Apoptosis , Angiogenesis and Cancer Therapies

Angiogenesis, the growth of new blood vessels from the existing vasculature, and is maintained in adult tissues by the balanced presence of both angiogenic inducers and inhibitors in the tissue milieu. When inducers predominate, vascular endothelial cells (VECs) become activated and in this activated VECs, distinct cell signaling pathways are initiated providing the specificity of anti-angiogenic therapies to the tumor vasculature. VEC apoptosis has been well documented in regressing vessels, and it has been shown that, in addition to activating the VECs, some inducers such as vascular endothelial growth factor also up-regulate Fas expression, thus sensitizing the cell to apoptotic stimuli. Endogenous angiogenesis inhibitors, such as thrombospondin-1(TSP-1) and pigment epithelium-derived factor (PEDF), stimulate signaling cascades within the VECs and also induce the expression of Fas ligand in activated VECs. Therefore, when inhibitors predominate, the apoptotic cascade is initiated ,thus anti-angiogenic therapies can target the inducer supply or directly target the VECs. Although clinical studies suggest that anti-angiogenic therapies may prove to be most effective when used in combination with traditional therapies [1]. Introduction Angiogenesis and Tumor Growth Angiogenesis, is a normal and necessary process during growth and development. It also occurs in the adult during wound healing and the reproductive cycles. However, in most normal adult issues, the vasculature is maintained in a quiescent state by the balanced presence of both pro-angiogenic and anti-angiogenic molecules in the tissue milieu [1]. Vascular endothelial cells (VECs) have a very low turn over time, estimated any where from 1000 days [1,2,3] to 7 years [1,4]. Judah Folkman first proposed in 1971 that tumor growth is dependent on the induction of angiogenesis [1,5]. It is demonstrated that this is due to a balance between tumor cell proliferation and apoptotic rates which applies to micrometastases, which remain dormant until a pro-angiogenic environment arises [1,6,7,8]. Tumors shift the balance to favor angiogenic induction by increasing expression of angiogenic inducers, decreasing expression of angiogenic inhibitors, or a combination of both [1,9] which result from the same genetic and epigenetic changes that drive tumor progression, such as oncogene expression, loss of tumor suppressor gene expression, and tissue hypoxia [1,9-12]. Through tumor cell stimulation angiogenic balance can indirectly altered to produce angiogenic factors and/or to decrease inhibitor production [1,13]. * Correspondence: [email protected] Department of Oral Pathology and Microbiology , School of Dental Sciences , Sharda University , Greater Noida, India. Neovascularization can also further stimulate tumor growth by providing the tumor with paracrine growth factors secreted by the VECs themselves, such as basic fibroblast growth factor (bFGF), interleukin-6, insulin-like growth factor, and platelet-derived growth factor, and also factors released by macrophages or other blood cells delivered to the tumor through the vasculature [1,13-16]. Furthermore, these vessels provide an avenue for tumor cells to metastasize to distant locations. Thus, the transition to a pro-angiogenic phenotype provides significant advantages for tumor growth and