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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.

Affiliations

Hyun Jung Hwang  1 , Ye-Rim Lee  1 , Donghee Kang  1 , Hyung Chul Lee  1 , Haeng Ran Seo  2 , Ji-Kan Ryu  3 , Yong-Nyun Kim  4 , Young-Gyu Ko  5 , Heon Joo Park  6 , Jae-Seon Lee  7
1 Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, South Korea; Department of Molecular Medicine, Inha University College of Medicine, Incheon, South Korea.
2 Cancer Biology Research Laboratory, Institute Pasteur Korea, Gyeonggi-do, South Korea.
3 Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, South Korea; Department of Urology, Inha University College of Medicine, Incheon, South Korea.
4 Division of Translational Research, Research Institute, National Cancer Center, Goyang, 10408, South Korea.
5 Division of Life Sciences, Korea University, Seoul, South Korea.
6 Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, South Korea; Department of Microbiology, Inha University College of Medicine, Incheon, South Korea.
7 Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, South Korea; Department of Molecular Medicine, Inha University College of Medicine, Incheon, South Korea. Electronic address: jaeslee@inha.ac.kr.