"Cancer stem cells"-lessons from Hercules to fight the Hydra.

Following the initial identification of hematopoietic tumor stem cells, such cells were also found in several solid tumor types. In urology, cancer stem cells have only been found in prostate tumors so far. The concept and detection of tumor stem cells rely heavily on findings derived from stem cell research. Therefore, in addition to identifying and characterizing urologic tumor stem cells, research in uro-oncology should also aim at better understanding the stem-cell biology of urologic organs. Insights in similarities and differences gleaned from these studies could be used to develop strategies for targeted destruction of tumor stem cells while sparing the physiological stem cells. The main target of future curative therapies in uro-oncology must therefore be the central, immortal head of the Hydra, the tumor stem cell.

Recycling of apoprotein E is associated with cholesterol efflux and high density lipoprotein internalization.

After receptor-mediated endocytosis of triglyceride-rich lipoproteins (TRL) into the liver, TRL particles are immediately disintegrated in peripheral endosomal compartments. Whereas core lipids and apoprotein B are delivered for degradation into lysosomes, TRL-derived apoE is efficiently recycled back to the plasma membrane. This is followed by apoE re-secretion and association of apoE with high density lipoproteins (HDL). Because HDL and apoE can independently promote cholesterol efflux, we investigated whether recycling of TRL-derived apoE in human hepatoma cells and fibroblasts could be linked to intracellular cholesterol transport. In this study we demonstrate that HDL(3) does not only act as an extracellular acceptor for recycled apoE but also stimulates the recycling of internalized TRL-derived apoE. Furthermore, radioactive pulse-chase experiments indicate that apoE recycling is accompanied by cholesterol efflux. Confocal imaging reveals co-localization of apoE and cholesterol in early endosome antigen 1-positive endosomes. During apoE re-secretion, HDL(3)-derived apoA-I is found in these early endosome antigen 1, cholesterol-containing endosomes. As shown by time-lapse fluorescence microscopy, apoE recycling involves the intracellular trafficking of apoA-I to pre-existing and TRL-derived apoE/cholesterol-containing endosomes in the periphery. Thus, these studies provide evidence for a new intracellular link between TRL-derived apoE, cellular cholesterol transport, and HDL metabolism.