Role of IL-1ß in Cancer Stem Cell Development and Cancer Recurrence
Tumor-initiating cells (TICs) possess stem-like properties and are responsible for the initiation and recurrence of gliomas. Elevated expression of TGF-ß and IL-1ß has been associated with poor prognosis in high grade glioma patients. We have recently demonstrated that TICs can be induced from glioma cells by IL-1ß and TGF-ß. Nestin-negative LN-229 monolayer glioma cells formed Nestin-positive spheres in the presence of IL-1ß and TGF-ß under serum-free condition. The cytokine-induced spheres displayed stem cell markers (Nestin, Bmi-1, Notch-2 and LIF) and increased invasiveness, drug resistance, and oncogenic potential in vitro and in immunocompromised (nu/nu) mice: hallmarks of TICs. The objective this project is to investigate the molecular mechanisms of IL-1ß-TGF-ß cross-talk in TIC development. Specifically, we will determine the receptor requirements for cross-signaling, signaling interactions between IL-1ß and TGF-ß, and the pathophysiological relevance of IL-1ß-TGF-ß cross-talk in cancer initiation and recurrence.