Editorial [Hot Topic: Angiogenesis in Tumor Growth and Metastasis (Executive Editor: Riichiro Abe)]

In this decade, novel strategy against cancer, antiangiogeneic therapy, was attempted. A major microenvironmental event in tumor growth and expansion is the ‘angiogenic switch’, an alteration in the balance of pro-angiogenic and anti-angiogenic molecules that leads to tumor neovascularization. Angiogenesis, a process by which new vascular networks are formed from pre-existing capillaries or circulating endothelial ceslls, is required for tumors to grow, invade and metastasize. Tumor vessels are genetically quite stable, and less likely to accumulate mutations that allow them to develop drug resistance in a rapid manner. Therefore, targeting vasculature that supports tumor growth, rather than cancer cells themselves, is considered the most promising approach to cancer therapy. In this issue, we describe the possible antiangiogenesis basis of this therapeutic strategy. Circulating endothelial cell (CEC) and progenitor (CEP) number and viability are modulated in various pathological conditions including cancer. Martin-Padura and Bertolini [1] described CEC and CEP play an important role in cancer progression and metastasis. Indeed, emerging clinical data support that CEC and CEP kinetics and viability might predict the efficacy on anticancer drug combinations that include antiangiogenic agents. On the basis of these observations, CEC and CEP measurements have attractive potential diagnostic and therapeutic applications for malignant diseases. Among ‘angiogeneic cytokine’, macrophage migration inhibitor factor (MIF) is a highly conserved and evolutionarily ancient mediator with pleiotropic effects that has been implicated in tumor growth and progression. Bifulco et al. [2] reviewed MIF's function in multiple processes fundamental to tumorigenesis such as tumor proliferation, evasion of apoptosis, angiogenesis and invasion. These pleiotropic functional aspects are paralleled by MIF's unique signaling properties, which involve activation of the ERK-1/2 and AKT pathways. These properties reflect features central to growth regulation, apoptosis and cell cycle control than is typical for an immune cytokine. The significance of these pro-tumorigenic properties has found support in several in vitro and in vivo models of cancer and in the positive association between MIF production and tumor aggressiveness and metastatic potential in a variety of human tumors. Pigment epithelium-derived factor (PEDF) has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, and is involved in the pathogenesis of angiogenic eye disease such as proliferative diabetic retinopathy. Abe et al. [3] reviewed a functional role for PEDF in tumor growth and angiogenesis. Recent studies reported the antitumor potential of PEDF in various cancer based on its antiangiogenic properties and PEDF direct inhibitory effect via tumor cell apoptosis. The discovery and evaluation of antiangiogenic substances initially relied on methods such as various models that use the cornea to assess blood vessel growth. Although they are important for understanding the mechanisms of blood vessel induction, these models do not represent tumor angiogenesis and are poorly suited to drug discovery. Amoh et al. [4] have utilized multicolored fluorescent proteins to develop imaging models of tumor angiogenesis, which are clinically-relevant imageable models to visualize and quantify angiogenesis and efficacy of inhibitors. Angiogenesis is a complex process which is critical for the growth, invasion, and metastasis of tumors. Fujita et al. [5] reviewed recent progress in this clinical filed. In the past ten years numerous new agents have been developed as angiogenesis inhibitors. Angiogenesis inhibitors can be classified by their targeted area of the angiogenic process; (1) VEGF and its receptors VEGFR (e.g. Bevacizumab); (2) tyrosine kinases within endothelial cells (Sunitinib); (3) proliferation of endothelial cells (Endostatin); (4) MMPs (Marimastat); (5) intercellular interactions via integrins (Cilengitide) and (6) combinations of the above mechanisms (Thalidomide). Some show anti-tumor effects with objective responses and stable disease, and some disappeared from clinical use due to unexpected side effects or insufficient efficacies. Further investigations of combined therapies including angiogenesis inhibitors will shed light on the treatment of advanced and metastasized malignancies.