Original Paper

Angiogenesis

, Volume 16, Issue 1, pp 29-44

Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration

  • Inho ChoiAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern CaliforniaDepartment of Pharmaceutical Engineering, Hoseo University
  • , Yong Suk LeeAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
  • , Hee Kyoung ChungAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
  • , Dongwon ChoiAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
  • , Tatiana EcoiffierAffiliated withCenter of Eye Disease and Development, Program in Vision Science, and School of Optometry, University of California
  • , Ha Neul LeeAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
  • , Kyu Eui KimAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
  • , Sunju LeeAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
  • , Eun Kyung ParkAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
    • , Yong Sun MaengAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
    • , Nam Yun KimAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
    • , Robert D. LadnerAffiliated withDepartment of Pathology, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
    • , Nicos A. PetasisAffiliated withNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern CaliforniaDepartment of Chemistry, Dornsife College of Letters, Arts & Sciences, University of Southern California
    • , Chester J. KohAffiliated withDivision of Pediatric Urology, Children’s Hospital Los Angeles and Keck School of Medicine, University of Southern California
    • , Lu ChenAffiliated withCenter of Eye Disease and Development, Program in Vision Science, and School of Optometry, University of California
    • , Heinz-Josef LenzAffiliated withDivision of Medical Oncology, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
    • , Young-Kwon HongAffiliated withDepartment of Surgery, Norris Comprehensive Cancer Center, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern CaliforniaNorris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California Email author 

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Abstract

Lymphedema is mainly caused by lymphatic obstruction and manifested as tissue swelling, often in the arms and legs. Lymphedema is one of the most common post-surgical complications in breast cancer patients and presents a painful and disfiguring chronic illness that has few treatment options. Here, we evaluated the therapeutic potential of interleukin (IL)-8 in lymphatic regeneration independent of its pro-inflammatory activity. We found that IL-8 promoted proliferation, tube formation, and migration of lymphatic endothelial cells (LECs) without activating the VEGF signaling. Additionally, IL-8 suppressed the major cell cycle inhibitor CDKN1C/p57KIP2 by downregulating its positive regulator PROX1, which is known as the master regulator of LEC-differentiation. Animal-based studies such as matrigel plug and cornea micropocket assays demonstrated potent efficacy of IL-8 in activating lymphangiogenesis in vivo. Moreover, we have generated a novel transgenic mouse model (K14-hIL8) that expresses human IL-8 in the skin and then crossed with lymphatic-specific fluorescent (Prox1-GFP) mouse. The resulting double transgenic mice showed that a stable expression of IL-8 could promote embryonic lymphangiogenesis. Moreover, an immunodeficient IL-8-expressing mouse line that was established by crossing K14-hIL8 mice with athymic nude mice displayed an enhanced tumor-associated lymphangiogenesis. Finally, when experimental lymphedema was introduced, K14-hIL8 mice showed an improved amelioration of lymphedema with an increased lymphatic regeneration. Together, we report that IL-8 can activate lymphangiogenesis in vitro and in vivo with a therapeutic efficacy in post-surgical lymphedema.

Keywords

Lymphangiogenesis Interleukin-8 Prox1 Lymphedema Lymphatic endothelial cells