Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data

Tumor dormancy is the ability of cancer cells to survive in a non-proliferating state. This condition can depend on three main mechanisms: cell cycle arrest (quiescence or cell dormancy), immunosurveillance (immunologic dormancy), or lack of functional blood vessels (angiogenic dormancy). In particular, under angiogenic dormancy, cancer cell proliferation is counterbalanced by apoptosis owing to poor vascularization, impeding tumor mass expansion beyond a microscopic size, with an asymptomatic and non-metastatic state. Tumor vasculogenic or non-angiogenic switch is essential to promote escape from tumor dormancy, leading to tumor mass proliferation and metastasis. In avascular lesions angiogenesis process results blocked from the equilibrium between pro- and anti-angiogenic factors, such as vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1), respectively. The angiogenic switch mainly depends on the disruption of this balance, in favor of pro-angiogenic factors, and on the recruitment of circulating endothelial progenitors (CEPs) that promote the formation of new blood vessels. Metronomic chemotherapy, the regular intake of doses able to sustain low but active concentrations of chemotherapeutic drugs during protracted time periods, is an encouraging therapeutic approach that has shown to upregulate anti-angiogenic factors such as TSP-1 and decline pro-angiogenic factors such as VEGF, suppressing the proangiogenic cells such as CEPs. In this perspective, metronomic chemotherapy may be one of the available therapeutic approaches capable to modulate favorably the angiogenic tumor dormancy, but further research is essential to better define this particular characteristic.