title: The HIF-1α/CXCR4 pathway supports hypoxia-induced metastasis of human osteosarcoma cells.
abstract: HIF-1α mediates hypoxia-induced expression of the chemokine receptor CXCR4 and contributes to metastasis in many different cancers. We have previously shown that hypoxia promotes migration of human osteosarcoma cells by activating the HIF-1α/CXCR4 pathway. Here, immunohistochemical analysis showed that unlike control osteochondroma samples, osteosarcoma specimens were characterized by elevated expression levels of HIF-1α and CXCR4. Moreover, we found that hypoxia-induced invasiveness was more pronounced in high metastatic potential F5M2 osteosarcoma cells than in low metastatic potential F4 cells, and that this induction was sensitive to treatment with the CXCR4 antagonist AMD3100 and the HIF-1α inhibitor KC7F2. Interestingly, hypoxia-induced CXCR4 expression persisted after cultured osteosarcoma cells were returned to normoxic conditions. These observations were confirmed by experiments in a mouse model of osteosarcoma lung metastasis showing that hypoxia stimulation of pulmonary metastasis was greater in F5M2 than in F4 cells, and was sensitive to treatment with AMD3100. Our study provides further evidence of the contributions of hypoxia and the HIF-1α/CXCR4 pathway to the progression of osteosarcoma, and suggests that this axis might be efficiently leveraged in the development of novel osteosarcoma therapeutics.
authors.affiliation: Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Guan
authors.affiliation: Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Geriatrics, Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, China.
authors.forename: Doufei
authors.initials: D
authors.lastname: Shi
authors.affiliation: Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Lianjia
authors.initials: L
authors.lastname: Yang
authors.affiliation: Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Microsurgery, Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, China. Electronic address: byfyzxd@126.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China. Electronic address: qiuxiuchun2009@live.cn.
authors.forename: Xiuchun
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China. Electronic address: gukezy@fmmu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002648:Child; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4
keywords: CXCR4; HIF-1α; Hypoxia; Metastasis; Osteosarcoma