Vascular endothelial growth factor signaling pathway as an emerging target in hematologic malignancies

Angiogenesis is important in a variety of physiologic and pathologic disorders. It is a central element in embryogenesis, ovulation, wound healing, diabetic retinopathy, and rheumatoid arthritis and in the establishment and spread of malignant tumors. Angiogenic factors include direct angiogens, indirect angiogens, and integrins. Direct angiogens stimulate the formation of new blood vessels directly. Indirect angiogens promote neovascular formation by paracrine stimulation of direct angiogens. Integrins mediate interactions between the developing vessels and components of the extracellular matrix. Vascular endothelial growth factor (VEGF) is a principal direct angiogen. By binding to 1 of 3 receptors (VEGFR-1, -2, or -3), it influences vasculogenesis during embryogenesis, physiologic and neoplastic angiogenesis, and lymphangiogenesis. Although the importance of angiogenesis in solid tumors has been recognized for some time, its exact significance in hematologic malignancies is less clear. Evidence now suggests that VEGF has a major role in the development and progression of hematologic malignancies such as acute leukemia, chronic leukemia, myelodysplasia, non-Hodgkin's lymphoma, and multiple myeloma. Potential therapeutic interventions to interrupt the VEGF signaling pathway of malignancy include antibodies that neutralize the growth factor and small molecules that inhibit the receptor tyrosine kinase activity of VEGF receptors.