DDIT3 Expression in Liposarcoma Development

Abstract

Liposarcomas are mesenchymal tumors containing variable numbers of lipoblasts or adipocytes. The most common entities, well differentiated/dedifferentiated liposarcoma (WDLS/DDLS) and myxoid/round cell liposarcoma (MLS/RCLS), are both characterized by genetic rearrangements that affect the expression of the transcription factor DDIT3. DDIT3 induces liposarcoma morphology when ectopically expressed in a human fibrosarcoma. The role of DDIT3 in lipomatous tumors is, however, unclear. We have analyzed the expression of DDIT3 in 37 cases of liposarcoma (WDLS/DDLS n = 10, MLS/RCLS n = 16, and pleomorphic liposarcomas (PLS) n = 11) and 11 cases of common benign lipomas. Major cell subpopulations of WDLS/DDLS and MLS/RCLS tumors were found to express DDIT3 or the derived fusion protein, whereas PLS cases showed only a few positive cells. The lipomas contained large subpopulations expressing DDIT3. No correlation between numbers of DDIT3 expressing cells and numbers of lipoblasts/adipocytes was found. In vitro adipogenic treatment of two DDIT3 expressing cell lines induced lipid accumulation in small subpopulations only. Our results suggest a dual, promoting and limiting, role for DDIT3 in the formation of lipoblasts and liposarcoma morphology.

Figure 1

DDIT3 immunohistochemistry analysis of lipomatous tumors. (a) Lipoma, nuclear, and DDIT3 expression (arrow) and capillaries are indicated by arrowheads. (b) WDLS/DDLS, nuclear, and cytoplasmic DDIT3 expression (arrow). (c) PLS, nuclear, and cytoplasmic DDIT3 expression in lipoblasts (arrow). (d) Mean value and standard deviation of percent positively stained cells in 10 cases of WDLS/DDLS, 16 cases of MLS/RCLS, 11 cases of PLS, and 11 cases of lipoma.

Figure 2

Adipocytic differentiation. (a) Schematic presentation of CEBPB, CEBPA, and DDIT3 expression in adipocyte differentiation. (b) Lipoblast formation and accumulation of lipids in GOT3 WDLS/DDLS derived cell line (top panels) and DDIT3 transfected HT1080 fibrosarcoma cell line (bottom panels) cultured in control or adipogenic medium. Oil Red O staining shows lipids in red.