Tumor Dormancy, Angiogenesis and Metronomic Chemotherapy

Angiogenic dormancy can be defined as the condition in which cancer cell proliferation is counterbalanced by apoptosis owing to poor vascularization. Indeed, the lack of tumor angiogenesis impedes tumor mass expansion beyond a microscopic size, resulting in an asymptomatic and non-metastatic state. Thus, the tumor angiogenic switch is essential to promote fast-growing and expansion of tumor masses and to develop the metastatic process. In the avascular tumor lesion, 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 of non-dormant tumors mainly depends on the disruption of the balance in the tumor microenvironment between anti-angiogenic and pro-angiogenic factors, in favor of the latter. Moreover, this tumors activate and recruit the circulating endothelial progenitors (CEPs) that facilitate the shift toward the generation of new blood vessels. Metronomic chemotherapy—a regular administration of drug doses able to maintain low but active concentrations of chemotherapeutic drugs during prolonged periods of time—is a promising therapeutic approach that can induce or re-induce the angiogenic tumor dormancy. Metronomic chemotherapy upregulates TSP-1 and decreases pro-angiogenic factors such as VEGF, and suppresses the proangiogenic cells such as CEPs both in adjuvant setting or in the treatment of metastatic disease. In this perspective, metronomic chemotherapy may be able to play a main role in the modulation of the angiogenic tumor dormancy, but further preclinical and clinical studies are needed to better investigate this particular aspect of this interesting therapeutic tool.