Huan-Huan Wang1, Yao-Li Cui2, Nicholas G Zaorsky3, Jie Lan4, Lei Deng4, Xian-Liang Zeng1, Zhi-Qiang Wu1, Zhen Tao1, Wen-Hao Guo5, Qing-Xin Wang1, Lu-Jun Zhao1, Zhi-Yong Yuan1, You Lu4, Ping Wang1, Mao-Bin Meng6. 1. 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. 2. 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. 3. Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. 4. 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. 5. 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. 6. 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.
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. CONCLUSION: 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.
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. CONCLUSION: 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.
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