Highlights of This Issue

Abstract

Neuropilins (NRP1 and NRP2) are receptors that bind VEGF and semaphorins and are expressed on endothelial and tumor cells. Geretti and colleagues reported previously that mutations in the VEGF-binding NRP2 B domain (MutB-NRP2) increased the affinity for VEGF substantially. It is now shown that MutB-NRP2 inhibits VEGF-induced activation of Akt in endothelial cells and inhibits VEGF-induced sprouting in 3-D embryoid bodies. When overexpressed in melanoma cells, MutB-NRP2 inhibits tumor growth and synergizes with Avastin (bevacizumab). These results show that MutB-NRP2 is a novel and potent VEGF antagonist and that targeting NRPs is a feasible antiangiogenesis, antitumor therapeutic strategy.Chromosomal fragile sites are particularly sensitive to DNA breaks and are frequent sites of rearrangement and loss in human cancers. Lai and colleagues showed that copy number loss and/or loss of heterozygosity at fragile sites occur at high frequency in early stage Barrett's esophagus. It was detected at over fifty different fragile sites and deletion at one site, FRA3B, was detected in over 80% of samples tested by array-CGH or quantitative PCR. This work suggests that fragile site instability could be an informative biomarker of genetic damage and cancer risk in these patients.Drug-resistant brain cancer stems cells are positive for the glycosylated transmembrane protein CD133. To determine if CD133 plays a functional role in drug resistance, we ectopically expressed CD133 in rat C6 glioma cells, which do not express CD133, but are normally sensitive to chemotherapeutic reagents. Overexpression of this protein resulted in reluctance to undergo apoptosis following exposure to both camptothecin and doxorubicin. This process was p53 independent with a concomitant increase in the multidrug resistance transporter ABCB1 transcription and functional activity. Thus, targeting CD133 could disrupt multidrug resistance and selectively target cancer stem cells.Targeting multiple receptor tyrosine kinases (TK) and blocking the crossactivation among multiple pathways by small molecules have the potential to be a new strategy for cancer therapy. Nakachi and colleagues showed a multiple receptor TK inhibitor AEE788 induced synergistic inhibitory effect on the epidermal growth factor receptor (EGFR)-TK inhibitor–resistant NSCLC cell line when combined with a downstream kinase inhibitor, RAD001. This effect is accomplished by the inactivation of c-Met and mTOR, but not EGFR. Their data showed c-Met could be crucial for combined target therapy.