Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance

摘要

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 style="fixed-case">NEC:human microvascular endothelial cells ( style="fixed-case">HMVEC) were treated with tumor‐conditioned medium (tumor style="fixed-case">CM). The style="fixed-case">ALDH ^high population increased along with upregulation of stem‐related genes such as multidrug resistance 1, style="fixed-case">CD90, style="fixed-case">ALP, and Oct‐4. Tumor style="fixed-case">CM also induced sphere‐forming ability in style="fixed-case">HMVEC. Platelet‐derived growth factor ( style="fixed-case">PDGF)‐A in tumor style="fixed-case">CM was shown to induce style="fixed-case">ALDH expression in style="fixed-case">HMVEC. Finally, style="fixed-case">ALDH ^high style="fixed-case">TEC were resistant to fluorouracil (5‐ style="fixed-case">FU) in vitro and in vivo. style="fixed-case">ALDH ^high style="fixed-case">TEC showed a higher grade of aneuploidy compared with that in style="fixed-case">ALDH ^low style="fixed-case">TEC. These results suggested that tumor‐secreting factor increases style="fixed-case">ALDH ^high style="fixed-case">TEC populations that are resistant to 5‐ style="fixed-case">FU. Therefore, style="fixed-case">ALDH^high style="fixed-case">TEC in tumor blood vessels might be an important target to overcome or prevent drug resistance.