The Phenotypes of Cancer – Cell Immortalization.

Hello there

Now, as already mentioned before on this blog, and as is well known in the scientific literature, cell immortalization, also called the development of infinite replicative potential, is one of the hallmarks of cancer

When a line of cells is called ‘immortal’ , it means that it can be grown indefinitely in cell culture as long as nutrition and oxygen is available. In cell lines that are not immortal even if you continue to supply nutrition and a favourable growth environment, cells stop dividing but remain metabolically active, have increased cytoplasm size and basically end up looking like fried eggs. We call such cells senescent

Cancer cells, or at least the subset that is capable of giving rise to tumours, don’t enter a state of senescence, they continue to divide, i.e, they are immortal.

To be able to understand why some cell lines are immortal and some enter senescence, one needs to be aware of what we call the end replication problem. Now there are caps at the end of chromosomes, made of DNA, that we call telomeres, these telomeres protect the ends of chromosomes from fusing with the ends of other chromosomes, in effect, they serve a kind of protective function.

Telomeres have been labelled using FISH, they are the yellow dots at the ends of chromosomes.

There is a slight kink in DNA replication that we call the end replication problem, the problem is that at one stage of DNA replication, RNA primers, on the lagging strand if I remember correctly will be removed and replaced with DNA by DNA polymerase III provided there is a 3′-OH for it to bind to, but in organisms with a linear genome this is not available, which means that the length of DNA that corresponded to the RNA primer during replication will not be duplicated. This results in telomere shortening.

Once telomeres are so short as to not be able to prevent chromosome to chromosome fusion, cellular crisis occurs. In cells where the pathways of apoptosis (programmed cell death) are fully functional such cells undergo apoptosis, but in cancerous/pre-cancerous cells with impaired apoptosis, they begin to undergo fusion-breakage-fusion cycles, which generates genomic instability and lots and lots of genomic variation. In some cases this leads to a dead end and cells end up with so much genomic instability that they are screwed. But in some cases, the extensive amounts of duplication, amplification and translocation that take place can generate genotypes that are positively selected for, and this can be a key point in the evolution of malignant disease.

Illustration showing how telomere shortening can, conditional to defunct apoptosis induction, trigger the genomic instability needed to evolve variation and reactivate telomerase.

This is often conditional on cells learning to stabilize their newly acquired variant genomes by reactivating pathways of telomere maintenance, of which there are two. One, which is the telomerase pathway, is the one found in a majority of cancer cells, the other is called the ALT pathway (or Alternative Lengthening of Telomeres) pathway.

The telomerase pathway.

Telomerase, which was first discovered in Tetrahymena thermophila(I have no idea how that name came about)
is a multi-unit enzyme that is capable of extending telomeres so that the end replication problem does not result in telomere shortening, it does this by adding the telomere repeat unit sequence to the parent DNA, which is extended before replication.

The way telomerase works has been illustrated below, reference Telomerase and cancer therapeutics, Calvin B. Harley, doi:10.1038/nrc2275

Click on the image to bring a larger version up.

Now telomerase not only stabilizes the genome and enables tumorigenesis to proceed, it also has the effect of suppressing apoptosis (See here for a reference)and upregulating the genes and pathways required for EMT (Epithelial Mesenchymal Transition) which is required for metastasis. Some evidence for this may be found here with particular reference to melanoma.

The ALT Pathway

The Alternative Lengthening of Telomeres pathway involves the use of homologous recombination to maintain telomere length, there are currently several mechanisms and models that have been proposed by which the pathway may function, and insofar this article is concerned those mechanisms are beyond the scope. However, if you so desire you may read an apposite in-depth review here (PDF).

Further reading material

Nature Scitable article on Telomeres of Human Chromosomes

Watch a video on the action of telomerase, here

Read a review of telomeres and telomerase in cancer here

The discovery of telomerase won its discoverers the Nobel Prize, read an illustrated presentation of what they did at the official Nobel Prize website here

You will also be able to find the researchers’ Nobel lectures using the tabs on the same page.

I hope you enjoyed reading this.

– Ankur ‘Exploreable’ Chakravarthy

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