Abstract A51: The HoxD locus: Its contribution to osteogenic phenotype and malignancy of Ewing sarcoma

Abstract

Abstract Ewing sarcoma (ES), an osteogenic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. Microarray analysis revealed genes of the HoxD locus to be clearly over-expressed in primary ES. Especially, genes such as HOXD10, HOXD11 and HOXD13 normally involved in bone formation and ossification pattern of bones are significantly over-expressed in ES. The expression of HOXD10, HOXD11 or HOXD13 seems not to be influenced via ES pathognomonic ews/ets translocations, since RNA interference of EWS-FLI1 or its over-expression in mesenchymal stem cells did not influence HOXD expression. However, RNA knock down of DKK2, a canonical WNT/β-catenin agonist and critical mediator of osteolytic tumor growth in ES resulted in a significant suppression of HOXD11 and HOXD13 expression. Subsequently, RNA interference of individual HoxD genes demonstrated HOXD11 and HOXD13 to be critical for in vitro proliferation and contact independent growth of ES. Similarly, in vitro invasiveness of ES lines was dependent on HOXD10, HOXD11 as well as HOXD13 and seemed mediated via MMP1, since down-regulation of individual HoxD genes similarly resulted in a suppression of MMP1 expression. But, HoxD genes only marginally influenced the expression of osteogenic genes in ES nor did they promote its chondrogenic or osteogenic differentiation. Whether HOXD10, HOXD11 or HOXD13 expression further metastasis or contribute to osteolytic tumor growth is currently investigated in a xenograft model using Rag2-/-gammaC-/- mice and data will be presented. Citation Format: Guenther HS Richter, Kristina von Heyking, Laura Roth, Miriam Ertl, Stefan Burdach. The HoxD locus: Its contribution to osteogenic phenotype and malignancy of Ewing sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A51.