title: Mesenchymal stem cells generate pericytes to promote tumor recurrence via vasculogenesis after stereotactic body radiation therapy.
abstract: BACKGROUND
  Stereotactic body radiation therapy (SBRT) is postulated to enhance the recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, which promote tumor recurrence. The aim of this study is to determine the molecular mechanisms behind SBRT stimulating MSC migration and differentiation.
  
  
  METHODS
  In vitro, mediated factors and migrated MSCs (post-SBRT) were generated. In vivo, bone-marrow derived MSCs were identified and harvested from green fluorescent protein (GFP)-expressing transgenic male mice and transplanted into sub-lethally irradiated recipient female mice to establish a model of bone marrow transplantation. Lewis lung carcinoma and malignant melanoma-bearing recipient mice were treated with SBRT, 14 Gy/1 fraction. The migration and differentiation potential of MSCs were characterized.
  
  
  RESULTS
  SBRT increased the release of stromal cell derived factor-1α (SDF-1α) and platelet-derived growth factor-B (PDGF-B) by tumor cells; these ligands bound to chemokine (C-X-C motif) receptor 4 (CXCR4) and platelet-derived growth factor receptor-β (PDGFR-β), respectively, on circulating bone marrow-derived MSCs, resulting in engraftment of the MSCs into the tumor parenchyma. The newly-homed MSCs differentiated into pericytes, which induced the tumor vasculogenesis, and promoted tumor regrowth. Targeted therapies, AMD3100 and imatinib abrogated MSC homing, vasculogenesis, and tumor regrowth.
  
  
  CONCLUSIONS
  Bone-marrow derived MSCs migrate to the tumor parenchyma and differentiate into pericytes, inducing tumor vasculogenesis after SBRT, and promoting tumor recurrence. MSC migration and maturation may be abrogated with AMD3100 and imatinib. This novel treatment strategy warrants clinical investigation.
authors.affiliation: Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Lymphoma and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
authors.forename: Yao-Li
authors.initials: YL
authors.lastname: Cui
authors.affiliation: Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Zaorsky
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Clinical Medicine School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lan
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Clinical Medicine School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Zeng
authors.affiliation: Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Clinical Medicine School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Guo
authors.affiliation: Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
authors.forename: Qing-Xin
authors.initials: QX
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
authors.forename: Lu-Jun
authors.initials: LJ
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Yuan
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Clinical Medicine School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: You
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. Electronic address: mmeng@tmu.edu.cn.
authors.forename: Mao-Bin
authors.initials: MB
authors.lastname: Meng
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D002454:Cell Differentiation / Q000235:genetics / Q000528:radiation effects; D002465:Cell Movement / Q000235:genetics / Q000528:radiation effects; D049452:Green Fluorescent Proteins; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects*; D059630:Mesenchymal Stem Cells / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000209:etiology / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000235:genetics; D020286:Pericytes / Q000378:metabolism; D016634:Radiosurgery / Q000009:adverse effects*; D059016:Tumor Microenvironment / Q000528:radiation effects
chemical_list: D049452:Green Fluorescent Proteins
keywords: Mesenchymal stem cells; Pericytes; Stereotactic body radiation therapy; Tumor recurrence; Vasculogenesis