Future Approaches for the Therapy of Malignant Glioma: Targeting Genes Mediating Invasion

Abstract

part of Malignant glioma is the most aggressive and consistently fatal of all brain cancers, without any effective therapies. The dismal prognosis of malignant gliomas is principally attributed to their highly invasive nature. The tumor enters into the surrounding normal brain tissue thus limiting complete removal by surgical resection and resulting in recurrence. A number of proteins and pathways have been implicated as being essential for glioma cell migration and invasion. Understanding the molecular mechanisms of glioma invasiveness is an essential step in developing rationally targeted effective therapies. Malignant gliomas (such as glioblastoma multi forme [GBM]) continue to cause a significant level of morbidity and mortality across a wide range of individuals. Gliomas, arising from astrocytes, are infiltrative and diffuse in nature and the most common and malignant of all human primary intracranial tumors. Irrespective of multimodal treatment, including debulking surgery, chemotherapy and radiation, patients with malignant glioma have a median survival rate of only 15 months [1]. The underlying reason for this dismal prognosis is the highly invasive nature of glioma into the brain parenchyma, resulting in recurrence even after aggressive surgical resection. The residual pool of invasive cells gives rise to recurrent tumors either immediately adjacent to the resection margins or within several centimeters of the resection cavity. Invading glioma cells routinely follow the white matter tracts and basement membranes of blood vessels. However, even though glioma cells penetrate into the glial region of the vascular basement membrane they lack the ability to disrupt/penetrate the endothelial basement membrane, thus confining the tumor growth within the CNS [2]. Glioma cell invasion involves a complex multistep process, including tumor cell interactions with the extracellular matrix (ECM) and with adjacent cells, tumor cell motility and proteolytic degradation of the ECM by tumor-secreted proteases, which is potentially controlled at each step by distinct genes and signaling pathways [3]. Therapies based on targeting these complex invasive processes have accomplished limited success, indicating that an increased understanding of the molecular mechanisms of glioma cell migration and invasion are mandatory for developing efficacious therapies to eradicate residual glioma cells following surgical resection. Several candidate genes, including members of the matrix metalloproteinase (MMP) gene family and their endogenous tissue inhibitors (TIMPs), have been recognized as regulators of glioma invasiveness. MMP-2 and MMP-9 have been extensively studied and are recognized as the most common and most expressed MMPs involved in glioma invasion [4]. MMPs enhance tumor cell invasion by degrading ECM proteins, activating signal-transduction cascades that promote motility and solubilizing ECM-bound growth factors [5]. Angiopoietin is overexpressed in invasive areas of glioblastoma and, in addition to promoting angiogenesis, also induces tumor cell infiltration by activating MMP-2 [6]. Marimastat is a low-molecular weight peptide mimetic inhibitor of MMPs [7]. Future approaches for the therapy of malignant glioma: targeting genes mediating invasion