**Abstract**

The Epstein-Barr virus (EBV) reactivation corresponds to the activation of EBV global replication involving not only the origin of the latent viral replication but also that of the origin of lytic replication. During this reactivation, a minority of B cells infected with EBV in its latent form enter the lytic phase. During this phase, all EBV proteins are produced, enabling the assembly of complete virions that lysate their host cells and infect neighboring cells (lytic cycle). This horizontal EBV transmission seeks to increase the pool of EBV-infected B cells. This chapter seeks to review the role of the lytic EBV proteins (particularly that of the ZEBRA protein) *in tumor development*. This protein is the main transcription factor of EBV, expressed during the activation of the lytic cycle. Recently, we demonstrated that this immediate early protein can be detected in the soluble state (s-ZEBRA) in the serum of patients with posttransplant lymphoproliferative disorder. We highlighted the role of ZEBRA in EBV pathogenesis in transplanted subjects, not only as a key protein in the activation of EBV replication but also as a protein "toxoid" released into the extracellular milieu. This release could result in increased secretion of immunomodulatory cytokines and that of angiogenesis-promoting factors conducive to tumor progression.

**Keywords:** tumor progression, tumorigenesis, EBV, lytic cycle, Zta/ZEBRA protein, lymphoma
