Fascin-1 enhances experimental osteosarcoma tumor formation and metastasis and is related to poor patient outcome

Matthias J Arlt,Jess G Snedeker,Bruno Fuchs,Unai Silvan,Aleksandar Kuzmanov,Adam A Sabile

doi:10.1186/s12885-019-5303-3

Matthias J Arlt, Jess G Snedeker + Show 4 more

Open Access

https://doi.org/10.1186/s12885-019-5303-3

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Abstract

BackgroundFascin-1, a prominent actin-bundling protein, is found to be upregulated in several human carcinomas. While it is accepted that Fascin-1 expression correlates with poor clinical outcome and decreased survival in various carcinomas, its role in sarcoma such as osteosarcoma (OS) remains unknown. In the present study, we evaluated the prognostic value and biological relevance of Fascin-1 in OS.MethodsThe correlation between Fascin-1 expression and the outcome of OS patients was determined by immunohistochemistry analysis of Fascin-1 expression in a tissue microarray of OS tissue specimens collected during primary tumor resection. To examine the effect of Fascin-1, shRNA and overexpression technology to alter Fascin-1 levels in OS cells were used in cellular assays as well as in intratibial xenograft OS models in SCID mice.ResultsKaplan-Meier survival analysis of Fascin-1 expression in OS tumor specimens revealed a direct relationship between Fascin-1 expression and poor patient survival. Furthermore, overexpression of Fascin-1 in OS cells significantly increased their migratory capacity as well as the activity of the matrix metalloprotease MMP-9, known to be critical for the execution of metastasis. Finally, using relevant xenograft mouse models, orthotopic intratibial transplantation of two different OS cell lines overexpressing Fascin-1 promoted tumor growth and lung metastasis.ConclusionsCollectively, our findings demonstrate for the first time that Fascin-1 has considerable potential as a novel prognostic biomarker in OS, and suggest that targeting of Fascin-1 might be a new anti-metastatic strategy in OS patient treatment.

Highlights

Fascin-1, a prominent actin-bundling protein, is found to be upregulated in several human carcinomas
Since the lack of statistical significance was likely related to the small number of patients, this finding implicate that Fascin-1 might be associated with worse outcome in subsets of OS patients who responded poorly to chemotherapy
Our study demonstrates that Fascin-1 expression significantly correlates with OS progression and metastasis, suggesting Fascin-1 as a potential prognostic biomarker for poor outcome of OS patients

Summary

Introduction

Fascin-1, a prominent actin-bundling protein, is found to be upregulated in several human carcinomas. While it is accepted that Fascin-1 expression correlates with poor clinical outcome and decreased survival in various carcinomas, its role in sarcoma such as osteosarcoma (OS) remains unknown. At the time of diagnosis, 20% of OS patients present detectable metastasis, and in the absence of chemotherapy more than 60% of those with localized disease develop metastases later on [3]. It is known that the regulation of the cell cytoskeleton is driven by a collective set of actin binding proteins, which mediate the organization of actin filaments into supramolecular arrangements [5]. A main class of actin binding proteins is the Fascin family, which comprises Fascin-1, − 2, and − 3.

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