LMP1 Causes Chronic Inflammation Prior to Neoplasia in Vivo

It has long been postulated that chronic inflammation can be tumourigenic but the exact mechanisms involved are poorly understood. Nasopharyngeal carcinoma, like many cancers, is heavily infiltrated with inflammatory cells, which could be contributory to tumourigenesis. To explore the role of LMP1 induced inflammation and oxidative stress in EBV associated malignancies, we utilize a transgenic mouse model of epithelial carcinogenesis in which LMP1CAO is expressed in the epidermis. The skin of these mice undergoes progressive inflammatory pathology prior to neoplasia and is infiltrated with T-cells, mast cells and neutrophils. Affected tissues show upregulation of several cytokines and inflammation associated proteins including CD30, CD30L, CD40, L-Selectin, IL-3, IL-1β and s100A9. LMP1D6-null mice (D6: decoy receptor for inflammatory chemokines) show acceleration of inflammatory processes, suggesting a role of chemokines in LMP1 induced cancer predisposition. The preneoplastic skin also shows dermal deposition of immunoglobulins and increased levels of complement component-3 (C-3). The critical role of mature B and/or T-cells in the advancing pathology is evidenced by their elimination, which limits the pathology to an early benign stage. By proteomic analysis, we have demonstrated upregulation of enzymatically inactive chitinase-like proteins, chitinase-3-like-4 (chi3l4/YM2), chitinase-3-like-1 (chi3l1/YKL40) and chitotriosidase (chit1), in the affected skin, suggesting a role in chronic inflammation. We have found a decrease in SOD1 levels and increase in H2O2 in preneoplastic skin indicating that the tissue is also under oxidative stress. Dissecting the mechanisms by which LMP1 induces inflammation prior to neoplasia may provide new insights for EBV associated cancer therapies