title: CXCR4-targeted therapy inhibits VEGF expression and chondrosarcoma angiogenesis and metastasis.
abstract: Chondrosarcoma is notable for its lack of response to conventional cytotoxic chemotherapy, propensity for developing lung metastases, and poor survival. Therefore, a better understanding of angiogenic and metastatic pathways is needed. Multiple pathways regulate angiogenesis and metastasis, including chemokines and their receptors. In this study, we investigated chemokine (C-X-C motif) receptor 4 (CXCR4) signaling in chondrosarcoma and tested the hypotheses that CXCR4 inhibition suppresses tumor angiogenesis and metastasis. CXCR4 expression, analyzed by real-time PCR and Western blot, was increased in human chondrosarcoma cell line JJ compared with normal chondrocytes and was further increased in JJ by hypoxia (2% O2), vascular endothelial growth factor A (VEGFA; 10 ng/mL), and in xenograft tumors in nude mice. The CXCR4 ligand CXCL12 (10 ng/mL) doubled secreted VEGFA, measured with ELISA, under hypoxic conditions and this conditioned media increased human umbilical vein endothelial cell tube formation. These effects were inhibited by CXCR4 siRNA or AMD3100 (5 μg/mL). In a xenograft mouse model, four weeks of AMD3100 treatment (1.25 mg/kg, intraperitoneally twice daily) inhibited tumor angiogenesis, tumor growth, and metastasis. VEGFA content in tumor extracts was decreased (7.19 ± 0.52 ng/mL control vs. 3.96 ± 0.66 treatment) and bioimaging of angiogenesis was decreased by 56%. Tumor volumes averaged 4.44 ± 0.68 cm(3) in control compared with 2.48 ± 0.61 cm(3) in the treatment group. The number of lung metastatic nodules was 23 ± 9 in control compared with 10 ± 6 in the treatment group (N = 8/group). Therefore, CXCR4-targeted therapy may be a treatment strategy for chondrosarcoma.
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Coro West Building, 1 Hoppin St, Providence, RI 02903, USA. Richard_Terek@Brown.edu
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Sun
authors.forename: Cherie
authors.initials: C
authors.lastname: Charbonneau
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Wentian
authors.initials: W
authors.lastname: Yang
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Richard M
authors.initials: RM
authors.lastname: Terek
mesh_terms: D000818:Animals; D001596:Benzylamines; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D000080027:Cyclams; D004195:Disease Models, Animal; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; C088327:plerixafor