Figure 2.

Figure 2 illustrates the multistep model of the pathogenesis of EBV positive NPC. A complex interplay of known genetic variations with environmental risk factors increases susceptibility to NPC. Subsequent chromosomal loss (3p, 9p, 11a), loss of function mutations (CDKN2A, cCDN1, RASSF1A, PTEN), and widespread hypermethylation lead to high-grade preinvasive lesions. Mutations in the NF-kB, MAPK/PI3K/STAT and TP53 pathways further drive tumorigenesis. Concurrently, EBV oncogenes upregulate the expression of various genes, perpetuating tumorigenesis. Early events in NPC pathogenesis and epigenetic changes Numerous environmental factors have stood out in its relation to NPC. Dietary habits, such as preserved fish and foods, as well as occupational exposures to wood dust, formaldehyde and cigarette smoke emerged as significant contributors which heightened risk of NPC. In early stages of NPC, in addition to various TLR and HLA polymorphisms, epigenetic alterations such as CpG Island hypermethylation, and chromosomal loss (3p, 9p21) play a pivotal role in silencing tumor suppressor genes, contributing to disease initiation and progression. Abnormalities in signaling pathways Dysregulation of the NF-KB, MAPK PI3K and STAT pathways are well known in NPC. LMP1 activates NF-KB by engaging both the canonical and non-canonical pathway, facilitating apoptotic evasion and immune escape. The MAPK, PI3K and STAT pathways are also activated via the TNF receptor, upregulating anti-apoptotic genes and pro-survival signals. LMP1 and tumorigenic properties LMP1 is one of the key players of tumor progression, orchestrating various mechanisms that drive malignancy. Through activation of the FGFR1, mTOR and, the NF-KB pathway, upregulation of MMP, fibronectin and integrin-a5, and enhanced VEGF expression, LMP1 stimulates new vessel formation, a critical factor facilitating tumor proliferation and metastasis. Simultaneously, LMP1 disrupts immune surveillance by hampering antigen presentation and amplifying anti-apoptotic signals, allowing it to evade immune detection and circumvent cell cycle checkpoints. EBV fosters a tumor suppressive microenvironment and this is enabled by LMP1 upregulation of IL-10 and upregulation of T helper cells. Uncontrolled cell proliferation is attained through LMP1 hyperphosphorylation of DK2 and Rb thus promoting G1/S progression, and LMP1 regulation of telomerases resulting in cell immortality. Other prominent EBV products include LMP2 and EBNA1, which are further detailed under Figure 3. An overview of the development of NPC In summary, Figure 2 provides a brief overview of the multi step model of NPC pathogenesis. This model posits that the development of NPC is a highly complex, multistage process of cumulative environmental exposures and genetic changes, spanning from initial infection and environmental encounters leading to epithelial dysplasia, and subsequent genetic and epigenetic alterations over time activating oncogenesis. Products of type II latency program then confer tumorigenic properties to NPC cells, enabling growth and aggressive invasion.