Up-regulation of VEGF Expression and Related Neo-angiogenesis in Childhood High-grade Gliomas: Implications for Anti-angiogenic Anti-neoplastic Therapy

Vascular endothelial growth factor (VEGF) is a homodimeric, disulfide-linked glycoprotein which exhibits endothelial cell-specific mitogenic properties. VEGF is also a potent inducer of vascular permeability. There is considerable experimental evidence that VEGF isoforms are strongly involved in provoking neoangiogenesis of neoplastic cells and, consequently, the growth and progression of primary neoplasms (i.e., astrocytic gliomas), including the formation of an invasive and metastatic immunophenotype (IP). During this immunohistochemical study, the presence and tissue localization of VEGF121 was observed in anaplastic, high-grade astrocytomas (AAs) and in glioblastoma multiforme (GBMs) employing the specific monoclonal antibody against it. A sensitive, four-step, alkaline phosphatase-conjugated antigen detection technique was used. The immunoreactivity demonstrated a cytoplasmic, cell surface and extracellular matrix localization pattern in more than 90% of the tumor cells, with high intensity immunoreactivity (++++, A,B) in every high-grade astrocytic glioma tissue. VEGF121 expression was identified mostly within the cytoplasm of tumor cells, suggesting an embryonic, undifferentiated and more malignant cellular IP of high-grade gliomas. Tumor-related neo-angiogenesis and endothelial cell proliferation were also present. The great majority of high-grade astrocytic gliomas are incurable with the three classic therapeutic modalities. In the future, the development of targeted anti-neoplastic treatment strategies, adapted to individual patients, will require molecular identification of the different classes of neoplasm (including subtypes of astrocytomas) according to their stages, biology, prognosis and therapeutic options. Malignant childhood astrocytomas (ASTRs) are neuroectodermal tumors appearing within the neuro-glial or macroglial central nervous system (CNS) (1). Gliomas can grow anywhere in the CNS. In children, they usually occur in the brain stem, the cerebrum, or the cerebellum, with the most common brain tumors developing from glial cell precursors (astrocytes, oligodendrocytes and ependymocytes). High-grade glial tumors, including glioblastomas (GBMs), are characterized by hypercellularity, pleomorphism, numerous mitoses, various degrees of necrosis, and multiple endothelial cell proliferations related to tumor neo- angiogenesis (2-4). Astrocytomas account for about 68% of the primary brain tumors occurring in children <20 years old and for over 50% of all intracranial tumors (2-7). GBM is a grade IV astrocytoma according to the World Health Organization (WHO) classification. It is a highly malignant and aggressive neoplasm, regarded as the prototype of neoplastic tissue capable of inducing neo- angiogenesis (8-10). The vascular phenotype of this tumor is a hallmark for histopathological diagnosis (11). Furthermore, glial tumors are characterized by a strong tendency for local invasiveness, but a relatively low distant metastatic potential. The majority of malignant glial tumors are incurable with the classic therapeutic modalities, including the combination of surgical resection, radiotherapy and chemotherapy, the survival rate not having changed substantially in the last 50 years. The prognosis of high-grade gliomas also remains unpredictable because the histological features alone provide an imperfect assessment and prognostication of the biological behavior of a given lesion. Vascular endothelial growth factor (VEGF) is a disulfide- linked homodimeric glycoprotein of about 40 kDa that promotes fluid and protein leakage from blood vessels,