Antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing an alternative circulatory system

Abstract

Antiangiogenesis therapy is one of the most promising approaches to cancer treatment. Its clinical success has come out but still too limited. Vascularization of tumor is a complex and heterogenous process. So far, it has been demonstrated that several additional mechanisms can provide the tumor with oxygen and nutrients. Moreover, it is now clear that vascularization of tumor does not necessarily depend on endothelial cells proliferation and sprouting of new capillaries. Vasculogenic mimicry (VM) as an alternative circulatory system, has been described in multiple malignant tumor types, and considered to be associated with a poor prognosis for the patient. VM serves as an adjunct to the existing vasculature system, thereby aiding tumor growth as well as contributing to the metastatic process. Moreover, hypoxia has been confirmed to promote some tumor cells to form vessel-like tubes in vitro and express genes associated with VM. Yet, the current antiangiogenesis strategies, which are directed mainly against the tumor endothelium and then cause hypoxia of tumor cells, have no effect on VM. Our central hypothesis is that when the endothelium-dependent vessels are inhibited by the effective angiogenesis inhibitors, the hypoxia of tumor cells caused by antiangiogenesis may increase VM compensatively which can replace the job of endothelium-dependent vessels to maintain the tumor blood supply and provide a convenient route of tumor metastasis. As a result, antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing VM. Thus, treatment strategies that target the tumor microcirculation should not only target endothelium-dependent vessels, but also take VM into account in tumors presenting VM.