Prognostic Significance Of Determination of Tumor Angiogenesis In Pediatric Solid Tumors

Abstract

Angiogenesis, neovascularization, is the process leading to formation of new blood vessels (Folkman, 1992). Angiogenesis is a crucial mechanism required for a number of physiological and pathological events. In physiological conditions, angiogenesis is a highly regulated phenomenon. It normally occurs during embryonic development, wound healing, and the menstruation cycle. Unregulated angiogenesis is seen in pathological conditions, such as psoriasis, diabetic retinopathy, and cancer (Tonini et al, 2003). The most dramatic angiogenesis-dependent disease is cancer. During tumor growth, angiogenesis is required for proper nourishment and removal of metabolic wastes from tumor sites (Gasparini and Harris, 1995).

Formation of solid tumors requires coordination of angiogenesis with continued tumor cell proliferation. However, despite such neovascularization, hypoxia is persistent and frequently found in tumors at the time of diagnosis. Hypoxia arises early in the process of tumor development because rapidly proliferating tumor cells outgrow the capacity of the host vasculature. Tumors with low oxygenation have a poor prognosis, and strong evidence suggests that this is because of the effects of hypoxia on malignant progression, angiogenesis, metastasis, and therapy resistance (Tonini et al, 2003). Although hypoxia inhibits cell proliferation and eventually cell death, hypoxia also provides angiogenic and metastatic signals, thus allowing prolonged survival in the absence of oxygen and generation of a persistent angiogenic signal (Dulak and Jozkowicz, 2003; Wouters et al., 2003).

Neoplastic cells may produce several angiogenic peptides, but vascular endothelial cells also secrete growth factors and cytokines that stimulate tumor cells proliferate or attract and stimulate inflammatory cells (Hamada et al, 2000). The extent of vasculature assessed by immunohistochemistry and microvessel counting predicts prognosis in many tumor types (Weidner, 1995). Urine and other body fluids of cancer patients have shown to contain endothelial chemokinetic and proliferative activity (Li et al, 1994).

Various growth factors have been shown to stimulate angiogenesis, including fibroblastic growth factors, transforming growth factor and vascular endothelial growth factor, (Mattern et al, 1996). The most potent and specific angiogenic factor is VEGF, also known as vascular permeability factor and vasculotropin (Banks et al, 1998). After developme:1t of sensitive enzyme immunoassay for basic fibroblast (Watanabe et al, 1991) and vascular endothelial growth