Viewing the tumor as an ecosystem involving reciprocal paracrine interactions between tumor cells and endothelial cells further underscores the importance of a persistent vascular supply for optimal tumor growth (2). Tumor angiogenesis is generally viewed as a consequence of the activation of an angiogenic switch a discrete genetic event in the succession of Rabbit polyclonal to ZBTB8OS genetic alterations underlying tumor progression that endows the tumor with the ability to recruit blood vessels from the neighboring tissue. tumor mass beyond Meisoindigo a size of a few cubic millimeters totally depends on de novo formation of a vascular network that provides the growing tumor with oxygen and essential nutrients (1). This thesis, now confirmed by a large body of experimental evidence, implies that tumors can potentially be starved to death by inhibiting their neovascularization. Viewing the tumor as an ecosystem involving reciprocal paracrine interactions between tumor cells and endothelial cells further underscores the importance of a persistent vascular supply for optimal tumor growth (2). Tumor angiogenesis is generally viewed as a consequence of the activation of an angiogenic switch a discrete genetic event in the succession of genetic alterations underlying tumor progression that endows the tumor with the ability to recruit blood vessels from the neighboring tissue. In several animal models, a discrete angiogenic switch has been exhibited Meisoindigo during early stages of tumor development that preceded the appearance of large malignant tumors (3). In theory, targeting the tumor vasculature rather than targeting tumor cells (an approach that is considered by Ohh and colleagues  in this issue of the allele. In tumors, the escape of VEGF from its otherwise tight control is usually in some cases achieved through activating mutations in oncogenes such as that concluded that much work is needed for a better understanding of the specific MMPs to be targeted and their precise role in the angiogenic response in order to develop more specific inhibitors with fewer side effects (22). Meisoindigo Another potential point of intervention is at the level of integrin-mediated adhesion of endothelial cells to ECM components. Specifically, antagonists of v integrins have been shown to disrupt tumor angiogenesis in vivo, and are currently in phase II clinical trials. The rationale for this approach is based on findings from Elicieri and coworkers that v3 integrin receptors are present on the surface of angiogenic endothelium but not on quiescent endothelium. Furthermore, ligation of v3 receptors promotes the survival of endothelial cells engaged in ongoing angiogenesis, as evidenced by the fact that v3 antagonists administered during angiogenesis induce endothelial cell apoptosis. Positive preclinical inhibition studies using human tumor xenografts and tumors in patches of human skin in SCID chimeric mice have prompted clinical trials using a humanized form of the v3 mAb LM609 (Vitaxin). For a recent review on their mechanisms of action and clinical development targeting the v integrins, see ref. 23. Epilogue The most important achievement of tumor angiogenesis research to date is the proof of the theory that antiangiogenic therapy is a viable option for the treatment of cancer. These prospects have fueled intensive research by scientists in both academia and the pharmaceutical industry. We are dealing with an unfolding chapter in developmental biology, with many questions still open regarding the nature of control mechanisms at the cellular, tissue, and organismal levels. In some cases, we are still missing a conceptual framework; in others, we are in the process of filling in the details. For example, the prevailing view of an avascular tumor mass acquiring the ability to recruit blood vessels from the neighboring tissue needs to be modified somewhat in order to accommodate recent observations. First, a subset of tumors and metastases initially grows by coopting existing host vessels before the induction of tumor neovascularization (24). Second, certain tumors (e.g., uveal melanomas) may generate vascular channels lacking endothelial cell lining (25). Nonetheless, most tumors are angiogenesis dependent at crucial stages of their growth. In addition to the therapeutic targets described above, interventions at other stages of the angiogenic Meisoindigo process are being explored. The realizations that vessel disassembly is required for the initiation of angiogenesis, and that the recruitment of pericytes is usually a key step in vessel maturation underscores the pivotal role of factors governing endothelial-periendothelial cell associations. In this respect, the roles of angiopoietin-1 in pericyte recruitment and vessel tightening, and the opposing effect of angiopoietin-2 in vessel destabilization (26) can be exploited to modify the phenotypes of tumor vessels. If some angiogenesis-specific grasp transcription factor can be Meisoindigo identified upon which different angiogenic stimuli converge, such a factor would be.