Brain Cancer Cells Go with the Flow: The Role of Interstitial Fluid Flow in Glioblastoma Invasion

Decades of cancer treatment have relied on therapeutic regimens that target cancer cell death and tumor removal. Surgery, chemotherapy, and radiotherapy serve as effective therapies for many cancers, but often, for more aggressive tumors, especially malignant brain tumors, additional care is warranted. To date, many researchers overlook critical mediators of cancer progression by targeting only the tumor cells and ignoring tissue dynamics. In solid tumors, biophysical forces in the tumor microenvironment (TME) play a critical role in overall survival and prognosis. Glioblastoma (GBM), the most common and lethal brain tumor, is no exception. Patients diagnosed with GBM rarely live more than two years following diagnosis, and current methods aimed at improving survival have not resulted in clinical success. In glioblastoma, dynamic transport processes have gone awry and thus can act to promote cancer cell infiltration, inhibit distribution and efficacy of therapy, and alter the surrounding brain tissue. Throughout this dissertation, we explore the influence of interstitial fluid flow (IFF) and its effects on invasion and overall progression of the most malignant brain tumor, glioblastoma.

The underlying mechanisms of IFF-induced alterations in GBM are poorly understood, and it is necessary to quantify IFF within the brain TME and elucidate its effects on the surrounding tissue. Taking full advantage of the 3D GBM microenvironment, we examined mechanisms of IFF-stimulated invasion, focusing on CXCR4- and CD44-dependent mechanisms. Combining MRI and transport approaches we developed and validated a noninvasive method to measure IFF in GBM. Within murine, canine, and human in vivo models of GBM, we quantified previously unknown interstitial flow velocities in the brain. Ultimately, we used these MRI methods to track the evolution of flow as it pertains to GBM invasion and progression. Overall, this dissertation provides a comprehensive evaluation and quantification of physiologically relevant interstitial flow in the GBM microenvironment and interrogates its contribution to GBM invasion using novel in vitro and in vivo methods.