From anti-angiogenesis to anti-lymphangiogenesis: emerging trends in cancer therapy.

The theory that angiogenesis could support tumor growth and therefore be a target for cancer therapy was explored in publications by Judah Folkman in the 1970s. This theory was then fostered by Folkman for over 2 decades until, via modern molecular and cell biology techniques, it was vindicated in animal tumor models, and subsequently with the successful clinical trials of a humanized monoclonal antibody which neutralizes vascular endothelial growth factor (VEGF). In the process of proving the "anti-angiogenesis" theory, researchers in vascular, cancer, and developmental biology have gained insight into how the vascular network operates at the molecular level. Following on from the wave of activity that accompanied the study of angiogenesis, some of the molecular mechanisms controlling the related process of lymphangiogenesis have now been identified. The growth of lymphatic vessels was found to be controlled by proteins related to VEGF, namely VEGF-C and VEGF-D, which are associated with a number of human tumor types. The experimental inhibition of this process in animal models has suggested that lymphangiogenic growth factors facilitate the metastatic spread of tumor cells via lymphatics. Unlike the anti-angiogenesis strategy, anti-lymphangiogenesis is yet to be tested clinically; however, the notion that anti-lymphangiogenesis may be beneficial for cancer therapy is supported by extensive data from animal models and clinicopatholgical data. History may show that anti-angiogenesis provided the vantage point from which anti-lymphangiogenesis was seen as a viable concept for targeting tumors and other pathological conditions.