Expression of the Epstein-Barr virus protein LMP1 mediates tumor regression in vivo.
By stimulating the expression of murine IP-10 and Mig, CXC chemokines that inhibit neovascularization and cause damage to established tumor vasculature, human B cells immortalized with Epstein-Barr virus (EBV) can promote an effective antitumor response in athymic mice. In the present study, we examined the potential role of EBV in the induction of this antitumor response. Using a panel of EBV+ and EBV- Burkitt lymphoma (BL) cell lines, a significant correlation was detected between the expression of the EBV latency gene LMP1 and the occurrence of spontaneous tumor regression in athymic mice. Inoculation of LMP1+ and LMP1- BL cells in the same subcutaneous site resulted in tumors that completely regressed in a manner indistinguishable from that induced by EBV-immortalized B cells. EBV-converted BL30 and BL41 sublines infected with B95-8 virus expressed LMP1, generated tumors that frequently regressed spontaneously, and promoted an effective antitumor response against progressively growing tumors. In contrast, the EBV- BL30 and BL41 cell lines and the EBV-converted BL30 and BL41 infected with P3HR-1 virus did not express LMP1 protein, and generated progressively growing tumors in nude mice. When transfected with the LMP1 gene, BL41 cells produced tumors that regressed spontaneously in most cases, and could induce the regression of tumors derived from BL41 cells transfected with vector alone. Tumors induced by LMP1-expressing cells expressed murine IP-10 and Mig and displayed histological evidence of extensive tumor tissue necrosis and vascular damage. We conclude that the EBV protein LMP1 is likely responsible for the antitumor response elicited by EBV-immortalized cells in athymic mice.
Cherney
B W
BW
Division of Hematologic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20852-1448, USA.
Sgadari
C
C
Kanegane
C
C
Wang
F
F
Tosato
G
G
D000818:Animals; D002051:Burkitt Lymphoma / Q000473:pathology* / Q000821:virology*; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009365:Neoplasm Regression, Spontaneous / Q000235:genetics*; D009856:Oncogene Proteins, Viral / Q000235:genetics; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D017735:Virus Latency / Q000235:genetics
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D009856:Oncogene Proteins, Viral; D014763:Viral Matrix Proteins