Chemotherapy Induced Glioma Stem Cell Niche

Glioblastoma Multiforme (GBM) is a highly fatal and the most common adult brain tumor with a median survival of about 14 months. Despite the advanced understanding of GBM biology as well as aggressive therapeutic interventions, the prognosis for patients with GBMs has remained unchanged for the last decade. The recent development of a cancer stem cell hypothesis proposes that GBMs are driven by a rare subset of tumor cells known as glioma stem cells (GSCs) which possess superior therapy resistant ability, which is considered to be responsible for sustaining the disease’s progression and initiate disease recurrence. However, there is an ongoing confusion regarding the glioma stem cell theory that has to do with their origin. The most common believe is that GSCs are derived from normal tissue stem cells, which acquire necessary genetic alteration during or as part of the cancer development process. On the other side of the spectrum, our lab along with others have recently demonstrated that under specific biological condition(s) such as low oxygen tension or stressful environment induced by anti-cancer therapies, the normal tumor cells have the ability to acquire stem-like state. We believe that such conversion between GBM cells and therapy-resistant GSCs and frustrating our attempts to develop effective therapeutic approaches for GBM. This mode of renewal would allow for the newly converted GSCs to be able to sustain uncontrollable tumor growth and initiate clinical relapse. Based on this reasoning, we now propose to investigate the mechanisms of such interconversion and examine the role of therapeutic stress in promoting tumor cells to acquire cancer stem-like state. Successfully completion of the proposed specific aims will not only allows us to formulate strategies to optimize the current conventional therapies against GBM, but also promote discovery of novel targets for this deadly disease.