Cancer Research

Hallmarks of Cancer 3: Immortality

Figure from Hanahan, Douglas, and Robert A. Weinberg. “The hallmarks of cancer.” cell 100.1 (2000): 57-70.

 

Mortality

Most of the cells in your body do not have an limitless ‘replicative potential’ – they cannot continually divide and produce new ‘daughter’ cells forever*. For most cells mortality is a safety backup that means even if a cell becomes damaged and mutated it won’t live forever. At the end of the cell’s replicative life it will die and the mutations will be lost with it.

The clock is ticking

Cells have an inbuilt clock that tells them when their time is up. Chromosomes, packets of DNA that hold our genetic information, have protective caps on their end called telomeres that shorten on each cell division. When the telomeres get too short the DNA unwinds and the cell dies. It’s a bit like shoelace aglets (the hard plastic bit at the end), over time the aglet gets damaged and shortened until one day it falls off and the shoelace unwinds.

Cancer cells become immortal

One of the hallmarks of a successful cancer cell is it’s ability to regenerate its telomeres – preventing them from shortening after each cell division. This is done by an enzyme called telomerase, a protein that is over expressed in cancer cells, that adds sections of DNA back onto the telomere end. By lengthening the telomeres the cancer cell gains limitless replicative potential. Telomerase is not expressed by the majority of healthy cells making a targeted telomerase inhibitor a potentially deadly target in the fight against cancer.

Image from nextbigfuture.com

Targeting telomerase

Whilst the development of an anti-cancer telomerase inhibitor has proven more difficult than originally expected, recently a telomerase inhibitor called imetelstat has produced promising results. Imetelstat induces telomere shortening and cell death in multiple cell types. This compound, also known as GRN163L, inhibits the production of the telomerase molecule and is currently progressing through phase I and II clinical trials. It is being used either as a standalone therapy for blood borne malignancies (like leukaemia and multiple myeloma) or as  an adjunct therapy, in combination with other chemotherapy drugs, for solid state tumours such as breast and lung cancer.

Cancer Immunotherapy

Telomerase is also an attractive target for cancer immunotherapy – a therapy that harnesses the body’s own defence systems to target cancer cells. Current immunotherapy clinical trials are teaching the immune system to produce antigens against cells expressing ‘hTERT peptides’ on their surface. These peptides indicate the cell is expressing telomerase and, if the immune system can be taught to identify these markers, cancer cells will be lit up like Christmas trees, ready for the body’s own defences to come and destroy these mutated cells.

Understanding the basic biology of cancer cells is allowing scientists to invent new ways of targeting cancer cells without harming the normal surrounding cells. To find out more about targeting telomerase you can read the Nature Medicine News article “No end in sight for telomerase-targeted cancer drugs

This is part 3 of the Hallmarks of Cancer Series (go back for part 1 and 2)

References:

Dosset, Magalie, et al. “Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor.”Clinical Cancer Research (2012).

Buseman, C. M., W. E. Wright, and J. W. Shay. “Is telomerase a viable target in cancer?.” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 730.1 (2012): 90-97.

* There are some exceptions, small numbers of dormant ‘adult stem cells’ are present in you tissues and organs that are activated during normal tissue growth and repair.

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