Effect of Interstitial Fluid Flow and Radiotherapy on Glioblastoma Invasiveness and Progression

Glioblastoma (GBM) is the most aggressive and malignant glioma. It accounts for 48.6% of all primary, malignant gliomas with a median survival of 15 months. Infiltration into the surrounding parenchyma is a hallmark of GBM. Radiotherapy is used to address the invasion; however, recent studies have implicated that radiation contributes to increased invasiveness of glioma. Although the effect of radiation on cells has been studied extensively, its effect on the transport of fluid is not well characterized. Transport in the brain which has significant roles in physiology, GBM pathophysiology, and GBM treatment. Thus, understanding the effect of radiation on transport within the lesion and surrounding interstitium will be beneficial in characterizing the effects of radiotherapy in GBM patients. This dissertation seeks to explore the relationship between radiation, transport, and movement of glioma cells and includes the following: 1) Characterizing in vitro motility metrics of glioma stem cell lines in and relating them to in vivo invasion. 2) Studying the effect of radiation on motility, flow-mediated invasion, extracellular matrix components, and transport within the lesion and interstitium. 3) Assessing transport in clinical images and relating transport parameters to progression of GBM. 4) Developing a novel pipeline for applying vector field topology to the study of interstitial fluid flow in glioma. Surprisingly, we found that motility metrics in vitro have a negative correlation trend with in vivo invasion. Next, we found that radiation causes a transient increase in advective flow, and a more sustained decrease in diffusivity in a murine glioma model. Tenascin C was found to correlate significantly with invasion and diffusivity, indicating that it might be a link between radiation, transport, and invasion. Furthermore, interstitial fluid flow was calculated and assessed in clinical images. This showed that interstitial fluid flow velocity magnitude in the tumor correlates with overall survival in GBM patients. Lastly, vector field topology was introduced as a novel method of studying transport that provides more detailed information to identify potential drivers of transport within a flow field. Altogether, this work presents novel insight into the effects of radiation on invasion and transport in GBM. Hopefully, this work can provide a foundation to build upon in efforts of improving treatment planning and clinical outcomes for GBM patients.