New Molecular Targets for Anti-Angiogenic Therapeutic Strategies

The concept of targeting tumor blood vessel formation, i.e. tumor angiogenesis, has long been accepted as a potential strategy for controlling tumor growth. Characterized by the ability to supply oxygen, growth factors, hormones and nutrients, tumor vasculature has been identified as a key factor for the maintenance and progression of many solid tumors. The development of tumor vasculature is regulated by a highly complex network of signal transduction pathways involving proand anti-angiogenic factors. This delicate, yet dynamic balance between the promotion and inhibition of vascularization provides an abundance of molecular targets for therapeutic intervention. Since more than 85% of cancer mortality results from solid tumors, the continual development of anti-vascular agents remains an important goal in the quest for novel anticancer therapies (Jain, 2005). Despite its supporting role in the nutrition and viability of human cancers, however, tumor angiogenesis was not always considered a hallmark of tumor progression (Hanahan & Folkman, 1996). Initial skepticism centered on the hypothesis that angiogenesis was only critical in the early phase of tumor development. Thus, many opponents believed that angiogenic inhibition would be largely ineffective in most late-stage cancers. Other skeptics argued that the concept of anti-angiogenic therapy was counterintuitive because destruction of the tumor vasculature would significantly compromise the delivery of cytotoxic agents to the tumor (Jain, 2005). Though these concerns are not without merit, an overwhelming body of evidence in early-stage and established tumors demonstrates a synergistic effect when inhibitors of angiogenesis are combined with chemotherapy and/or radiotherapy. Despite the advantages of anti-angiogenic therapy, some have proposed that vascular destruction promotes the increased adaptation of tumor cells to areas of insufficient vascularization. The basis for this concern can be found through closer examination of the vascular abnormalities often identified in the tumor microenvironment. Characterized by aberrant morphology and increased compression of blood and lymphatic vessels, the tumor vascular network is an environment of interstitial hypertension and hypoxia (low oxygen availability) (Hanahan & Folkman, 1996; Jain, 2005). While some cancer cells are able to survive these harsh conditions of nutrient deprivation and impaired oxygenation, many of these tumor cells undergo programmed cell death. Nevertheless, anti-vascular therapy is feared to select for tumor cells with enhanced invasive and metastatic potential. Equipped