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Introduction Brain tumors are the most common solid tumor of childhood, second in frequency only to leukemia [1]. Astrocytomas represent the most common primary brain tumor of childhood comprising almost 50% of all brain tumors in this age group [2]. Of these, 20% are high-grade, or anaplastic lesions. Unlike adults with low-grade astrocytomas who frequently progress to higher grade lesions over time, the malignant transformation of a low-grade astrocytoma to highgrade one in a child is a rare event [3]. Medulloblastoma is another common brain tumor in childhood accounting for about 25% of pediatric brain tumors. This tumor is highly proliferative with a propensity to invade the fourth ventricle as well as the overlying subarachnoid spaces. As such, medulloblastoma is characterized by widespread dissemination along cerebrospi-nal fluid pathways. Unfortunately, many children who suffer from malignant astrocytoma and medulloblastoma will die from their tumors despite recent advances in surgery, radiation, and chemotherapy [4]. Improving the prognosis for these children will involve not only the identification of better treatment modalities, but a greater understanding of the pathogenetic basis for these tumors. Recently, several studies have shown that a class of genes which control cell cycle regulation play an important role in the pathogenesis of several different human tumors, including brain tumors. Uncontrolled cellular proliferation is a hallmark of neoplasia. Experimental studies on the mechanisms of cell proliferation have begun to elucidate a basic tenet in cell cycle dysregulation in tumors, namely that uncontrolled proliferation may be caused by altered expression of positive growth regulators such as cyclins and cyclin-dependent kinases (CDKs), or the loss of negative regulators, including CDK inhibitors (CDKIs), and the retino-blastoma protein (pRB). As a result, a cell is no longer able to respond to important internal or external cues that check its growth. In this review, we will discuss the impact of markers of tumor proliferation on our understanding of tumor growth and response to therapy; we will examine the alterations in several cell cycle regulatory genes as they have been described for human brain tumors with an emphasis on those described in pediatric brain tumors; finally, we will provide data which argue cogently for the targeting of cell cycle genes as a novel means by which the process of cell proliferation in pediatric brain tumors can be directly inhibited. Cell Proliferation Markers The human brain is a unique organ from a cell kinetic standpoint. Neurons become incapable of cell division in the early postnatal period. Although glial cells retain their proliferative potential, as is demonstrated in the process of reactive gliosis, it is still unclear what the initiating events are that transform a normal cell into a highly proliferative malignant brain tumor cell. However, a number of studies have now been performed which have characterized the proliferative indices of human brain tumors, including pediatric brain tumors. The original cell kinetic studies conducted by Hoshino et al. [5–9] on brain tumors