Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells

Hyun Jung Hwang, Ye Rim Lee, Donghee Kang, Hyung Chul Lee, Haeng Ran Seo, Ji Kan Ryu, Yong Nyun Kim, Young Gyu Ko, Heon Joo Park, Jae Seon Lee

Research output: Contribution to journalArticle

Abstract

The effects of senescence associated secretory phenotype (SASP) from therapy-induced senescent endothelial cells on tumor microenvironment (TME) remains to be clarified. Here, we investigated effects of ionizing radiation (IR)- and doxorubicin-induced senescent HUVEC on TME. MDA-MB-231 cancer cells treated with conditioned medium (CM) from senescent HUVEC or co-cultured with senescent HUVEC significantly increased cancer cell proliferation, migration, and invasion. We found that CXCL11 plays a principal role in the senescent CM-induced aggressive activities of MDA-MB-231 cells. When we treated HUVEC with a neutralizing anti-CXCL11 antibody or CXCL11 SiRNA, or treated MDA-MB-231 cells with CXCR3 SiRNA, we observed synergistic diminution of the ability of the HUVEC SASP to alter the migration and spheroid invasion of cancer cells. ERK activation was involved in the HUVEC SASP-induced aggressive activity of MDA-MB-231 cells. Finally, we observed the in vivo effect of CXCL11 from the senescent HUVEC in tumor-bearing mice. Together, our results demonstrate that SASP from endothelial cells experiencing therapy-induced senescence promotes the aggressive behavior of cancer cells, and that CXCL11 can potentially be targeted to prevent the adverse effects of therapy-induced senescent endothelial cells on the tumor microenvironment.

Original languageEnglish
Pages (from-to)100-110
Number of pages11
JournalCancer letters
Volume490
DOIs
Publication statusPublished - 2020 Oct 10

Keywords

  • CXCL11
  • Endothelial cells
  • Therapy-induced senescence
  • Tumor microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Hwang, H. J., Lee, Y. R., Kang, D., Lee, H. C., Seo, H. R., Ryu, J. K., Kim, Y. N., Ko, Y. G., Park, H. J., & Lee, J. S. (2020). Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells. Cancer letters, 490, 100-110. https://doi.org/10.1016/j.canlet.2020.06.019