Alternative Lengthening of Telomeres
Some cells that do not produce telomerase are still able to maintain telomere length. Roger Reddel,[5] of the Children's Medical Research Institute in Sydney, Australia, is investigating this phenomenon, which is known as "alternative lengthening of telomeres" (ALT).[6] Although little is known about how ALT occurs, it has been shown to take place in some tumor cell types, such as osteosarcomas, soft tissue sarcomas, glioblastomas, and nonsmall-cell carcinomas of the lung. Examination of the chromosome ends in these cells revealed that they had telomeres of varying lengths, ranging from very short to very long. This indicated that the cells did not seem to sense or respond to telomere length.
Reddel and colleagues fused an ALT cell line with 7 different telomerase-positive cell lines, to see if one pathway could suppress the other. Six of these fusions resulted in suppression of the ALT pathway, and 1 fusion resulted in loss of telomerase activity. Cells with ALT activity accumulate nuclear bodies that contain short DNA fragments, telomere-binding proteins, and DNA recombination proteins. As a correlation was found between telomere length and the presence of these nuclear bodies, formation of these bodies might be an alternative way for cells to lengthen telomeres in the absence of telomerase.
Reddel's group has developed a method to detect ALT in tumor samples, which involves immunostaining paraffin sections for nuclear bodies. Using this technique, they showed that 16 of 34 osteosarcoma samples and 17 of 38 soft-tissue sarcoma samples tested had ALT. In a patient cohort of 77 individuals with grade 4 osteosarcoma, ALT was associated with longer survival time, even though both pathways allowed crisis escape and the cellular growth rates were similar. This suggests that telomerase upregulation is associated with more aggressive tumors, and ALT might be used as a salvage pathway when telomerase is inhibited.
Medscape General Medicine. 2003;5(1) © 2003 Medscape
Cite this: Kristine D Novak. Telomeres and Telomerases in Cancer - Medscape - Jan 24, 2003.
