYT-SSX2 fusion has a weaker de-repression effect on the E-cadherin promoter than does SYT-SSX1, so it is difficult for SYT-SSX2-expressing tumors to achieve sufficient capacity for epithelial differentiation to form glandular structures. This review provides an interesting model for this epithelial differentiation that shows a possible mechanism for the aberrant mesenchymal to epithelial transition of SS and suggests that it might better be considered an epithelial to mesenchymal transition.

Keywords: E-cadherin; SYT-SSX1; SYT-SSX2; Synovial sarcoma; chromosomal translocation t(X;18)(p11.2;q11.2); epithelial differentiation.

Figure 1

Proposed model for epithelial differentiation in synovial sarcoma. Tumor cells with the chromosomal translocation t(X;18)(p11.2;q11.2) possess an inherently higher propensity for epithelial differentiation than other mesenchymal tumors, especially spindle cell sarcomas. This is caused by dissociation of Snail or Slug from the E-cadherin promoter by SYT-SSX1 or SYT-SSX2, respectively, which relieves the repression of E-cadherin transcription. However, some SS with SYT-SSX1 lose E-cadherin expression because of mutation of E-cadherin, resulting in monophasic histology. The ratio of the expression levels of SYT-SSX1 and Snail is also associated with the expression of E-cadherin: the lower the SYT-SSX1/Snail ratio, the lower the expression of E-cadherin, thus affecting the tumor histology. In addition, Wnt signal activation caused by mutation of β-catenin, APC, or Axin1 and 2 is associated with monophasic histology. The remodeling of the extracellular matrix is also important. Only tumors that survive these steps can finally exhibit biphasic histology. On the other hand, the SYT-SSX2 fusion is a weaker de-repressor of the E-cadherin promoter than is SYT-SSX1, so it is difficult for SYT-SSX2-positive tumors to acquire enough capacity for epithelial differentiation to show glandular formation.

Figure 2

Difference of E-cadherin expression in biphasic synovial sarcoma with the SYT-SSX1 fusion. The SYT-SSX1/Snail ratio is thought to be higher in the glandular component of biphasic SS with the SYT-SSX1 fusion, causing greater de-repression of the E-cadherin promoter and leading to stronger expression of the protein. On the other hand, the SYT-SSX1/Snail ratio is thought to be lower in the spindle cell component of biphasic SS with the SYT-SSX1 fusion, resulting in weaker de-repression of the E-cadherin promoter and leading to weak or nonexistent expression of this protein. Furthermore, in the spindle cell component, the expression of Snail is more strongly up-regulated by activated Wnt signaling and thus hampers the expression of E-cadherin.