ABSTRACT
Glioblastoma multiforme (GBM) causes significant neurological morbidity and short survival times. Brain invasion by GBM is associated with poor prognosis. Recent clinical trials of bevacizumab in newly-diagnosed GBM found no beneficial effects on overall survival times; however, the baseline health-related quality of life and performance status were maintained longer in the bevacizumab group and the glucocorticoid requirement was lower. Here, we construct a clinical-scale model of GBM whose predictions uncover a new pattern of recurrence in 11/70 bevacizumab-treated patients. The findings support an exception to the Folkman hypothesis: GBM grows in the absence of angiogenesis by a cycle of proliferation and brain invasion that expands necrosis. Furthermore, necrosis is positively correlated with brain invasion in 26 newly-diagnosed GBM. The unintuitive results explain the unusual clinical effects of bevacizumab and suggest new hypotheses on the dynamic clinical effects of migration by active transport, a mechanism of hypoxia-driven brain invasion.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Adult , Aged , Bevacizumab/adverse effects , Brain Neoplasms/physiopathology , Cell Hypoxia , Female , Glioblastoma/immunology , Glioblastoma/physiopathology , Humans , Male , Middle Aged , Necrosis/chemically induced , Neoplasm Invasiveness/physiopathology , Quality of LifeABSTRACT
Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N'G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.
Subject(s)
Brain Neoplasms/metabolism , Cell Proliferation/physiology , Glioma/metabolism , Protein-Arginine N-Methyltransferases/metabolism , Adult , Aged , Arginine/analogs & derivatives , Arginine/metabolism , Brain Neoplasms/pathology , Cell Differentiation/genetics , Cell Proliferation/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Colony-Forming Units Assay , Epithelium/metabolism , Epithelium/pathology , Female , Glial Fibrillary Acidic Protein/metabolism , Glioma/pathology , Humans , MAP Kinase Signaling System/genetics , Male , Middle Aged , Neurons/metabolism , Phosphopyruvate Hydratase/metabolism , Protein-Arginine N-Methyltransferases/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolismABSTRACT
Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (female gender, younger age, no alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a significant clinical problem. Two new agents, palonosetron and aprepitant, have recently been approved for the prevention of both acute and delayed CINV. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. Aprepitant is the first agent available in the new drug class of neurokinin-1 receptor (NK-1) antagonists. There are a number of 5-HT3 receptor antagonists and NK-1 receptor antagonists currently in Phase II and III clinical trials. Revised antiemetic guidelines for the prevention of CINV are reviewed. Future studies may consider the use of palonosetron and aprepitant with current and other new agents (olanzapine, gabapentin) in moderately and highly emetogenic chemotherapy, as well as in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.
