Pediatric sarcomas display a variable EpCAM expression in a histology-dependent manner

Abstract

EpCAM is a transmembrane glycoprotein typically overexpressed in cancer of epithelial origin and mainly involved in the epithelial-to–mesenchymal transition (EMT) of tumor cells that spread and disseminate. Strategies for the targeting and capture of EpCAM-expressing tumor cells are showing promise in cancers prone to metastatize, both as diagnostic tools and potential therapies. Sarcomas are among the most aggressive tumors in children, with a common mesenchymal origin that comprises both soft tissue sarcomas (STS) and bone sarcomas. The aim of this study was to assess EpCAM expression in pediatric sarcomas and correlate its expression with disease progression. To do so, we analyzed a set of cell lines and primary tumor tissues from rhabdomyosarcoma (RMS), Ewing sarcoma (ES), synovial sarcoma (SS) and desmoplastic small round cell tumor (DSRCT) STS, or osteosarcoma (OS) bone cancer. We demonstrated that EpCAM was variably expressed in pediatric sarcomas, with DSRCT, a rare, aggressive and almost fatal tumor type, characterized by the highest EpCAM expression levels. Interestingly, although EpCAM expression was lower in RMS tumors, high levels at diagnosis correlated with reduced patients' overall survival (p < 0.05). Indeed, membrane-bound EpCAM was detected in circulating sarcoma tumor cells, revealing its potential to be used as dissemination biomarker in this type of childhood cancers. This reinforces the concept that pediatric sarcomas do express both epithelial and mesenchymal markers and reside in an intermediate condition that most likely contributes to their aggressive phenotype and low survival rate.

Heterogeneous Circulating Tumor Cells in Sarcoma: Implication for Clinical Practice

“…It has been proven that EpCAM expression can be acquired during tumor progression [ 150 ] and is highly expressed in cancer stem cells [ 151 ]. The numbers of CTC-positive in patients with sarcoma and total CTCs in pediatric sarcomas are similar to data previously reported at diagnosis in carcinomas [ 152 ], with progressive disease and poor outcome in patients with the highest EpCAM levels [ 141 ].…”

“…Comparative expression of epithelial markers and adhesion molecules indicated heterogeneous expression across types [ 136 , 137 , 138 , 139 ]. Accordingly, a strong variance in EpCAM expression has been documented between histotypes in pediatric sarcomas and the association with patient outcome [ 140 , 141 ]. The metastable EMT state is common in aggressive sarcomas and frequently contributes to drug resistance [ 142 ].…”

“…A dynamic expression of EpCAM during tumor evolution has been observed in diverse sarcoma subtypes, with a correlation between high EpCAM expression and significantly poorer patient’s OS and adverse outcome [ 141 ]. In patients with RMS, no significant difference in EpCAM expression has been observed between the onset at diagnosis and relapse, during the follow-up.…”

“…It has been proven that EpCAM expression can be acquired during the progression of tumors [ 150 ] with a high expression in cancer stem cells [ 151 ]. By using the CellSearch™ System for CTC capturing, CTCs have been detected in the peripheral blood of patients with pediatric bone sarcoma and STS, which are not of hematopoietic origin [ 141 ]. CTCs were assayed in 11 patients at diagnosis before starting the therapy, by using epithelial and mesenchymal markers to capture CTCs, such as cytokeratins (CK8/18/19) and Desmin.…”

Case Report: Circulating Tumor Cells as a Response Biomarker in ALK-Positive Metastatic Inflammatory Myofibroblastic Tumor

“…In patients with renal cell carcinoma (RCC) we demonstrated that the enumeration of CTCs is actionable during targeted therapy and correlates with patients' clinical conditions and final outcome (negative at complete remission, whilst positive over the follow-up period in patients experienced relapse) ( 25 ). In children with soft tissue and bone sarcomas, such as rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, the higher was the expression of EpCAM and the number of CTCs at diagnosis the worse was the prognosis ( 26 ).…”