KAI1(CD82) is a key molecule to control angiogenesis and switch angiogenic milieu to quiescent state
- J Hematol Oncol. 2021 Sep 16;14(1):148. doi: 10.1186/s13045-021-01147-6.
- 1. National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul, Republic of Korea.
- 2. Center of Cell- and Bio-Therapy (CBT), Seoul National University Hospital, Seoul, Republic of Korea.
- 3. Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea.
- 4. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
- 5. Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
- 6. Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea.
- 7. Genomics Core Facility, Department of Transdisciplinary Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
- 8. ExoCoBio Inc, Gasan digital 1-ro, Geumcheon-gu, Seoul, 08594, Republic of Korea.
- 9. Creative Research Initiative Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, 151-742, Republic of Korea.
- 10. National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul, Republic of Korea. [email protected].
- 11. Center of Cell- and Bio-Therapy (CBT), Seoul National University Hospital, Seoul, Republic of Korea. [email protected].
- 12. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea. [email protected].
- 13. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea. [email protected].
- # Contributed equally.
Background: Little is known about endogenous inhibitors of angiogenic growth factors. In this study, we identified a novel endogenous anti-angiogenic factor expressed in pericytes and clarified its underlying mechanism and clinical significance.
Methods: Herein, we found Kai1 knockout mice showed significantly enhanced angiogenesis. Then, we investigated the anti-angiogenic roll of Kai1 in vitro and in vivo.
Results: KAI1 was mainly expressed in pericytes rather than in endothelial cells. It localized at the membrane surface after palmitoylation by zDHHC4 enzyme and induced LIF through the Src/p53 pathway. LIF released from pericytes in turn suppressed angiogenic factors in endothelial cells as well as in pericytes themselves, leading to inhibition of angiogenesis. Interestingly, KAI1 had another mechanism to inhibit angiogenesis: It directly bound to VEGF and PDGF and inhibited activation of their receptors. In the two different in vivo Cancer models, KAI1 supplementation significantly inhibited tumor angiogenesis and growth. A peptide derived from the large extracellular loop of KAI1 has been shown to have anti-angiogenic effects to block the progression of breast Cancer and retinal neovascularization in vivo.
Conclusions: KAI1 from PC is a novel molecular regulator that counterbalances the effect of angiogenic factors.