**5. Conclusions and perspectives**

Tumor angiogenesis has been widely mentioned as a process that new blood vessels are devel‐ oped from preexisting host blood vessels surrounding the tumors. However, we propose a paradigm change. Our results suggest that CD133‐positive CSCs differentiate into tumor vas‐ cular endothelial cells and might be able to form tumor vessels.

Since Folkman hypothesized the notion of targeting tumor endothelial cells with anti‐ angiogenic therapy, numerous anti‐angiogenic drugs have been discovered. Previously, we reported that CD133‐positive capillary tubes were formed in vitro. Statins, which are widely used as cholesterol‐lowering agents, strongly inhibited the capillary tube forma‐ tion [26]. Statin diminished intraplaque angiogenesis [27] and reduced the growth and spread of many cancers [28, 29]. Khaidakov et al. suggested that statin had anti‐angiogenic effects [30]. We propose that the anti‐angiogenic effects of statins can be considered for the cancer therapy.

## **Acknowledgements**

This work was supported in part by JSPS KAKENHI Grant Numbers JP25462779 and JP16K11353.
