Glioblastoma multiforme (GBM) is a debilitating disease that is associated with poor prognosis, short median patient survival and a very limited response to therapies. GBM has a very complex pathogenesis that involves mutations and alterations of several key cellular pathways that are involved in cell proliferation, survival, migration and angiogenesis. Therefore, efforts that are directed toward better understanding of GBM pathogenesis are essential to the development of efficient therapies that provide hope and extent patient survival. In this review, we outline the alterations commonly associated with GBM pathogenesis and summarize therapeutic strategies that are aimed at targeting aberrant cellular pathways in GBM.

The RAS/MAP kinase and the RAS/PI3K/AKT pathways play a key role in the regulation of proliferation, differentiation and survival. The induction of these pathways depends on Receptor Tyrosine Kinases (RTKs) that are activated upon ligand binding. In cancer, constitutive and aberrant activations of components of those pathways result in increased proliferation, survival and metastasis. For instance, mutations affecting RTKs, Ras, B-Raf, PI3K and AKT are common in perpetuating the malignancy of several types of cancers and from different tissue origins. Therefore, these signaling pathways became prime targets for cancer therapy. This review aims to provide an overview about the most frequently encountered mutations, the pathogenesis that results from such mutations and the known therapeutic strategies developed to counteract their aberrant functions.

Interferons (IFNs) are a family of secreted proteins with antiviral, antiproliferative and immunomodulatory activities. The di erent biological actions of IFN are believed to be mediated by the products of speci®cally induced cellular genes in the target cells. The promyelocytic leukaemia (PML) protein localizes both in the nucleoplasm and in matrix-associated multi-protein complexes known as nuclear bodies (NBs). PML is essential for the proper formation and the integrity of the NBs. Modi®cation of PML by the Small Ubiquitin MOdi®er (SUMO) was shown to be required for its localization in NBs. The number and the intensity of PML NBs increase in response to interferon (IFN). Inactivation of the IFN-induced PML gene by its fusion to retinoic acid receptor alpha alters the normal localization of PML from the punctuate nuclear patterns of NBs to microdispersed tiny dots and results in uncontrolled growth in Acute Promyelocytic Leukaemia. The NBs-associated proteins, PML, Sp100, Sp140, Sp110, ISG20 and PA28 are induced by IFN suggesting that nuclear bodies could play a role in IFN response. Although the function of PML NBs is still unclear, some results indicate that they may represent preferential targets for viral infections and that PML could play a role in the mechanism of the antiviral action of IFNs. Viruses, which require the cellular machinery for their replication, have evolved di erent ways to counteract the action of IFN by inhibiting IFN signalling, by blocking the activities of speci®c antiviral mediators or by altering PML expression and/or localization on nuclear bodies. Oncogene (2001) 20, 7274 ± 7286.

Tumors are composed of different types of cancer cells that contribute to tumor heterogeneity. Among these populations of cells, cancer stem cells (CSCs) play an important role in cancer initiation and progression. Like their stem cells counterpart, CSCs are also characterized by self‐renewal and the capacity to differentiate. A particular population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into cells of mesodermal characteristics. Several studies have reported the potential pro‐or anti‐tumorigenic influence of MSCs on tumor initiation and progression. In fact, MSCs are recruited to the site of wound healing to repair damaged tissues, an event that is also associated with tumorigenesis. In other cases, resident or migrating MSCs can favor tumor angiogenesis and increase tumor aggressiveness. This interplay between MSCs and cancer cells is fundamental for cancerogenesis, progression, and metastasis. Therefore, an interesting topic is the relationship between cancer cells, CSCs, and MSCs, since contrasting reports about their respective influences have been reported. In this review, we discuss recent findings related to conflicting results on the influence of normal and CSCs in cancer development. The understanding of the role of MSCs in cancer is also important in cancer management. Stem Cells Translational Medicine 2017;6:2115–2125