The role of APRIL (TNFSF13) in carcinogenesis

This thesis focuses on the role of APRIL (TNFSF13, TALL-2 or TRDL-1) during malignant transformation, either as a micro-environmental or as a tumor-intrinsic factor. APRIL is a member of the Tumor Necrosis Factor super family that binds to the receptors called BCMA (for ‘B Cell Maturation Antigen’, also known as TNFRSF17) and TACI (for ‘Transmembrane Activator and Calcium modulator and cyclophilin ligand Interactor’, also known as TNFRSF13B) and HSPG (Heparan Sulphate Proteoglicans). APRIL has been previously shown to support cell growth of b cells and epithelial cells. The work contained within this thesis examines the APRIL signaling axis in multiple model systems. We unraveled the APRIL receptor dependency on different aspects of B cell biology, splenic and long-lived plasma cells. Through different experimental designs we revealed important contributing roles for APRIL signaling in tumor progression in both colorectal cancer and Chronic Lymphocityc Leukemia. In a clinical study we observed that high circulating APRIL levels correspond to advanced disease features on rectal cancer patients, which indicates that serum APRIL levels may serve as a diagnostic tool for selecting patients with a high risk of local failure and occult metastasis. In conclusion, this thesis contributes to the understanding of cytokine biology within the context of malignant transformation and provide conceptual support to the development and use of agents with the potential of targeting the APRIL system in cancer.