Neuronal Differentiation of Synovial Sarcoma and Its Therapeutic Application

Abstract

Synovial sarcoma is a rare sarcoma of unknown histologic origin. We previously reported the gene expression profile of synovial sarcoma was closely related to that of malignant peripheral nerve sheath tumors, and the fibroblast growth factor (FGF) signal was one of the main growth signals in synovial sarcoma. Here we further demonstrate the neural origin of synovial sarcoma using primary tumors and cell lines. The expression of neural tissuerelated genes was confirmed in synovial sarcoma tumor tissues, but the expression of some genes was absent in synovial sarcoma cell lines. Treatment of synovial sarcoma cell lines with BMP4 or FGF2 enhanced or restored the expression of neural tissue-related genes and induced a neuron-like morphology with positive Tuj-1 expression. Treatment with all-trans-retinoic acid also induced the expression of neural tissue-related genes in association with growth inhibition, which was not observed in other cell lines except a malignant peripheral nerve sheath tumor cell line. A growth-inhibitory effect of all-trans-retinoic acid was also observed for xenografted tumors in athymic mice. The simultaneous treatment with FGF signal inhibitors enhanced the growth-inhibitory effect of all-trans-retinoic acid, suggesting the combination of growth signaling inhibition and differentiation induction could be a potential molecular target for treating synovial sarcoma.

Synovial Sarcoma Is a Stem Cell Malignancy

“…On the contrary, the present study showed that the expression of some neural tissue-related genes was downregulated upon SS18-SSX silencing at the transcriptional and translational levels, suggesting that SS18-SSX expression itself may be responsible, at least in part, for neuronal phenotype of SS through the regulation of neural tissue-related genes. These experimental data are consistent with the findings of sequential studies that SS was clustered into one group with malignant peripheral nerve sheath tumor and several SS cell lines can undergo neural differentiation upon treatment with various differentiation-inducing agents [40,41]. Moreover, those data may be parallel to the growing evidence that expression of the neural-specific markers of Ewing's sarcoma is a result of upregulation by EWS-FLI1 fusion protein rather than dependent on the cellular origin of Ewing's sarcoma [42,43].…”

Synovial Sarcoma: Recent Discoveries as a Roadmap to New Avenues for Therapy

“…Many of the above findings have been confirmed at the protein level in patient specimens, including FZD10 (54), HES1 (55), NY-ESO-1 (56), BMPR2 (57), SALL2 and EGFR (58), BCL2 (59), SOX9 (60), FGFs and their receptors (61), PDGFRA (52), and Wnt pathway mediators (discussed further in the next section).…”

Are BMPs Involved in Normal Nerve and Following Transection?: A Pilot Study

“…In addition, although the literature contains many in vitro studies showing the neurotrophic function of BMPs [1,3,10,12,15], their distribution and the pattern of expression has not previously been demonstrated in vivo. We therefore determined (1) whether BMP-2, -7 and their receptors (BMPRs) are expressed in the normal sciatic nerves of rats; (2) if so, where they are distributed in the injured nerve; and (3) whether BMPs and BMPRs are expressed in the vessels within the perineurium after the nerve transection.…”