Vaccines targeting the neovasculature of tumors

Cancer mortality is related to the spread of neoplastic cells to distant loci where the cells, supported by existing blood vessels and angiogenesis, proliferate and give rise to secondary tumors. Tumor angiogenesis is up-regulated by a number of conditions including hypoxia, hypoglycemia, mechanical disruption, and genetic and inflammatory alterations [1] that lead to activation of growth factors and pro-angiogenic genes [2,3]. The stringent regulation of angiogenesis in normal tissues is often lacking in tumor angiogenesis, resulting in immature and leaky tumor vessels. Furthermore, compared to the tissue-vessel distribution in normal tissue, there is an uneven distribution of vessels within tumors, leading to tumor hypoxia and inefficient transport of chemotherapeutic drugs. In contrast to normal endothelial cells, in which the vast majority are quiescent, tumor endothelial cells actively proliferate, driven by hypoxia and increased levels of angiogenic factors and their cognate receptors. These differences between quiescent and angiogenic endothelial cells resulted in the first clinical anti-angiogenesis trial on human cancer two decades ago. There are now several anti-angiogenic therapies that have received FDA approval including sunitinib, sorafenib, and bevacizumab; and with more than 40 anti-angiogenic drugs in clinical trials [4], further advances are anticipated [5-11].Differences among tumor endothelial cells and non-malignant endothelial cells may not only be quantitative but in some instances may also be qualitative. With serial analysis of gene expression, investigators compared gene expression from endothelial cells isolated from normal or malignant tissue, and found that several transcripts (e.g., CD276) were specifically elevated in the tumor endothelium [12,13]. Although most receptors/proteins that are increased in the tumor endothelium are also up-regulated in physiologic angiogenic processes, CD276 is not increased in the vessels of wounds or the