Drug Management of Prostate Cancer by William D. Figg Cindy H. Chau & Eric J. Small

Author:William D. Figg, Cindy H. Chau & Eric J. Small
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

Keywords

AngiogenesisProstate cancerDrugsBevacizumab

Mechanism of Angiogenesis

For survival, tumor cells must obtain a steady supply of oxygen and nutrients needed to support metabolic activity. A tumor that relies on existing vasculature can reach a size of only about 2 mm. In tumor cells, increased production of pro-angiogenic factors occurs as the result of a phenomenon known as the “angiogenic switch.” Pathological angiogenesis results from disruption of the regulatory processes that normally maintain the stability of the vascular system. Although usually confined to a localized area, the growth of new blood vessels during pathological angiogenesis is excessive and it often involves the intrusion of these vessels into an area where their presence is harmful. Growth factors generated as a result of the “angiogenic switch” enable a tumor to increase its supply of nutrients via tumor angiogenesis. Tumor angiogenesis begins when vascular endothelial growth factor (VEGF) and other growth factors diffuse away from the tumor and come into contact with established blood vessels of surrounding tissues. These factors activate endothelial cells that line the walls of existing vessels, trigger the angiogenic cascade, and lead to the sprouting of new capillaries [1].

VEGF plays a central role in the regulation of angiogenesis. Many environmental factors stimulate VEGF expression, including hypoxia, low pH, hormones (e.g., progesterone, estrogen), growth factors (e.g., epidermal growth factor [EGF], TGF-β[beta], bFGF, PDGF, insulin-like growth factor [IGF]-1), and cytokines (e.g., IL-1α[alpha], IL-6). Tumorigenic mutations involving p53, p73, src, ras, vHL, and Bcr-Abl can also stimulate VEGF expression. VEGF binds and activates its receptor (VEGFR), resulting in stimulation of downstream signaling cascades such as phospholipase C, protein kinase C, the cytoplasmic tyrosine kinase src, αvβ5 integrins, phosphatidylinositol-3-kinase, ras, and MAP kinase. These downstream signaling pathways in endothelial cells lead to inhibition of apoptosis, stimulation of mitosis, and cytoskeletal changes associated with motility [1].

VEGF (also known as VEGF-A) is part of a family of related proteins with similar structural motifs, including placenta growth factor (PlGF), VEGF-B, VEGF-C, VEGF-D, and VEGF-E (viral VEGF homolog), identified in the parapoxvirus Orf virus (Fig. 18.1). The family of VEGF proteins binds to several different VEGFRs with distinct binding and signaling properties. VEGFR1 (Flt-1), VEGFR2 (Flk-1, KDR), and VEGFR3 (Flt-4) have similar structural features and form homodimers upon ligand binding. Alternative splicing leads to the production of a soluble form of VEGFR-1, which does not bind to the membrane and functions as a negative regulator of VEGF signaling. The neuropilins, a distinct family of receptors, also interact with members of the VEGF family. Neuropilin-1 may function as co-receptor, enhancing VEGF interactions with VEGFR2. VEGFR1 interacts with PlGF, VEGF-B, and VEGF-A. The function of VEGFR1 remains to be elucidated. VEGFR1 signaling is only weakly activated by VEGF. VEGFR1 may function as a decoy receptor, much like soluble VEGFR1. VEGFR2 interacts with VEGF-C and D in addition to VEGF. This receptor is the major mediator of the mitogenic and angiogenic effects of VEGF. VEGFR-3 only interacts with VEGF-C and D and is involved in lymphangiogenesis [1].

Fig. 18.1VEGF family pathways

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