Glioma angiogenesis: Towards novel RNA therapeutics

Abstract

Brain tumors exhibit marked and aberrant blood vessel formation indicating angiogenic endothelial cells as a potential target for brain tumor treatment. The brain tumor blood vessels are used for nutrient delivery, and possibly for cancer cell migration. The process of angiogenesis is complex and involves multiple players. The current angiogenesis inhibitors used in clinical trials mostly target single angiogenic proteins and so far show limited effects on tumor growth. Besides the conventional angiogenesis inhibitors, RNA-based inhibitors such as small-interfering RNAs (siRNAs) are being analyzed for their capacity to silence the message of proteins involved in neovascularization. More recently, a new family of non-coding RNAs, named angiomirs [microRNAs (miRNAs) involved in angiogenesis] has emerged. These small RNAs have the advantage over siRNAs in that they have the potential of silencing multiple messages at the same time and therefore they might become therapeutically relevant in a "one-hit multiple-target" context against brain tumor angiogenesis. In this review we will discuss the emerging technologies in anti-angiogenesis emphasizing on RNA-based therapeutics.

Figure 1

Different classes of angiogenesis inhibitors.

Figure 2

miR-296-mediated induction and inhibition of angiogenesis. (A) HBMVEC cells were cultured on Matrigel-coated plates in basal medium (EBM; Cambrex) only, basal medium supplemented with a cocktail of angiogenic factors (EGM), or with U87-human glioma cells expressing the cyan fluorescent protein (CFP) in order to induce miR-296 and tubule formation. Transfection efficiency of endothelial cells in monolayer culture was determined (>99%) by using siRNA-Cy3 molecules. (B) HBMVECs were transfected with miR-296 inhibitor or non-related control molecules and analyzed for tubule formation. At 48 hr after inhibition of U87 or cocktail-induced miR-296, less chaotic tubule networks were observed. (C) HBMVECs were transfected with anti-miR-296 inhibitor or non-related control molecules and analyzed for migration capacity. Inhibition of miR-296 resulted in a significant decrease in migration. (D) Overexpression of miR-296 at 24 hr after transfection of premiR-296 molecules resulted in increased angiogenesis in vitro. Size bars, 300 µm (Adapted from Würdinger et al. Cancer Cell 2008).