Moloney murine leukemia virus-induced tumors show altered levels of proapoptotic and antiapoptotic proteins.
Moloney murine leukemia virus (M-MuLV) is a replication-competent, simple retrovirus that induces T-cell lymphomas when inoculated into neonatal mice. The tumor cells are typically derived from immature T cells. During preleukemic times, a marked decrease in thymic size is apparent in M-MuLV-inoculated mice. We previously demonstrated that this thymic regression is correlated with enhanced levels of thymocyte apoptosis (C. Bonzon and H. Fan, J. Virol. 73:2434-2441, 1999). In this study, we investigated the apoptotic state of M-MuLV-induced tumors. M-MuLV-induced tumors were screened for expression of the apoptotic proteins Fas and Bcl-2 by three-color flow cytometric analysis. Single-positive (SP; CD4(+) CD8(-) and CD4(-) CD8(+)) tumor cells generally displayed lower cell surface expression of Fas than SP thymocytes from uninoculated control mice. Double-positive (DP; CD4(+) CD8(+)) M-MuLV-induced tumor cells fell into two categories: those with normal high levels of Fas and those with low levels of Fas. Additionally, the vast majority of DP tumors showed elevated Bcl-2 levels. The DP tumor cells retaining normal/high Fas expression were capable of transducing an apoptotic signal upon anti-Fas engagement. In addition, DP and CD4(+) SP tumor populations displayed higher levels of Fas ligand than normal thymocytes with the same phenotypes. In contrast, CD8(+) SP and CD4(-) CD8(-) tumors did not show elevated Fas ligand expression. There was no significant correlation between Fas and Fas ligand expression in the DP tumors, suggesting that Fas Ligand expression was not the driving force behind Fas down-regulation. These results suggest that both the Fas death receptor and mitochondrial pathways of apoptotic death are active in M-MuLV-induced tumors and that they must be modulated to permit cell survival and tumor outgrowth.
Bonzon
C
C
Department of Molecular Biology and Biochemistry and Cancer Research Institute, University of California, Irvine, California 92697, USA.
Fan
H
H
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000378:metabolism; D016516:CD4-CD8 Ratio; D016827:CD8 Antigens / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D007942:Leukemia, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008979:Moloney murine leukemia virus / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012192:Retroviridae Infections / Q000378:metabolism* / Q000473:pathology; D013953:Thymus Neoplasms / Q000378:metabolism* / Q000473:pathology; D014412:Tumor Virus Infections / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism
D015704:CD4 Antigens; D016827:CD8 Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor