Tumor Cell Infiltration into the Brain in Glioblastoma: From Mechanisms to Clinical Perspectives

SIMPLE SUMMARY: The estimated survival time for glioblastoma patients is extremely low; only about 5% of patients survive five years post diagnosis. The standard of care for glioblastoma patients involves surgery, radiation therapy, and chemotherapy with temozolomide. However, due to the extremely invasive capability of glioblastoma cells, tumors develop very diffusely, integrating into the healthy brain tissue. Indeed, the separation of healthy brain tissue and the tumor boundaries, by standard surgical microscopy, is very challenging. Therefore, the maximum safe removal of the tumor mass is difficult, leaving some tumor cells behind. Therefore, understanding the molecular mechanisms of tumor cell infiltration and developing anti-invasive approaches are of the utmost priority. Here, we provide a review of the characteristics and molecular mechanisms of glioblastoma invasion, and include a perspective of clinical applications. ABSTRACT: Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One major factor for the failure of existing therapeutic approaches is the highly invasive nature of glioblastomas. The extreme infiltrating capacity of tumor cells into the brain parenchyma makes complete surgical removal difficult; glioblastomas almost inevitably recur in a more therapy-resistant state, sometimes at distant sites in the brain. Therefore, there are major efforts to understand the molecular mechanisms underpinning glioblastoma invasion; however, there is no approved therapy directed against the invasive phenotype as of now. Here, we review the major molecular mechanisms of glioblastoma cell invasion, including the routes followed by glioblastoma cells, the interaction of tumor cells within the brain environment and the extracellular matrix components, and the roles of tumor cell adhesion and extracellular matrix remodeling. We also include a perspective of high-throughput approaches utilized to discover novel players for invasion and clinical targeting of invasive glioblastoma cells.