Therapeutic Targeting of Lymphoma-Associated Vascular Pericytes,

Abstract 3725

Growing evidence has implicated the tumor microenvironment, demarcated by neo-vessels, as an essential disease compartment which influences neoplastic growth and clinical outcome in human lymphoma. The mechanisms whereby stromal cells contribute to the pathogenesis and progression of lymphoma remain poorly understood. Pericytes / vascular smooth muscle cells (VSMC), regulated by platelet-derived growth factor receptor β (PDGFRβ) signaling, play important roles in endothelial cell survival and vascular stability. We hypothesized that the functionality and stability of an effective lymphoma-associated vascular network depends upon the integrity of vascular pericytes, and that biologic agents which selectively target vascular pericytes would induce endothelial dysfunction and impair lymphoma growth. We tested our hypothesis in SCID mice bearing human diffuse large B-cell lymphoma (DLBCL) cell lines by treating with selective PDGFRβ inhibitors including imatinib mesylate and monoclonal anti-PDGFRβ antibody. Treatment with imatinib impaired tumor growth of human lymphoma xenografts including Farage, Karpas422 and OCI-Ly7, while the tumor cells themselves neither expressed PDGFRβ nor were inhibited by imatinib directly. Confocal microscopic analysis of the xenograft tumor tissue showed decreased microvessel density, decreased vascular functional flow, as well as increased vascular leak and apoptosis in the imatinib-treated cohorts, compared to untreated controls. 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 suspensions of xenograft tumor tissue revealed decreased numbers of mature pericytes and endothelia, as well as their progenitors, with imatinib treatment. Compared to imatinib, treatment with anti-PDGFRβ monoclonal antibody partially inhibited the growth of Farage lymphomas by depleting pericytes and attenuating angiogenesis. Lastly, microarray analysis of differentially expressed genes in PDGFRβ⁺ VSMC treated with imatinib showed significant down-regulation of genes implicated in proliferation, survival and angiogenesis, including those within the PI3K/AKT and MAPK/ERK1/2 pathways downstream of PDGFRβ signaling. Taken together, these data suggest that effective targeting of angiogenesis within the tumor microenvironment, without directly targeting tumor cells, can translate into therapeutic effects in DLBCL lymphoma models. PDGFRβ⁺ pericytes may represent a novel, non-endothelial, anti-angiogenic target for lymphoma therapy.