Cellular Immortality in Brain Tumors: An Overview

Abstract

Brain tumors are a diverse group of neoplasms that continue to present a formidable challenge in our attempt to achieve cures and a reduction in morbidity. Our conceptual framework of human brain cancer has been redrawn in the current decade. There is a growing acceptance that brain tumour formation is a phenotypic outcome of dysregulated neurogenesis, with tumors viewed as abnormally differentiated neural tissue. In relation, there is accumulating evidence that brain tumors, similar to leukaemia and many solid tumors, are organized as a developmental hierarchy which is maintained by a small fraction of cells endowed with many shared properties of tissue stem cells. Proof that neurogenesis persists throughout adult life, compliments this concept. Although the cancer cell of origin is unclear, the proliferative zones that harbour stem cells in the embryonic, post-natal and adult brain are attractive candidates within which tumour-initiation may ensue. Dysregulated, unlimited proliferation and an ability to bypass senescence are acquired capabilities of cancerous cells. These abilities in part require the establishment of a telomere maintenance mechanism for counteracting the shortening of chromosomal termini. A strategy based upon the synthesis of telomeric repeat sequences by the ribonucleoprotein telomerase, is prevalent in ~90% of human tumors studied, including the majority of brain tumors. This review will provide a developmental perspective with respect to normal (neurogenesis) and aberrant (tumourigenesis) cellular turnover, differentiation and function. Within this context our current knowledge of brain tumour telomere/telomerase biology will be discussed with respect to both its developmental and therapeutic relevance to the hierarchical model of brain tumourigenesis presented by the cancer stem cell paradigm.