뇌암 줄기 세포의 집적 및 유지에 대한 신호 기작 연구

Abstract

Glioblastoma is the most common and one of the most aggressive type of primary brain tumor with a median survival of around 12-month average after diagnosis despite optimal therapy. The major limitations of glioma treatment are the prevalence of recurrence after surgery, infiltration into surrounding brain regions, and intrinsic or acquired resistance to chemo- and radiotherapy. Accumulating evidence suggests that a tiny subpopulation of total cellularity of glioblastoma has distinct properties similar to somatic neural stem cells, displaying self-renewal, multilineage differentiation and tumorigenic potential. These glioma stem-like cells (GSCs), also known as glioma-initiating cells, contributes to resistance to chemotherapy and radiotherapy, infiltration to other brain regions, and the recurrence of gliomas. The identification of cancer stem cells and their roles in GBM progression and therapeutic resistance has altered our understanding of glioma tumor biology and causing a reevaluation of current therapies for malignant gliomas. Cancer cure requires elimination of all tumor cells, even small fractions like GSCs. Novel therapies directed against GSCs may help improve the currently dreadful record of clinical activity with conventional therapy. Although controversy still exists as to the methods for isolating and characterizing GSCs and defining the role of non-stem cancer population, GSCs represent a subpopulation of cancer cells with extraordinary capacities to promote tumor repopulation, angiogenesis, invasion and therapeutic resistance (summarized in Fig. 1), making them a critical cell population that should be targeted for antiglioma therapies. However, critical molecular mechanisms that govern the stemness, invasion to surrounding regions and resistance to anticancer treatment remain largely unknown. In this study, I attempted to understand the molecular signaling pathways that govern the maintenance of GSCs. By using sphere-culture conditions that enrich GSC population, I studied the functions of the JNK, small GTPase Rac1, PKCδ and PI3K/AKT signalings and found that those molecules are critical regulators for the maintenance of GSCs. Finally, converging these signaling pathways, I attempted to connect them and draw the signaling networks regulating tumor progression in brain. These findings may open new avenues to guide novel tumor therapeutic approaches in future.