One aspect we’ve discussed before about cancer development is the requirement that the cells (more specifically cancer stem cells) become immortal, able to replicate into daughter cells indefinitely. This is seen most prominently in HeLa cells, cervical cancer cells taken from Henrietta Lacks, who died in 1951. These cells have an overactive telomerase enzyme and have continued to replicate in research labs around the world since they were collected.
Telomerase is an enzyme that adds short pieces of DNA onto the end of chromosomes (telomeres) after replication, necessary because the mechanism for replication shortens the telomeres with every round. If enough of the telomere is lost a signal is sent to the cell to quit replication. In stem cells and progenitor cells this signals the end of self renewal.
Another pathway able to produce renewal and proliferation is the Wnt/β-catenin pathway. This pathway has been shown to be important in maintaining cells in a stem cell-like state and are thought to be able to initiate tumorigenesis.
A paper published July 2 in Nature has shown how these two pathways are linked, finding a molecular bridge between the immortality and stem cell/proliferative pathways in the cell. The researchers were looking at a portion of telomerase called TERT (telomerase reverse transcriptase). Early looks at the molecule found that overexpression in mice could lead to anagen in the epidermis, the same result that happens when β-catenin is overexpressed.
Using the gastrointestinal tract of mice, where Wnt signaling through β-catenin is required for stem cell maintenance, the researchers showed that inducing TERT expression in the crypts significantly upregulated Axin2 expression, a gene target of the Wnt/β-catenin signaling pathway (figure b). This in vivo display of pathway convergence is great evidence for the link between the two. Furthermore, the research team used catalytically inactive TERT to show that its function in Wnt signaling is not based on its telomerase activtiy.
The link between these two pathways I guess shouldn’t be too surprising. In cells which are programmed to be stem cells and divide many times throughout an organism’s life it should be expected that a pathway to maintain chromosomal integrity would communicate with the pathway that is pushing the cell to divide. What may be surprising is just how intimately these two are linked with the actual telomerase enzyme associated directly with the chromatin and Wnt signaling targets.
Another reason I love this paper is the amazing images of Xenopus homeotic transformations. Since the Wnt pathway is also involved in axis formation and early patterning when you knock out TERT you do some weird things to the frog’s body plan. These images show how the vertebra and ribs are shifted from their location or display axis abnormalities, further putting the nail in the coffin for the link between TERT and Wnt signaling.
The significance of this finding may lead to another chemical therapeutic target in the future. Now two pathways may be able to be controlled in one swoop. Ideally a drug would be able to knockout TERT activity which would have the dual effect of ending immortality in that cell and forcing it out of a stem cell state. Since most cancers have the higher morbidity and mortality with more stem cell like cells in primary tumors this could be a means at a genetic double shot. Once you can get cells to commit to a differentiation status it is very hard for them to reclaim the ability to proliferate and produce daughter cells.
As the authors say:
“Our findings provide a mechanism to understand previous observations showing that TERT overexpression activates epidermal stem cells, as well as previous findings linking TERT to proliferation, survival and stem-cell biology in diverse contexts. Our data reveal unanticipated level of convergence between the telomerase and Wnt/β-catenin signalling pathways with important implications for understanding development, stem-cell regulation and cancer.”
Park, J., Venteicher, A., Hong, J., Choi, J., Jun, S., Shkreli, M., Chang, W., Meng, Z., Cheung, P., Ji, H., McLaughlin, M., Veenstra, T., Nusse, R., McCrea, P., & Artandi, S. (2009). Telomerase modulates Wnt signalling by association with target gene chromatin Nature, 460 (7251), 66-72 DOI: 10.1038/nature08137