The Clinical and Biologic Importance of Neovascularization and Angiogenic Signaling Pathways in Chronic Lymphocytic Leukemia

Angiogenesis has been found to be an important regulator in the growth and metastasis of solid tumors. More recent studies have also demonstrated the importance of this biologic process in normal hematopoietic cell development and the pathophysiology of several hematologic malignancies. This review provides an overview of the clinical and biologic importance of angiogenesis in chronic lymphocytic leukemia (CLL). Patients with CLL have detectable levels of both plasma and cellular pro- and anti-angiogenic cytokines, as well as abnormal neovascularization in the marrow and lymph nodes. Recent evidence suggests a vascular endothelial growth factor (VEGF)-based autocrine pathway promotes the survival of CLL B cells in part through upregulation of anti-apoptotic proteins. Additionally, interactions between CLL B cells and their microenvironment generate alterations in the secretion of angiogenic factors that result in enhanced leukemic B-cell resistance to apoptotic cell death. From a clinical stanpoint, interpatient variation is observed in markers of angiogenesis and appears to have prognostic implications. Several clinical trials evaluating the efficacy of anti-angiogenic agents for treatment of patients with CLL are underway with promising preliminary results. Additional research is needed to identify the regulation of aberrant and critical angiogenic pathways in CLL B cells, to determine how angiogenic markers can be used to improve prognostication for CLL patients, and to explore how the angiogenic characteristics of CLL B cells can best be manipulated for therapeutic benefit.