Synovial Sarcoma: From Genetics to Genetic-based Animal Modeling

Abstract

Synovial sarcomas are highly aggressive mesenchymal cancers that show modest response to conventional cytotoxic chemotherapy, suggesting a definite need for improved biotargeted agents. Progress has been hampered by the lack of insight into pathogenesis of this deadly disease. The presence of a specific diagnostic t(X;18) translocation leading to expression of the unique SYT-SSX fusion protein in effectively all cases of synovial sarcoma suggests a role in the etiology. Other nonspecific anomalies such as overexpression of Bcl-2, HER-2/neu, and EGFR have been reported, but their role in the pathogenesis remains unclear. Using gene targeting, we recently generated mice conditionally expressing the human SYT-SSX2 fusion gene from mouse endogenous ROSA26 promoter in chosen tissue types in the presence of Cre recombinase. These mice develop synovial sarcoma when SYT-SSX2 is expressed within myoblasts, thereby identifying a source of this enigmatic tumor and establishing a mouse model of this disease that recapitulates the clinical, histologic, immunohistochemical, and transcriptional profile of human synovial sarcomas. We review the genetics of synovial sarcoma and discuss the usefulness of genetics-based mouse models as a valuable research tool in the hunt for key molecular determinants of this lethal disease as well as a preclinical platform for designing and evaluating novel treatment strategies.

Breast metastasis of monomorphic synovial sarcoma of right thigh

“…It has an annual incidence of 2.5 per 100,000. It accounts for approximately 8% of all human soft tissue sarcomas [6], and commonly occurs in children and young adults with a male to female ratio of 1.2:1 [7]. Metastatic lesions of the breast only account for 0.5-2% of all breast malignant tumors Characteristics of metastatic breast tumors usually include presence in the superficial tissues and well-defined multinodular masses in the upper outer quadrant of the breast.…”

p53 expression in synovial sarcoma and its association with prognostic factors

“…p53 expression and mitosis of the cases with SYT gene translocation there was no association between p53 expression with mitosis, this is similar as reported by Oda et al 8 This may indicated that p53 signaling pathway was not the only major factor affecting tumor mitosis. Haldar et al 3 explain there are other signaling pathways that influence synovial sarcoma growth. SYT-SSX fusion proteins can increase expression of factors that promote cell proliferation, such as cyclin D1, β-catenin, IGF2, IGF-1R, ERK1, ERK2, p-ERK and can decreased expression of factors that suppress cell proliferation, such as EGR1 and COM1.…”

“…The proportion of both cell are varied and can be classified as several histological subtypes: biphasic subtype, monophasic subtype (monophasic fibrous or rarely monophasic epithelial), and poor differentiated subtype. 3 The tumors contain characteristic translocation t(X;18) (p11.2;q11.2) that produce fusion of SYT gene in chromosome 18 with member of SSX gene family in X damaged cells proliferate and may leads to malignant neoplasms. 5,6 It has been reported that the prognosis associated with mitosis <10/10 HPF (high power field), tumor diameter <5 cm, no necrosis, patients age ≤ 20 years and if tumor can be eradicated by surgery.…”

CD133 Negatively Regulates TumorigenicityviaAKT Pathway in Synovial Sarcoma

“…Currently, synovial sarcoma is thought to arise from undifferentiated mesenchymal cells. Prognosis of synovial sarcoma is poor as the 5-and 10-year survival rates are 36% and 20%, respectively [2].…”