Antiangiogenesis with bevacizumab, an antibody against vascular endothelial growth factor (VEGF), has been used for devascularization to limit the growth of malignant glioma. However, the benefits are transient due to elusive mechanisms underlying resistance to the antiangiogenic therapy. Glioma stem cells (GSCs) are capable of forming vasculogenic mimicry (VM), an alternative microvascular circulation independent of VEGF-driven angiogenesis. Herein, we report that the formation of VM was promoted by bevacizumab-induced macroautophagy/autophagy in GSCs, which was associated with tumor resistance to antiangiogenic therapy. We established a 3-dimensional collagen scaffold to examine the formation of VM and autophagy by GSCs, and found that rapamycin increased the number of VM and enhanced KDR/VEGFR-2 phosphorylation. Treatment with chloroquine, or knockdown of the autophagy gene ATG5, inhibited the formation of VM and KDR phosphorylation in GSCs. Notably, neutralization of GSCs-produced VEGF with bevacizumab failed to recapitulate the effect of chloroquine treatment and ATG5 knockdown, suggesting that autophagy-promoted formation of VM was independent of tumor cell-derived VEGF. ROS was elevated when autophagy was induced in GSCs and activated KDR phosphorylation through the phosphoinositide 3-kinase (PI3K)-AKT pathway. A ROS inhibitor, N-acetylcysteine, abolished KDR phosphorylation and the formation of VM by GSCs. By examination of the specimens from 95 patients with glioblastoma, we found that ATG5 and p-KDR expression was strongly associated with the density of VM in tumors and poor clinical outcome. Our results thus demonstrate a crucial role of autophagy in the formation of VM by GSCs, which may serve as a therapeutic target in drug-resistant glioma.

Questionnaires may be an efficient approach to monitor periodontal health in China. Dietrich's models, with age, smoking and self-reported mobility as predictors, can be used to monitor periodontal health for Chinese prosthodontic patients.

Cervical cancer is the most common malignant disease responsible for the deaths of a large number of women in the developing world. Although certain strains of human papillomavirus (HPV) have been identified as the cause of this disease, events that lead to formation of malignant tumors are not fully clear. STAT3 is a major oncogenic transcription factor involved in the development and progression of a number of human tumors. However, the mechanisms that result in loss of control over STAT3 activity are not understood. Gene associated with Retinoid-Interferon-induced Mortality-19 (GRIM-19) is a tumor-suppressive protein identified using a genetic technique in the interferon/retinoid-induced cell death pathway. Here, we show that reduction in GRIM-19 protein levels occur in a number of primary human cervical cancers. Consequently, these tumors tend to express a high basal level of STAT3 and its downstream target genes. More importantly, using a surrogate model, we show that restoration of GRIM-19 levels reestablishes the control over STAT3-dependent gene expression and tumor growth in vivo. GRIM-19 suppressed the expression of tumor invasion- and angiogenesis-associated factors to limit tumor growth. This study identifies another major novel molecular pathway inactivated during the development of human cervical cancer.