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Abstract: Background: The initiation and progression of various types of tumors, including glioma, are driven by a population of cells with stem cell properties. Glioma stem cells (GSCs) are located in specialized microenvironments (niches) within tumors. These niches represent the hallmarks of malignant gliomas (vascular proliferations, hypoxia/necrosis) and bear analogy to the microenvironments in which physiological stem cells in the brain are found. Scope of the review: Here we review the progress that has been made towards uncovering the function of the perivascular and the hypoxic niche and the molecular pathways that control the properties of GSCs within them. We propose models of how the different niches and GSC pools in them interact with each other. Major conclusions: GSCs are not merely passive residents of their niches, but actively contribute to the shaping of the niches through a complex crosstalk with different components of the microenvironment. For example, GSCs play a dominant role in promoting new blood vessel formation through a variety of mechanisms, including the hypoxia dependent stimulation of angiogenesis, recruitment of endothelial progenitor cells and direct transdifferentiation into endothelial cells. Recent work has also revealed that GSCs can recruit and modulate the function of various immune cells to suppress anti-tumor immune responses and to foster tumor-promoting inflammation, which in turn could support the maintenance of GSCs. General significance: These findings underscore the central role of the GSC microenvironment in driving glioma progression making the GSC niche a prime therapeutic target for the design of therapies aimed at eradicating GSCs. This article is part of a Special Issue entitled Biochemistry of Stem Cells. [Copyright &y& Elsevier]

Modern tumor therapy has achieved considerable progress, but many tumors remain refractory to treatment or relapse following initial remission. Recent evidence points to one possible reason for this limited therapeutic efficiency: that the design of anticancer agents so far may not have been aimed at the right target. While conventional tumor therapies have targeted the main mass of tumor cells, there is now compelling evidence that tumor initiation and progression are driven by a subpopulation of tumor cells that possess stem cell properties and are resistant to traditional cancer treatments-the cancer stem cells (CSCs). CSCs have been identified in most types of cancer and can be separated from the rest of the tumor cells using appropriate markers. CSCs are regulated by molecular mechanisms and specific, perivascular, and hypoxic microenvironments, which largely overlap with those controlling stem cells from normal tissues. Our improved understanding of CSC biology has already provided a number of novel targets and drug discovery platforms for the design of specific therapies that aim to eradicate the CSC subpopulation. Therapeutic approaches can be targeted either at eliminating the CSCs themselves or at disrupting the niches in which CSCs reside. Moreover, the importance of CSCs for tumor growth, resistance, and progression implies that clinical trials and preclinical studies of anticancer therapies should include as a key element an assessment of the abundance and persistence of CSCs. Thus, CSC research holds great promise for providing important new impetus to the fields of tumor biology and clinical oncology. [ABSTRACT FROM AUTHOR]

Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis, and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of endogenous extracellular RNA (eRNA) than nontumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than nontumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of VEGF signaling. In addition, eRNA liberated TNF-α from macrophages in a manner requiring activation of the TNF-α-converting enzyme TACE. Accordingly, supernatants derived from eRNA-treated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-α release evoked by eRNA relied upon signaling activation of mitogen-activated protein kinases and the NF-κB pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-α release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an antiinvasive regimen for cancer treatment. [ABSTRACT FROM AUTHOR]

Glioma growth and progression depend on a specialized subpopulation of tumour cells, termed tumour stem cells. Thus, tumour stem cells represent a critical therapeutic target, but the molecular mechanisms that regulate them are poorly understood. Hypoxia plays a key role in tumour progression and in this study we provide evidence that the hypoxic tumour microenvironment also controls tumour stem cells. We define a detailed molecular signature of tumour stem cell genes, which are overexpressed by tumour cells in vascular and perinecrotic/hypoxic niches. Mechanistically, we show that hypoxia plays a key role in the regulation of the tumour stem cell phenotype through hypoxia-inducible factor 2α and subsequent induction of specific tumour stem cell signature genes, including mastermind-like protein 3 (Notch pathway), nuclear factor of activated T cells 2 (calcineurin pathway) and aspartate beta-hydroxylase domain-containing protein 2. Notably, a number of these genes belong to pathways regulating the stem cell phenotype. Consistently, tumour stem cell signature genes are overexpressed in newly formed gliomas and are associated with worse clinical prognosis. We propose that tumour stem cells are maintained within a hypoxic niche, providing a functional link between the well-established role of hypoxia in stem cell and tumour biology. The identification of molecular regulators of tumour stem cells in the hypoxic niche points to specific signalling mechanisms that may be used to target the glioblastoma stem cell population. [ABSTRACT FROM PUBLISHER]

We investigated angiogenic patterns and expression of hypoxia-related tissue factors and their prognostic impact in 100 cases of intracranial ependymoma. Angiogenic patterns were evaluated by anti-CD34 immunolabeling. Hypoxia-related factors carbonic anhydrase 9 (CA9) and hypoxia-inducible factor 1 alpha (HIF-1a) were visualized by immunohistochemistry, and vascular endothelial growth factor (VEGF) mRNA by in situ hybridization. Expression patterns of VEGF and CA9 are similar with regard to distribution (perinecrotic) and extent. HIF-1a expression occurs in a significantly smaller fraction of cases and only in a few tumor cells without clear association with necrosis. Expression of VEGF and CA9, but not HIF-1a, is associated with a bizarre angiogenic subtype. Combined expression of two or three hypoxia markers (high hypoxia score) associates with presence of necrosis, high proliferation index, bizarre vascular pattern, and increased cellularity. Univariate analysis indicated that patients with high hypoxia score had significantly shorter survival. On multivariate analysis, only proliferation index and extent of resection remained independent predictive factors. We conclude that bizarre vascular pattern, necrosis and high hypoxia score are frequently detectable in intracranial ependymoma, but seem less important for patient outcome than tumor cell proliferation. [ABSTRACT FROM AUTHOR]