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An increased awareness of the potential oncomodulatory properties of human cytomegalovirus (HCMV) has evolved over the last decade. We first reported the presence of HCMV in human glioblastomas, and subsequently these findings have been corroborated by other groups. However, some controversy has been associated with the immunohistochemical and in situ hybridization techniques used, since standard immunohistochemical and in situ hybridization techniques have been insufficient to detect low level HCMV antigens and nucleic acids in some tumor tissues. Here, we present detailed methods that can be used for the sensitive detection of low level HCMV antigens and nucleic acids in human glioblastoma specimens. Using these techniques, HCMV is frequently detected in frozen and formalin fixed paraffin-embedded tissue specimens. Furthermore, we demonstrate how human primary glioblastoma cells can be cultured in vitro, and how these cells can be used for detection of HCMV by immunofluorescence, in situ hybridization, western blot, and RT-PCR. [ABSTRACT FROM AUTHOR]

Free nucleic acids are elevated in serum or plasma of patients with various cancers and indicate responsiveness to therapy. Circulating nucleosomes in serum and cerebrospinal fluid (CSF) of 45 patients were studied (10 with glioblastoma, 20 with non-acute neurological disorders, 10 with subarachnoid haemorrhage, and five with non-ruptured aneurysms). Patients with recurrent glioblastoma underwent tumour resection and local chemotherapy. Samples were taken before treatment and daily during the first week after surgery. There were no significant differences between pre-therapeutic nucleosome levels in the various patient groups. In patients with glioblastoma treated by surgery and local chemotherapy, levels of serum and CSF nucleosomes increased moderately during the week after surgery. Postoperatively, three of the 10 patients with glioblastoma developed cerebral oedema when CSF levels increased almost 200-fold reaching a maximum on day 3 after surgery in contrast to patients without oedema. Monitoring CSF levels of nucleosomes in patients with glioblastoma may indicate the development of postoperative complications and warrants further investigations. [ABSTRACT FROM AUTHOR]

High-grade astrocytomas (HGAs) are the most common adult primary malignant brain tumor, which include anaplastic astrocytoma (AA; World Health Organization [WHO] grade III) and glioblastoma multiforme (GBM; WHO grade IV). Although HGAs represent an overall uncommon cancer, they are associated with morbidity and high mortality. Despite state-of-the-art multimodality treatments, the median survival of GBM patients is 12–15 months, whereas that of AA is 2–3 years [1]. Current treatments for HGA include surgery, radiation, and chemotherapy. Temozolomide, an oral alkylating chemotherapy, has been approved for newly diagnosed GBM and recurrent AA. It offers significant, albeit modest, survival benefit for unselected HGA patients. [ABSTRACT FROM AUTHOR]

Following the discovery that leukemic cells exhibit properties of hematopoietic stem cells, the prospective isolation of stem-like cells with high tumorigenicity has been reported for a variety of tumors. These ˵cancer stem cells″ (CSCs) are so named because they exhibit the capacity for sustained self-renewal and possess the ability to regenerate transplanted tumor masses resembling the primary tumor in immunodeficient mice. However, the existence of CSCs remains contentious in the field of cancer biology, in part because of the application of inconsistent and inaccurate definitions and disputes over terminology. Herein, we review the discovery of CSCs, examine in detail their physical and functional characteristics, the mechanisms that lead to their formation, and how their contribution to solid tumor formation impacts cancer therapies. [ABSTRACT FROM AUTHOR]

Cancers of the brain comprise a genetically and morphologically heterogeneous class of proliferating neural cells derived from incompletely differentiated brain tumor stem cells (BTSCs). The molecular and genetic mechanisms that contribute to their development and propagation are incompletely understood, however, current research is expanding our knowledge as to what specific gene activation and deactivation mechanisms are triggered during the onset of brain cell neoplasia. Apparently, only relatively small populations of BTSCs are capable of driving the proliferative and invasive nature of these cancers, and the intrinsic ability to reinitiate and propagate aberrant cell growth at any metabolic cost. This chapter provides a current overview of gene expression patterns in glioma and glioblastoma multiforme (GBM), with special emphasis on messenger RNA (mRNA) and micro RNA (miRNA) speciation and abundance, and how our recent understanding of specific mRNA–miRNA interactions have increased our comprehension of this insidious neoplastic process. [ABSTRACT FROM AUTHOR]

