Angiogenesis and antiangiogenic therapy in non-Hodgkin's lymphoma

Abstract

Angiogenesis, the growth of new blood vessels, requires dynamic expansion, assembly and stabilization of vascular endothelial cells in response to proangiogenic stimuli. Antiangiogenic strategies have become an important therapeutic modality for solid tumors. While many aspects of postnatal pathological angiogenesis have been extensively studied in the context of nonhematopoietic neoplasms, the precise role of these processes in lymphoma pathogenesis is under active investigation. Lymphoma growth and progression is potentiated by at least two distinct angiogenic mechanisms: autocrine stimulation of tumor cells via expression of vascular endothelial growth factor (VEGF) and VEGF receptors by lymphoma cells, as well as paracrine influences of proangiogenic tumor microenvironment on both local neovascular transformation and recruitment of circulating bone marrow-derived progenitors. Lymphoma-associated infiltrating host cells including hematopoietic monocytes, T cells and mesenchymal pericytes have increasingly been associated with the pathogenesis and prognosis of lymphoma, in part providing perivascular guidance and support to neoangiogenesis. Collectively, these distinct angiogenic mechanisms appear to be important therapeutic targets in selected non-Hodgkin's lymphoma (NHL) subtypes. Understanding these pathways has led to the introduction of antiangiogenic treatment strategies into the clinic where they are currently under assessment in several ongoing studies of NHL patients.

Figure 1.

Overview of the lymphoma vascular microenvironment. (A) Tumor cells produce VEGF-A and other angiogenic factors such as bFGF, PlGF and VEGF-C which promote neo-angiogenesis via at least two mechanisms: sprouting angiogenesis of mature resident endothelial cells and vasculogenesis from recruitment of bone marrow-derived progenitor cells. (B) VEGF-A also supports the survival, proliferation and migration of lymphoma cells which express VEGFR1 and VEGFR2 in an autocrine fashion. (C) Malignant stroma, composed of fibroblasts, inflammatory and immune cells, provides additional angiogenic factors. Tumor-associated fibroblasts produce chemokines such as SDF-1, which recruits bone-marrow-derived angiogenic cells. Tumor-associated macrophages produce VEGF-A, VEGF-C, and MMP-9, among others, to support endothelial proliferation. Tumor cells may also release stromal cell-recruitment factors, such as PDGF-A. (D) Endothelial cells produce PDGF-B, which promotes recruitment of pericytes via activation of PDGFR-β. bFGF, basic fibroblast growth factor; BMC, bone marrow-derived cells; MMP-9, matrix metalloproteinase-9; PlGF, placental growth factor; PDGF, platelet-derived growth factor; SDF-1, stromal cell-derived factor 1.