Abstract
Ewing sarcomas predominantly arise in pelvic and stylopod bones (i.e., femur and humerus), likely as a consequence of EWS-FLI1 oncogene-induced transformation of mesenchymal stem/progenitor cells (MSCs). MSCs located in the embryonic superficial zone cells (eSZ) of limbs express anatomically distinct posterior Hox genes. Significantly, high expression of posterior HOXD genes, especially HOXD13, is a hallmark of Ewing sarcoma. These data drove our hypothesis that Hox genes in posterior skeleton MSCs contribute to Ewing sarcoma tumorigenesis. We isolated eSZ cells from stylopod and zeugopod (i.e., tibia/fibula, radius/ulna) bones, from wild-type and Hoxd13 mutant embryos, and tested the impact of EWS-FLI1 transduction on cell proliferation, gene expression, and tumorigenicity. Our data demonstrate that both stylopod and zeugopod eSZ cells tolerate EWS-FLI1 but that stylopod eSZ cells are relatively more susceptible, demonstrating changes in proliferation and gene expression consistent with initiation of malignant transformation. Significantly, loss of Hoxd13 had no impact, showing that it is dispensable for the initiation of EWS-FLI1-induced transformation in mouse MSCs. These findings show that MSCs from anatomically distinct sites are differentially susceptible to EWS-FLI1-induced transformation, supporting the premise that the dominant presentation of Ewing sarcoma in pelvic and stylopod bones is attributable to anatomically-defined differences in MSCs.
Highlights
Ewing sarcoma exhibits a characteristic pattern of primary tumor sites
We recently reported that high expression of posterior Homeobox D gene cluster (HOXD) genes is a hallmark of Ewing sarcoma and that ectopic expression of EWS-FLI1 in neural crest-derived
We recently showed that mesenchymal stem and progenitor cells (MSCs) within the embryonic superficial zone (eSZ) cells express high levels of regionally-restricted Hox genes [21]
Summary
Ewing sarcoma exhibits a characteristic pattern of primary tumor sites. The most common primary locations for Ewing sarcoma in adolescents and young adults are in the pelvis (26%) and the femur (20%) [1]. Very rarely are primary Ewing tumors found in the bones of the skull (2%) or hand (1%) [1]. Studies of in vitro and ex vivo transduction/transplantation experiments have shown that, while most primary cells do not tolerate EWS-FLI1 [6,7], select populations of mesenchymal stem and progenitor cells (MSCs) are permissive and capable of initiating transformation. Human bone marrow- and neural crest-derived MSCs tolerate EWS-FLI1 and induce an oncogenic transcription program, but are unable to form tumors when subcutaneously injected into immunodeficient mice [8,9,10,11]. Ex vivo transduction/transplantation models of isolated primary murine MSCs have been relatively more successful, but these models demonstrate conflicting results, with evidence to both support and refute the claim that EWS-FLI1 can, by itself, transform primary MSCs [13,14,15,16]
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