Interactions between hypoxia, HIF, type 2 IP3 receptors and invasion of glioblastoma

点击翻译按钮获取中文摘要

Most cancers form solid tumours, within which cells inappropriately proliferate. Since the development of an effective blood supply lags behind growth of the tumour, the tumour cells are exposed to much lower oxygen concentrations than most cells. This hypoxia leads to expression of a protein (HIF) that coordinates adaptive responses to the lack of oxygen. HIF causes tumour cells to loosen their attachments to each other, and so become more likely to leave the primary tumour and migrate elsewhere. This is a major clinical problem because most cancer deaths are caused by tumours spreading to form new tumours elsewhere in the body (metastases).Glioblastoma is the most common primary brain tumour. These tumours rarely spread beyond the brain, but they do invade surrounding brain tissue, preventing complete surgical removal and usually leading to death within months of diagnosis. As with other solid tumours, this invasion begins in a hypoxic environment, within which the tumour cells express HIF. Our analyses of glioblastoma cells suggest a pathway through which hypoxia and HIF may lead to disruption of adhesions between the cells and thereby increased invasion of surrounding brain tissue. Surprisingly this pathway involves down-regulation of a protein (IP3R2) that differs minimally from its close relatives that are much more abundant in glioblastoma cells. Since this protein is a channel through which calcium ions can leak into the cell to regulate cellular activities, we suggest that IP3R2 is unique among its relatives in selectively delivering its calcium signals to targets that regulate the adhesions between cells.We will address the mechanisms linking hypoxia, through HIF, to down-regulation of the IP3R2 protein. We will then ask how that leads to disruption of adhesions between cells and to increased invasion. We suggest that understanding these early steps in invasion might identify new targets for more effective treatment of glioblastoma.