Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Endothelial Cells and Promotes Vascular Mimicry.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months. One key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by anticancer therapeutics. Moreover, GBM tumors are highly vascularized with aberrant vessels that complicate the delivery of antitumor agents. Recent research has demonstrated that GBM cells have the ability to transdifferentiate into endothelial cells (ECs), illustrating that GBM cells may use plasticity in concert with vascularization leading to the creation of tumor-derived blood vessels. The mechanism behind this transdifferentiation, however, remains unclear. Here, we show that treatment with temozolomide (TMZ) chemotherapy induces time-dependent expression of markers for glioma stem cells (GSCs) and immature and mature ECs. In addition, GBM tumors growing as orthotopic xenografts in nude mice showed increased expression of GSC and EC markers after TMZ treatment. Ex vivo FACS analysis showed the presence of immature and mature EC populations. Furthermore, immunofluorescence analysis revealed increased tumor-derived vessels in TMZ-recurrent tumors. Overall, this study identifies chemotherapeutic stress as a new driver of transdifferentiation of tumor cells to endothelial cells and highlights cellular plasticity as a key player in therapeutic resistance and tumor recurrence.

Monoamines in glioblastoma: complex biology with therapeutic potential.

Glioblastoma (GBM) is characterized by extremely poor prognoses, despite the use of gross surgical resection, alkylating chemotherapeutic agents, and radiotherapy. Evidence increasingly highlights the role of the tumor microenvironment in enabling this aggressive phenotype. Despite this interest, the role of neurotransmitters, brain-specific messengers underlying synaptic transmission, remains murky. These signaling molecules influence a complex network of molecular pathways and cellular behaviors in many CNS-resident cells, including neural stem cells and progenitor cells, neurons, and glia cells. Critically, available data convincingly demonstrate that neurotransmitters can influence proliferation, quiescence, and differentiation status of these cells. This ability to affect progenitors and glia-GBM-initiating cells-and their availability in the CNS strongly support the notion that neurotransmitters participate in the onset and progression of GBM. This review will focus on dopamine and serotonin, as studies indicate they contribute to gliomagenesis. Particular attention will be paid to how these neurotransmitters and their receptors can be utilized as novel therapeutic targets. Overall, this review will analyze the complex biology governing the interaction of GBM with neurotransmitter signaling and highlight how this interplay shapes the aggressive nature of GBM.

Rogue one: another faction of the Wnt empire implicated in assisting GBM progression.

It remains incumbent on researchers to conceive novel treatments for the most common primary malignancy of the brain in adults, glioblastoma multiforme (GBM), as the standard of care for patients today fails to yield a median survival beyond two years following diagnosis. Recent studies have tended towards appreciating the cellular heterogeneity of GBM tumors, focusing on the subpopulation of highly plastic glioblastoma stem cells (GSCs). In the November 2016 issue of Cell, Hu and colleagues developed a de nova GBM model derived from immortalized neural stem cells and, using this model, they demonstrated that GSCs can generate CD133+/CD144+ cells with endothelial cell-like characteristics. Contrasts between the epigenetic state and gene expression level before and after oncogenic transformation of this utilized de novo model for GBM implicated WNT5A, which has been previously shown to play a role in endothelial cell proliferation and migration via non-canonical Wnt signaling, as a mediator of the process. The transdifferentiation was accompanied by alterations in the histone marks at the gene loci of WNT5A, and its transcription factors PAX6 and DXL5. The authors hypothesize that activation of AKT, an aberration of the RTK/PTEN/PI3K pathway observed in the majority of GBM cases, triggers these epigenetic changes causing WNT5A expression. This phenomenon is of obvious clinical significance, as it provides an insight into how GBM may circumvent therapies targeting angiogenesis to achieve the neovascularization required to sustain invasive growth. The unveiling of this atypical differentiation process also raises questions about its interaction with the radiotherapy and chemotherapy commonly used to counter GBM progression. Here, we review the recent efforts to understand the complex mechanisms behind the plasticity of GSCs.