DIFFUSE, FIBRILLARY ASTROCYTOMAS
Diffuse, fibrillary astrocytomas are the most common type of primary brain tumor in adults. These tumors are classified histopathologically into three grades of malignancy: World Health Organization (WHO) grade II astrocytoma, WHO grade III anaplastic astrocytoma, and WHO grade IV glioblastoma multiforme (GBM). WHO grade II astrocytomas are the most indolent of the diffuse astrocytoma spectrum. Nonetheless, these low-grade tumors are infiltrative and have a marked potential for malignant progression, and any biologic model for astrocytomas must account for these cardinal features of malignant progression and invasion.
The p53 gene, a tumor-suppressor gene located on chromosome 17p, has an integral role in a number of cellular processes, including cell cycle arrest, response to DNA damage, apoptosis, angiogenesis, and differentiation; as a result, p53 has been called the guardian of the genome. The p53 gene is involved in the early stages of astrocytoma tumorigenesis. For instance, p53 mutations and allelic loss of chromosome 17p are observed in approximately one-third of all three grades of adult astrocytomas, suggesting that inactivation of p53 is important in the formation of the grade II tumors. Moreover, high-grade astrocytomas with homogeneous p53 mutations evolve clonally from subpopulations of similarly mutated cells present in initially low-grade tumors. Such mutation studies are complemented by functional studies that have recapitulated the role of the p53 inactivation in the early stages of astrocytoma formation. For instance, cortical astrocytes from mice without functional p53 appear immortalized when grown in vitro and rapidly acquire a transformed phenotype. Cortical astrocytes from mice with one functional copy of p53 behave more like wild-type astrocytes and only show signs of immortalization and transformation after they have lost the one functional p53 copy. Those cells without functional p53 become markedly aneuploid, confirming prior work showing that p53 loss results in genomic instability cellular phone electromagnetic radiation and that astrocytomas with mutant p53 are often aneuploid. Thus, the abrogation of astrocytic p53 function appears to facilitate some events integral to neoplastic transformation, setting the stage for further malignant progression.
Many growth factors and their receptors are overexpressed in astrocytomas, including platelet-derived growth factor (PDGF), fibroblast growth factors (FGFs), and vascular endothelial growth factor (VEGF). For example, PDGF ligands and receptors are expressed approximately equally in all grades of astrocytoma, suggesting that such overexpression is also important in the initial stages of astrocytoma formation. Tumors often overexpress cognate PDGF ligands and receptors in an autocrine stimulatory fashion. The mechanisms for PDGF overexpression in most cases have not been elucidated, although rare astrocytomas display amplification of the PDGF alpha-receptor gene. Loss of chromosome 17p in the region of the p53 gene is closely correlated with PDGF alpha-receptor overexpression; 17p loss is most often seen in those astrocytomas that have PDGF alpha-receptor overexpression. These observations may imply that p53 mutations have an oncogenic effect only in the presence of PDGF alpha-receptor overexpression. This interdependence is highlighted by observations that mouse astrocytes without functional p53 become transformed only in the presence of specific growth factors.
Astrocytomas display a remarkable tendency to infiltrate the surrounding brain, confounding therapeutic attempts at local control. These invasive abilities are often apparent in low-grade as well as high-grade tumors, implying that the invasive phenotype is acquired early in tumorigenesis. Investigations into astrocytoma invasion have highlighted the complex nature of cell-cell and cell-extracellular-matrix interactions. A variety of cell surface molecules such as CD44 glycoproteins, gangliosides, and integrins are differentially expressed in astrocytomas. Some, such as the A2B5 ganglioside, are expressed primarily by nondividing cells that are migrating; others appear somewhat specific for neoplastic astrocytes. Many of the growth factors expressed in astrocytomas, such as FGF, EGF, and VEGF, also stimulate migration.
Less common molecular changes also occur in grade II astrocytomas. Loss of chromosome 22q, for instance, suggests the presence of a chromosome 22q glioma tumor suppressor gene. Although the neurofibromatosis 2 (NF2) gene was a likely candidate for this gene, NF2 mutations do not occur in astrocytomas and deletion mapping of chromosome 22q in astrocytomas has suggested a more telomeric locus.