Imatinib Disrupts Lymphoma Angiogenesis by Targeting Vascular Pericytes

Pericytes/vascular smooth muscle cells (VSMCs), regulated by platelet-derived growth factor receptor β (PDGFRβ) signaling, play important roles in endothelial survival and vascular stability. Here we report that treatment with imatinib, an inhibitor of PDGFRβ, led to significant tumor growth impairment associated with increased apoptosis in human lymphoma xenografts including Farage, Karpas422 and OCI-Ly7 in SCID mice. Confocal analysis of the tumor tissue showed decreased microvessel density, decreased vascular flow, and increased vascular leak in the imatinib-treated cohorts. Imatinib targeted tumor-associated PDGFRβ+ pericytes in vivo by inducing apoptosis and disruption of the PDGFRβ+ perivascular network, and PDGFRβ+ VSMC in vitro by inhibition of proliferation. FACS analysis of mononuclear cell suspension of tumor tissues revealed decreased mature pericytes and endothelial cells, as well as their progenitors with imatinib treatment. Compared to imatinib, treatment with anti-PDGFRβ monoclonal antibody partially inhibited the growth of Farage lymphomas. Lastly, microarray analysis of differentially expressed genes in PDGFRβ+ VSMC following imatinib treatment showed significant down-regulation of genes implicated in proliferation, survival and angiogenesis, including those within PI3K/AKT and MAPK/ERK1/2 pathways downstream of PDGFRβ signaling. Taken together, targeting PDGFRβ+ pericytes in lymphoma presents a novel and complementary target to endothelial cells for efficacious antiangiogenic therapy. PDGFRb+ murine vascular smooth muscle cells (VSMCs) were treated in 10 uM imatinib for 24 or 48 hours. Gene expression changes in response to imatinib treatment were examined using NimbleGen MM8_60mer gene expression microarrays by comparing expression patterns at 24- and 48-hours treatment to the baseline level (0 hours).