Tumor Endothelial Cells with High Aldehyde Dehydrogenase Activity Show drug resistance

Summary

Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TECs) exhibit several altered phenotypes compared with normal endothelial cells (NECs). For example, TECs have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TECs contain stem-like populations with high aldehyde dehydrogenase (ALDH) activity (ALDH^highTEC). ALDH^highTECs had proangiogenic properties compared with ALDH^low TECs. However, the association between ALDH^highTECs and drug resistance remains unclear. In this study, we found that ALDH mRNA expression and activity were higher in both human and mouse TECs than in NECs. Human NEC:human microvascular endothelial cells (HMVECs) were treated by tumor-conditioned medium (tumor CM). The ALDH^high TEC population increased along with the upregulation of stem-related genes such as multidrug resistance 1, CD90, ALP, and Oct-4. Tumor CM also induced sphere-forming ability in HMVECs. Platelet-derived growth factor (PDGF)-A in tumor CM was shown to induce ALDH expression in HMVECs. Finally, ALDH^high TECs were resistant to 5-FU in vitro and in vivo. ALDH^high TECs showed a higher grade of aneuploidy compared with that in the ALDH^l°^w TECs. These results suggested that tumor-secreting factor increases ALDH^high TEC populations that are resistant to 5-FU. Therefore, ALDH^high TECs in tumor blood vessels might be an important target to overcome or prevent drug resistance.

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