Targeting the Wnt Pathway in Synovial Sarcoma Models

Barham, Whitney; Frump, Andrea L.; Sherrill, Taylor P.; Garcia, Christina B.; Saito-Diaz, Kenyi; VanSaun, Michael N.; Fingleton, Barbara; Gleaves, Linda A.; Orton, Darren; Capecchi, Mario R.; Blackwell, Timothy S.; Lee, Ethan; Yull, Fiona E.; Eid, Josiane E.

doi:10.1158/2159-8290.cd-13-0138

Cited by 64 publications

(64 citation statements)

References 50 publications

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“…Similar to prior studies [22,25], we observed frequent b-catenin expression in synovial sarcoma. Synovial sarcoma is characterized by translocation t(X; 18)(p11; q11) [26], resulting in SS18 gene rearrangement with one of three SSX gene fusion partners (SSX1, SSX2, or SSX4); SS18-SSX activation of the Wnt signaling pathway has been demonstrated using in vitro and in vivo studies [27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

Fletcher

2016

Head and Neck Pathol

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Sinonasal hemangiopericytoma (HPC) is a tumor showing pericytic myoid differentiation and which arises in the nasal cavity and paranasal sinuses. CTNNB1 mutations appear to be a consistent aberration in sinonasal HPC, and nuclear expression of b-catenin has been reported. Our aim was to evaluate the frequency of b-catenin expression in sinonasal HPC and its histologic mimics in the upper aerodigestive tract. Cases were retrieved from the surgical pathology and consultation files. Immunohistochemical staining for b-catenin was performed on 50 soft tissue tumors arising in the sinonasal tract or oral cavity, and nuclear staining was recorded semiquantitatively by extent and intensity. Nuclear reactivity for b-catenin was present in 19/20 cases of sinonasal HPC; 17 showed moderate-to-strong multifocal or diffuse staining, and 2 had moderate focal nuclear reactivity. All solitary fibrous tumors (SFT) (10/10) showed focal-to-multifocal nuclear staining, varying from weak to strong in intensity. Most cases of synovial sarcoma (9/10) showed nuclear b-catenin expression in the spindle cell component, ranging from focal-weak to strong-multifocal. No cases of myopericytoma (0/10) showed any nuclear b-catenin expression. bcatenin expression is prevalent in sinonasal HPC, but is also frequent in SFT and synovial sarcoma. Our findings indicate that b-catenin is not a useful diagnostic tool in the evaluation of spindle cell tumors with a prominent hemangiopericytoma-like vasculature in the sinonasal tract and oral cavity, and that definitive diagnosis relies on the use of a broader immunohistochemical panel.

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Section: Discussionmentioning

confidence: 99%

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

Fletcher

2016

Head and Neck Pathol

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“…A potential solution is to assess the dependence of particular sarcomas on more common targetable cancer pathways. In this regard, one recent development is the identification of aberrant Wnt/b-catenin signaling in synovial sarcoma models (68) and rhabdomyosarcoma (69). Combination targeted therapy again may have merit: a phase II trial of sorafenib and everolimus combination therapy achieved 45% 6-month progression-free survival (PFS; ref.…”

Section: Sarcoma Treatment: Current and Future Prospectsmentioning

confidence: 99%

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

Lim

Poulin

Nielsen

2015

Clinical Cancer Research

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There are more than 100 sarcoma subtypes, each uncommon and diagnostically challenging. Conventional chemotherapy has little benefit for most soft-tissue sarcomas; new treatment strategies are needed. Multiple recent genomic studies have provided detailed insights into sarcoma biology, including more accurate classification by molecular subtype, identification of recurrent mutations in oncogenic pathways, and evidence of epigenetic dysregulation. Advances in immunotherapy (adoptive immune cell transfer, tumor vaccine strategies, and immune checkpoint inhibition) have also provided a better understanding of how immuno-oncology might best be applied to sarcoma treatment, including connections to oncogenic pathways that may support combination strategies with conventional and targeted therapies. In this article, we review the latest sarcoma genomic studies and immuno-oncology developments and discuss how the findings suggest potential strategies to improve diagnosis and treatment across multiple sarcoma subtypes.

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“…It is also known that the JUN gene plays a very important role in the canonical Wnt signaling pathway, primarily by interacting with b-catenin -TCFs transcriptional complex. Therefore, b-catenin expression indicates increased transcription in GCTB, as well as possible hyperactivation of the JUN gene [14,15,16].…”

Section: Discussionmentioning

confidence: 99%

“…The following matrix metalloproteinases are highly positive in GCTB: MMP-2, MMP-13 and MMP-9. The role of MMP-13 is to optimize bone resorption by giant osteoclast-like cells, whereas its high expressivity in GCTB could be responsible for the occurrence of osteolysis and pathological fractures [15,16,17,18].…”

Section: Discussionmentioning

confidence: 99%

Significance of β-catenin expression for the incidence of pathological fractures in giant cell tumors of bone

Sopta¹,

Lujic²,

Kovacevic³

et al. 2016

pjp

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Aim of the study is to determine the possible roles of p53, cyclin D1, B-catenin and Ki-67 in the increase in risk of fractures in patients with giant cell tumor of bone. The study included a total of 164 patients with giant cell tumor of bone (GCTB), 21 (12.8%) with and 143 (87.2%) without fracture. The samples were analyzed immunohistochemically for expression of Ki-67, p53, cyclin D1 and b-catenin. According to the immunohistochemical expression of p53 and Ki-67 in mononuclear stromal cells, as well as of cyclin D1 in multinuclear giant cells, there was no significant association with immunopositivity and risk of fractures. However, our research revealed that patients with cytoplasmic expression of b-catenin in stromal cells had three times more frequent occurrence of pathological fractures, which was highly statistically significant (χ 2 = 7.065; p = 0.008). Moreover, a highly statistically significant correlation between the nuclear expression of b-catenin in giant cells and the incidence of pathological fractures was also found (χ 2 = 8.824; p = 0.003). The study showed that b-catenin expression highly correlates with the incidence of pathological fractures in patients with GCTB. Taking into account that b-catenin is closely linked to activation of the Wnt signaling pathway in GCTB pathogenesis, one could postulate that activation of the Wnt pathway is one of the contributing factors to locally destructive behavior of this tumor, as well as to the incidence of pathological fractures.

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Targeting the Wnt Pathway in Synovial Sarcoma Models

Cited by 64 publications

References 50 publications

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

Significance of β-catenin expression for the incidence of pathological fractures in giant cell tumors of bone

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