Biological therapies for metastatic breast cancer: Antiangiogenesis

Angiogenesis, the development of new vessels from pre-existing vasculature, is a crucial mechanism for tumor growth [1]. Tumor cells may be in a state of dormancy from months to years until "the angiogenic switch," which is promoted by releasing soluble factors. It can occur at different stages of the tumor progression pathway, depending on the tumor type and the environment [2]. The microenvironment can provoke a shift toward proangiogenic factors via metabolic changes (low oxygen tension, low pH, hypoglycemia), mechanical stresses (pressure generated by proliferating cells), the immune/inflammatory response, and mutations [3, 4]. Some oncogenes and tumor-suppressor genes operate and contribute by causing upregulation of endogenous angiogenesis stimulators or downregulation of inhibitors [2]. Recently, other mechanisms of enhancing vasculature have also been described. These pathways differ sufficiently from normal tissues to be considered as therapy targets, but with so many it is perhaps unlikely that one alone will be suitable for all patients, all stages, and all sites of metastasis. This review describes the pathways and mechanisms so far relevant to breast cancer, but in many cases pathways have not yet been studied in this disease. Current antiangiogenic therapy is beginning to fulfill its promise and will be reviewed, highlighting potential problems in conducting trials in this area. © Springer-Verlag Berlin Heidelberg 2006.