Eun-Jung Lim1,2, Seungmo Kim1, Yoonjee Oh3, Yongjoon Suh1, Neha Kaushik1, Ji-Hyun Lee4, Hae-June Lee5, Min-Jung Kim6, Myung-Jin Park7, Rae-Kwon Kim8, Junghwa Cha9, Se Hoon Kim10, Jin-Kyoung Shim1, Junjeong Choi9,11, Jong Hee Chang4, Yong Kil Hong12, Yong Min Huh13, Pilnam Kim1,11, Seok-Gu Kang1, Su-Jae Lee1. 1. Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea. 2. Memorial Sloan Kettering, Cancer Center, New York, New York, USA. 3. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea. 4. Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. 5. Division of Radiation Effect, Korea Institute of Radiological & Medical Sciences, Seoul, Korea. 6. Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. 7. Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. 8. Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Korea. 9. College of Pharmacy, Yonsei Institute of Pharmaceutical Science, Yonsei University, Incheon, Korea. 10. Department of Pathology, Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea. 11. KAIST Institute for Health Science and Technology, Daejeon, Korea. 12. Department of Neurosurgery, Seoul St Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea. 13. Department of Radiology, Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea.
Abstract
BACKGROUND: Mesenchymal stemlike cells (MSLCs) have been detected in many types of cancer including brain tumors and have received attention as stromal cells in the tumor microenvironment. However, the cellular mechanisms underlying their participation in cancer progression remain largely unexplored. The aim of this study was to determine whether MSLCs have a tumorigenic role in brain tumors. METHODS: To figure out molecular and cellular mechanisms in glioma invasion, we have cultured glioma with MSLCs in a co-culture system. RESULTS: Here, we show that MSLCs in human glioblastoma (GBM) secrete complement component C5a, which is known for its role as a complement factor. MSLC-secreted C5a increases expression of zinc finger E-box-binding homeobox 1 (ZEB1) via activation of p38 mitogen-activated protein kinase (MAPK) in GBM cells, thereby enhancing the invasion of GBM cells into parenchymal brain tissue. CONCLUSION: Our results reveal a mechanism by which MSLCs undergo crosstalk with GBM cells through the C5a/p38 MAPK/ZEB1 signaling loop and act as a booster in GBM progression. KEY POINTS: 1. MSLCs activate p38 MAPK-ZEB1 signaling in GBM cells through C5a in a paracrine manner, thereby boosting the invasiveness of GBM cells in the tumor microenvironment.2. Neutralizing of C5a could be a potential therapeutic target for GBM by inhibition of mesenchymal phenotype.
BACKGROUND: Mesenchymal stemlike cells (MSLCs) have been detected in many types of cancer including brain tumors and have received attention as stromal cells in the tumor microenvironment. However, the cellular mechanisms underlying their participation in cancer progression remain largely unexplored. The aim of this study was to determine whether MSLCs have a tumorigenic role in brain tumors. METHODS: To figure out molecular and cellular mechanisms in glioma invasion, we have cultured glioma with MSLCs in a co-culture system. RESULTS: Here, we show that MSLCs in human glioblastoma (GBM) secrete complement component C5a, which is known for its role as a complement factor. MSLC-secreted C5a increases expression of zinc finger E-box-binding homeobox 1 (ZEB1) via activation of p38 mitogen-activated protein kinase (MAPK) in GBM cells, thereby enhancing the invasion of GBM cells into parenchymal brain tissue. CONCLUSION: Our results reveal a mechanism by which MSLCs undergo crosstalk with GBM cells through the C5a/p38 MAPK/ZEB1 signaling loop and act as a booster in GBM progression. KEY POINTS: 1. MSLCs activate p38 MAPK-ZEB1 signaling in GBM cells through C5a in a paracrine manner, thereby boosting the invasiveness of GBM cells in the tumor microenvironment.2. Neutralizing of C5a could be a potential therapeutic target for GBM by inhibition of mesenchymal phenotype.
Authors: Roel G W Verhaak; Katherine A Hoadley; Elizabeth Purdom; Victoria Wang; Yuan Qi; Matthew D Wilkerson; C Ryan Miller; Li Ding; Todd Golub; Jill P Mesirov; Gabriele Alexe; Michael Lawrence; Michael O'Kelly; Pablo Tamayo; Barbara A Weir; Stacey Gabriel; Wendy Winckler; Supriya Gupta; Lakshmi Jakkula; Heidi S Feiler; J Graeme Hodgson; C David James; Jann N Sarkaria; Cameron Brennan; Ari Kahn; Paul T Spellman; Richard K Wilson; Terence P Speed; Joe W Gray; Matthew Meyerson; Gad Getz; Charles M Perou; D Neil Hayes Journal: Cancer Cell Date: 2010-01-19 Impact factor: 31.743
Authors: Aarif Y Khakoo; Shibani Pati; Stasia A Anderson; William Reid; Mohamed F Elshal; Ilsa I Rovira; Ahn T Nguyen; Daniela Malide; Christian A Combs; Gentzon Hall; Jianhu Zhang; Mark Raffeld; Terry B Rogers; William Stetler-Stevenson; Joseph A Frank; Marvin Reitz; Toren Finkel Journal: J Exp Med Date: 2006-04-24 Impact factor: 14.307
Authors: Florian A Siebzehnrubl; Daniel J Silver; Bugra Tugertimur; Loic P Deleyrolle; Dorit Siebzehnrubl; Matthew R Sarkisian; Kelly G Devers; Antony T Yachnis; Marius D Kupper; Daniel Neal; Nancy H Nabilsi; Michael P Kladde; Oleg Suslov; Simone Brabletz; Thomas Brabletz; Brent A Reynolds; Dennis A Steindler Journal: EMBO Mol Med Date: 2013-07-01 Impact factor: 12.137
Authors: Hyeong-Cheol Oh; Jin-Kyoung Shim; Junseong Park; Ji-Hyun Lee; Ran Joo Choi; Nam Hee Kim; Hyun Sil Kim; Ju Hyung Moon; Eui Hyun Kim; Jong Hee Chang; Jong In Yook; Seok-Gu Kang Journal: J Cancer Res Clin Oncol Date: 2020-07-25 Impact factor: 4.553