Gliomas are the most frequent malignant intracranial tumors arising from the brain or spinal cord tissue. The most malignant among them is glioblastoma multiforme (GBM), which constitutes approximately 20–25% of all primary intracranial neoplasms with an incidence of 3–4/100,000. This type of tumor is characterized by progressive overgrowth of neoplastic glial cells with widespread and relentless invasion, resulting in acquisition of resistance to treatment and a poor prognosis due to recurrence. These features hamper efficient surgical intervention of the disease. Current chemo/radiotherapy conditions act sublethally but cannot effectively suppress the proliferation of glioma cells. Despite some progress, the therapeutic options are yet limited, and novel therapeutic strategies are clearly needed. Targeting of disease-specific molecules involved in the proliferation, apoptosis, and invasion of the tumor cells as well as in tumor angiogenesis may offer a high potential for the development of more effective therapies for GBM. RNA interference (RNAi) has been emerging not only for in vitro target validation, but also for a novel therapeutic strategy based on the highly specific and efficient silencing of a target gene. Indeed, RNAi has shown to act against GBM efficiently in numerous preclinical studies. Many efforts have been devoted to overcome the three major obstacles in use of RNAi in vivo; their specificity, instability, and poor cellular delivery of bioactive small interfering RNA (siRNA) across the blood–brain barrier. The identification of effective target and the establishment of novel siRNA delivery systems are needed for the clinical applications of RNAi for treatment of GBM. [ABSTRACT FROM AUTHOR]

Phosphatidyl-inositol-3 kinases (PI3Ks) are a family of intracellular lipid kinases that are frequently hyperactivated in glioblastoma. The PI3K complex links growth factor signaling with cellular proliferation, differentiation, metabolism, and survival. mTOR (mammalian target of rapamycin) acts as both downstream effector and upstream regulator of PI3K, thus highlighting its importance in glioblastoma. This review will highlight laboratory and clinical evidence of mTOR΄s role in glioblastoma. Mechanisms of escape from mTOR inhibition will also be discussed, as well as future clinical strategies of mTOR inhibition. [ABSTRACT FROM AUTHOR]

Glioblastoma bears one of the most severe prognoses of human cancers. At this time, the available therapy is directed against specific pathological mechanisms of these tumors, as proliferation, angiogenesis, or immunosuppression. This approach neglects systems biology: Several compartments as tumor, local precursor, immuno- and endothelial cells, the extracellular matrix and intratumoral vessels communicatively interact with the host΄s organs. The development of a tumor is a dynamic process, comparable to a developing organ, and is highly dependent on interactions between different structures and compartments within the tumor. Large-scale unbiased assays will be needed to investigate the specific molecular and cellular patterns of each individual glioblastoma. Most likely, new models will be individually compiled in the future work-up of glioblastomas, generating information for the setup of a multi-targeted personalized concept approaching the systems biology of glioblastoma. These new approaches include advanced in vivo models using engineered animals and in silico models based on bioinformatic methods. Interventions will influence all levels of tumor biology, including the genetic, epigenetic, proteomic, and metabolomic level. First publications aim to define targets for treatment using systems biology approaches. In our opinion, a clinically meaningful improvement will only be possible with interventions that are multi-targeted and consequently inhibit glioma-initiating cells, enhance local antitumor immune responses, and target the most relevant molecular mechanisms responsible for tumor cell proliferation and invasion. This review will focus on the most prevalent and malignant primary brain tumor of men, glioblastoma, which is notorious for its therapy resistance to classical treatments. [ABSTRACT FROM AUTHOR]