Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes

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 beta (PDGFR beta), impaired growth of lymphoma in both human xenograft and murine allograft models. Lymphoma cells themselves neither expressed PDGFR beta 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 PDGFR beta(+) pericytes and loss of perivascular integrity. In vitro, imatinib inhibited PDGFR beta(+) VSMC proliferation and PDGF-BB signaling, whereas small interfering RNA knockdown of PDGFR beta 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-PDGFR beta monoclonal antibody partially inhibited lymphoma growth. Last, microarray analysis (Gene Expression Omnibus database accession number GSE30752) of PDGFR beta(+) VSMCs following imatinib treatment showed down-regulation of genes implicated in vascular cell proliferation, survival, and assembly, including those representing multiple pathways downstream of PDGFR beta. Taken together, these data indicate that PDGFR beta(+) pericytes may represent a novel, nonendothelial, antiangiogenic target for lymphoma therapy.