title: Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes.
abstract: Pericytes and vascular smooth muscle cells (VSMCs), which are recruited to developing blood vessels by platelet-derived growth factor BB, support endothelial cell survival and vascular stability. Here, we report that imatinib, a tyrosine kinase inhibitor of platelet-derived growth factor receptor β (PDGFRβ), impaired growth of lymphoma in both human xenograft and murine allograft models. Lymphoma cells themselves neither expressed PDGFRβ nor were growth inhibited by imatinib. Tumor growth inhibition was associated with decreased microvascular density and increased vascular leakage. In vivo, imatinib induced apoptosis of tumor-associated PDGFRβ(+) pericytes and loss of perivascular integrity. In vitro, imatinib inhibited PDGFRβ(+) VSMC proliferation and PDGF-BB signaling, whereas small interfering RNA knockdown of PDGFRβ in pericytes protected them against imatinib-mediated growth inhibition. Fluorescence-activated cell sorter analysis of tumor tissue revealed depletion of pericytes, endothelial cells, and their progenitors following imatinib treatment. Compared with imatinib, treatment with an anti-PDGFRβ monoclonal antibody partially inhibited lymphoma growth. Last, microarray analysis (Gene Expression Omnibus database accession number GSE30752) of PDGFRβ(+) VSMCs following imatinib treatment showed down-regulation of genes implicated in vascular cell proliferation, survival, and assembly, including those representing multiple pathways downstream of PDGFRβ. Taken together, these data indicate that PDGFRβ(+) pericytes may represent a novel, nonendothelial, antiangiogenic target for lymphoma therapy.
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. jruan@med.cornell.edu
authors: Jia
authors: J
authors: Ruan
authors: Min
authors: M
authors: Luo
authors: Chunjie
authors: C
authors: Wang
authors: Lei
authors: L
authors: Fan
authors: Shao Ning
authors: SN
authors: Yang
authors: Mariano
authors: M
authors: Cardenas
authors: Huimin
authors: H
authors: Geng
authors: John P
authors: JP
authors: Leonard
authors: Ari
authors: A
authors: Melnick
authors: Leandro
authors: L
authors: Cerchietti
authors: Katherine A
authors: KA
authors: Hajjar
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D020411:Oligonucleotide Array Sequence Analysis; D020286:Pericytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D001549:Benzamides; D014408:Biomarkers, Tumor; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta
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