Normalization of the tumor microvasculature based on targeting and modulation of the tumor microenvironment.

Angiogenesis is an essential process for tumor development. Owing to the imbalance between pro- and anti-angiogenic factors, the tumor vasculature possesses the characteristics of tortuous, hyperpermeable vessels and compressive force, resulting in a reduction in the effect of traditional chemotherapy and radiotherapy. Anti-angiogenesis has emerged as a promising strategy for cancer treatment. Tumor angiogenesis, however, has been proved to be a complex process in which the tumor microenvironment (TME) plays a vital role in the initiation and development of the tumor microvasculature. The host stromal cells in the TME, such as cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and Treg cells, contribute to angiogenesis. Furthermore, the abnormal metabolic environment, such as hypoxia and acidosis, leads to the up-regulated expression of angiogenic factors. Indeed, normalization of the tumor microvasculature via targeting and modulating the TME has become a promising strategy for anti-angiogenesis and anti-tumor therapy. In this review, we summarize the abnormalities of the tumor microvasculature, tumor angiogenesis induced by an abnormal metabolic environment and host stromal cells, as well as drug delivery therapies to restore the balance between pro- and anti-angiogenic factors by targeting and normalizing the tumor vasculature in the TME.