Search

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]

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]

Cumulative acquisition of genetic alterations affecting oncogenes or tumor suppressor genes may select for tumor cell clones with enhanced proliferation and survival potential. As a result oxygen and nutrient consumption increases, leading to a tumor microenvironment characterized by low oxygen tension, low glucose levels, and an acidic pH. Hypoxia-inducible transcription factors (HIF) are activated in response to hypoxia, apparently via reduced activity of the recently identified class of 2-oxoglutarate dependent oxygenases, as well as various tumor specific genetic alterations. A widespread HIF activation can be observed in a variety of malignant tumors. The HIF system induces adaptive responses including angiogenesis, glycolysis, and pH regulation which confer increased resistance towards the hostile tumor microenvironment. Apart from protumorigenic the wide-ranging HIF pathway may also have antitumorigenic components, which might, however, be counteracted by specific genetic mechanisms. Thus mounting evidence suggests that the HIF system plays a decisive role in tumor physiology and progression. Moreover, recent insight into this pathway has opened novel and potentially selective therapeutic approaches. [ABSTRACT FROM AUTHOR]