CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis

Abstract

Ewing sarcoma (EWS) is an aggressive bone tumor of uncertain cellular origin. CD99 is a membrane protein that is expressed in most cases of EWS, although its function in the disease is unknown. Here we have shown that endogenous CD99 expression modulates EWS tumor differentiation and malignancy. We determined that knocking down CD99 expression in human EWS cell lines reduced their ability to form tumors and bone metastases when xenografted into immunodeficient mice and diminished their tumorigenic characteristics in vitro. Further, reduction of CD99 expression resulted in neurite outgrowth and increased expression of β-III tubulin and markers of neural differentiation. Analysis of a panel of human EWS cells revealed an inverse correlation between CD99 and H-neurofilament expression, as well as an inverse correlation between neural differentiation and oncogenic transformation. As knockdown of CD99 also led to an increase in phosphorylation of ERK1/2, we suggest that the CD99-mediated prevention of neural differentiation of EWS occurs through MAPK pathway modulation. Together, these data indicate a new role for CD99 in preventing neural differentiation of EWS cells and suggest that blockade of CD99 or its downstream molecular pathway may be a new therapeutic approach for EWS.

A Leukemia-Associated CD34/CD123/CD25/CD99+ Immunophenotype IdentifiesFLT3-Mutated Clones in Acute Myeloid Leukemia

“…In normal BM, we detect CD99 expression on CD34 þ cells, but it does not correlate with CD123 or CD25. Interestingly, CD99 expression by tumor cells has been described in Ewing Sarcoma, where this antigen is the potential target of immunotherapy (38). Bachas and colleagues (29,31) have studied in detail the subclones detectable within the leukemic blasts of AML patients and analyzed their role in the development of relapse.…”

CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

“…In pathology, CD99 is found on the cell surface of EWS, acute lymphoblastic leukemia, thymic tumors, some spindle cell tumors (e.g., synovial sarcoma), hemangiopericytoma, meningioma, and malignant glioma, in which it confers high invasiveness and low survival rates (13,(15)(16)(17)(18). In EWS, the EWS-FLI1 oncogenic activity (19) is facilitated by CD99 likely because it hampers cell differentiation maintaining an high proliferation rate (20). Indeed CD99 knockdown in EWS cells induces terminal neural differentiation and reduces tumor growth and bone metastasis upon transplantation into immunodeficient mice (20).…”

“…In EWS, the EWS-FLI1 oncogenic activity (19) is facilitated by CD99 likely because it hampers cell differentiation maintaining an high proliferation rate (20). Indeed CD99 knockdown in EWS cells induces terminal neural differentiation and reduces tumor growth and bone metastasis upon transplantation into immunodeficient mice (20). In turn, EWS-FLI1 maintains high levels of CD99 expression (20)(21)(22)(23).…”

CD99-positive soft tissue sarcoma with chromosomal translocation between 1 and 16 and inversion of chromosome 5

“…EWS revealed an inverse correlation between CD99 and neural markers, as well as an inverse correlation between neural differentiation and oncogenic transformation (1). Therefore, CD99 expression may correlate with tumorigenesis and malignant potential.…”

“…CD99 is a membranous protein that is expressed in most cases of Ewing sarcoma (EWS), synovial sarcoma (SS) and low-grade fibromyxoid sarcoma (LGFMS), although its involvement in these diseases is unknown. However, knocking down CD99 expression in human EWS cell lines reduced their ability to form tumors and bone metastases when xenografted into immunodeficient mice, and diminished their tumorigenic characteristics in vitro (1). Therefore, CD99 may be a marker of aggressiveness.…”