Tumor Endothelial Cells with High Aldehyde Dehydrogenase Activity Show drug resistance.

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