Role of Apoptosis in Anti-Angiogenic Cancer Therapies

Abstract

Angiogenesis, the growth of new blood vessels from the existing vasculature, is necessary for normal growth and development and in the adult during wound healing and the reproductive cycles. In most adult tissues, however, the vasculature is maintained in a quiescent state by the balanced presence of both angiogenic inducers and inhibitors in the tissue milieu. For progressive growth and metastasis, cancer cells must shift this balance to favor angiogenic induction. When inducers predominate, vascular endothelial cells (VECs) become activated, proliferating and migrating toward the source of the angiogenic inducer. In the activated VECs, distinct cell signaling pathways are initiated compared with that of quiescent VECs, 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. Depleting the supply of angiogenic inducers can also induce apoptosis, and thus, anti-angiogenic therapies can target the inducer supply or directly target the VECs. Although clinical studies are promising, most to date suggest that anti-angiogenic therapies may prove to be most effective when used in combination with traditional therapies.

Evaluate the response of Apoptosis, Angiogenesis and Cancer Therapies

“…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].…”

“…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].…”

“…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][10][11][12]. Through tumor cell stimulation angiogenic balance can indirectly altered to produce angiogenic factors and/or to decrease inhibitor production [1,13].…”

“…Therefore, when inhibitors predominate, the apoptotic cascade is initiated ,thus antiangiogenic 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].…”