TitleImatinib disrupts lymphoma angiogenesis by targeting vascular pericytes.
Publication TypeJournal Article
Year of Publication2013
AuthorsRuan, Jia, Luo Min, Wang Chunjie, Fan Lei, Yang Shao Ning, Cardenas Mariano, Geng Huimin, Leonard John P., Melnick Ari, Cerchietti Leandro, and Hajjar Katherine A.
JournalBlood
Volume121
Issue26
Pagination5192-202
Date Published2013 Jun 27
ISSN1528-0020
KeywordsAngiogenesis Inhibitors, Animals, Antibodies, Monoclonal, Apoptosis, Benzamides, Biomarkers, Tumor, Blotting, Western, Cell Differentiation, Cell Proliferation, Gene Expression Profiling, Humans, Imatinib Mesylate, Immunoenzyme Techniques, Lymphoma, Large B-Cell, Diffuse, Lymphoma, T-Cell, Mice, Mice, SCID, Neovascularization, Pathologic, Oligonucleotide Array Sequence Analysis, Pericytes, Piperazines, Platelet-Derived Growth Factor, Pyrimidines, Real-Time Polymerase Chain Reaction, Receptor, Platelet-Derived Growth Factor beta, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, RNA, Small Interfering, Signal Transduction, Tumor Cells, Cultured
Abstract

<p>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.</p>

DOI10.1182/blood-2013-03-490763
Alternate JournalBlood
PubMed ID23632889
PubMed Central IDPMC3695363
Grant ListK08 HL091517 / HL / NHLBI NIH HHS / United States
R01 HL042493 / HL / NHLBI NIH HHS / United States
R01 HL090985 / HL / NHLBI NIH HHS / United States