This dissertation identifies novel roles for the insulin-like growth factor (IGF) system and cathepsin B in Kaposi sarcoma–associated herpesvirus (KSHV)-mediated tumorigenesis. Using a physiologically relevant tissue culture model of KSHV-infected endothelial cells and global transcriptional profiling, key components of the IGF system—including IGFBP-1, -2, and -6, the insulin receptor, and the IGF-II receptor—were found to be dysregulated and functionally important in Kaposi sarcoma. Additionally, cathepsin B was shown to regulate tumor invasion, and a previously unrecognized functional link between the IGF-II receptor and cathepsin B was identified as essential for KSHV-driven tumorigenesis. These findings reveal new mechanisms underlying Kaposi sarcoma and suggest potential therapeutic targets.
