title: Blocking SDF-1α/CXCR4 downregulates PDGF-B and inhibits bone marrow-derived pericyte differentiation and tumor vascular expansion in Ewing tumors.
abstract: Bone marrow cells (BMC) are critical to the expansion of the tumor vessel network that supports Ewing sarcoma growth. BMCs migrate to the tumor and differentiate into endothelial cells and pericytes. We recently demonstrated that stromal-derived growth factor 1α (SDF-1α) regulates platelet-derived growth factor B (PDGF-B) and that this pathway plays a critical role in bone marrow-derived pericyte differentiation in vitro. We investigated the role of SDF-1α/PDGF-B in the tumor microenvironment in vivo in promoting bone marrow-derived pericyte differentiation in Ewing tumors. The CXCR4 antagonist AMD 3100 was used to disrupt the SDF-1α/CXCR4 axis in vivo in two xenograft Ewing tumor models. BMCs from GFP(+) transgenic mice were transplanted into lethally irradiated nude mice to track BMC migration to the tumor site. Following BMC engraftment, tumor-bearing mice received daily subcutaneous injections of either PBS or AMD 3100 for 3 weeks. Tumors were resected and tumor sections were analyzed by immunohistochemistry. AMD 3100 inhibited BMC differentiation into desmin(+) and NG2(+) pericytes, affected the morphology of the tumor vasculature, decreased perfusion, and increased tumor cell apoptosis. We observed smaller vessels with tiny lumens and a decrease in the microvessel density. AMD 3100 also inhibited PDGF-B protein expression in vitro and in vivo. SDF-1α in the tumor microenvironment plays a critical role in promoting pericyte formation and Ewing sarcoma tumor neovascularization by regulating PDGF-B expression. Interfering with this pathway affects tumor vascular morphology and expansion.
authors.affiliation: Corresponding Author: Eugenie S. Kleinerman, Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston TX 77030. ekleiner@mdanderson.org.
authors.forename: Randala
authors.initials: R
authors.lastname: Hamdan
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhou
authors.forename: Eugenie S
authors.initials: ES
authors.lastname: Kleinerman
mesh_terms: D000818:Animals; D001596:Benzylamines; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000080027:Cyclams; D015536:Down-Regulation; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D020286:Pericytes / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D023041:Xenograft Model Antitumor Assays
chemical_list: D001596:Benzylamines; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D020574:Proto-Oncogene Proteins c-sis; D019718:Receptors, CXCR4; C088327:plerixafor