Molecular Mechanisms of Tumor Angiogenesis

It is well established that progression from a pre-malignant to malignant invasive tumor phenotype is dependent on angiogenesis1-7. As such, a hallmark of all solid cancers is their ability to induce the formation of their own blood supply thereby sustaining their growth and is characterized by increases in endothelial cell (EC) proliferation and blood vessel heterogeneity8-10. The ‘angiogenic switch’, is a complex balance of multiple proand antiangiogenic factors secreted by both host and tumor cells, which when balanced in favor of proangiogenic factors will trigger new vessel formation (Figure 1)1-7. The expression of these proand antiangiogenic regulators is dependent on various physiological and pathological factors in addition to the tumor type, stage and microenvironment2,8. It has been shown previously that although tumor angiogenesis to some extent recapitulates the normal process of angiogenesis, it is not well organized and leads to the majority of solid cancers having tortuous and dilated vessels that have abnormal physiological function. This commonly leads to insufficient blood flow, poor delivery of oxygen and nutrients, inadequate removal of waste, increased vessel permeability and tumor edema due to alteration in EC tight junctions and contacts2,11-15. These inefficiencies in blood flow result in changes within tumor microenvironment that can trigger further expression of a battery of angiogenic factors, setting up a continuous cycle of dysfunctional vessel formation1,2,8,9. The precise mechanisms governing expression of proor anti-angiogenic factors are still not fully understood. In response to oncogene activation and/or metabolic stress, such as that seen in solid tumors, tumor cells can directly secrete growth factors including vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1) stimulating the angiogenic switch to enhance vessel formation17-23 (Figure 1), or attracting macrophages that can indirectly promote release of angiogenic factors10. Multiple candidate factors that signal tumor cells to initiate this cascade have been proposed1,2,11-14. The main contributors include hypoxia and increased physical forces, both generated in rapidly growing tumors, that disrupt the EC connections within the extracellular matrix (ECM), and the products of oncogenes and mutated tumor suppressor genes1,2,11-14. The relative contribution of various angiogenic pathways, their interactions and combinatorial impact on tumor angiogenesis is not precisely known and requires further characterization in order to establish a comprehensive picture of tumor angiogenesis.