Angiogenesis and inflammation as target for cancer prevention

Angiogenesis is necessary for solid tumor growth and dissemination, thus representing a promising target not only in cancer therapy but also in prevention. The principle of cancer chemoprevention is based on the use of agents that, while devoid of collateral effects, are able to interfere with processes associated with malignant progression, including cancer related inflammation (CRI). Since our solid expertise in working with many chemoprevention agents, we have observed that angiogenesis is a common and key target of most chemopreventive molecules. In this view, we termed “angioprevention” the concept that effective chemoprevention are also able to target angiogenesis . The cancer microenvironment includes a series of complex interactions and communications between tumor cells and host cells, in particular endothelial and inflammatory cells, that promote progression to malignancy. Our goal is to identify molecules and pathways to prevent tumor development by targeting the microenvironment and inflammatory angiogenesis. We have shown that a wide array of molecules, including flavonoids, antioxidants and retinoids, act in the tumor micro-environment and inhibit the recruitment and/or activation of endothelial cells. We have shown that N-acetylcysteine (NAC), the green tea flavonoid epigallocatechin3-gallate (EGCG) and the chalcone Xanthohumol (XN), and the Akt inhibitor deguelin all prevent angiogenesis. Interestingly, the synthetic retinoid 4-hydroxyfenretinide (4HPR) also shows similar anti-angiogenic and anti-tumor effects. We therefore demonstrated the anti angiogenic potential in vitro and in vivo of a poliphenol-rich purified extract from olive mill wastewater (OMWW-patent pending). To examine the molecular mechanisms involved in our selected compound anti angiogenic/angiopreventive activity, we have performed microarray expression profiling on endothelial cells in response to angiopreventive molecules showing their interaction with pathway involved in the inflammatory response. We have now shown that the triterpenoid CDDO-Methylesther is a remarkably potent inhibitor of angiogenesis and angiogenic tumor growth, effective at doses as low as 0.003 mg/kg body weight. Finally, we have recently demonstrated that metformin, a wide used anti diabetic drug, represents a valid chemopreventive and angiopreventive agent, particularly in a context of obesity.