Why are cancer cells immortal?

Cancer cells are unique in many ways. They divide uncontrollably forming lumps of cells called tumors. They do not stick to each other like normal cells and can float away to other locations forming additional tumors. And unlike normal cells, cancer cells are immortal.

Many pathways contribute to why cancer cells are immortal. Some of them are known while others are still obscure. However, the immortality of cancer cells is one of the key characteristics that make advanced cancer so lethal and so untreatable. Identifying various pathways that get activated or inactivated in cancer cells during their immortalization can provide us with targets for cancer monitoring and treatment.

What does it mean for a cell to be immortal?

One of the hallmarks of cancer cells is that they are immortal. They can continue to divide over and over without dying. On the other hand, normal body cells have a finite lifespan. After dividing to make new cells a certain number of times, the cells enter senescence (a dormant period) or apoptosis (cell suicide). Healthy human cells can divide and reproduce at most 50-60 times. Long-living cells in the body, such as the brain’s neuron cells which last a lifetime, and the cardiac muscle cells which live for about 40 years do not divide.

Tracking age through telomeres

One of the ways dividing cells keep track of their age is through their telomere length.

Telomeres are regions at the ends of chromosomes that protect the integrity of the chromosomes and allow the cells to divide successfully. Telomeres are long pieces of DNA composed of hundreds of repeats of specific short sequences, such as the “TTAGGG” sequence in vertebrates. The role of telomeres is to prevent the chromosomes from tangling up during cell division.

Every time a cell divides, the telomeres at the ends get a little shorter. After a number of cell divisions, the telomeres get so short and frayed that they can no longer protect the ends of chromosomes. When the cell begins another division cycle, the chromosomes, now with sticky ends, become tangled and unable to separate enough to support division. The cell then enters senescence or apoptosis and dies.

Most cancer cells evade senescence by continuing to grow their telomeres enough that they don’t lose them even as the cells go through multiple divisions.

How cancer cells keep growing their telomeres

There are two main known mechanisms by which cancer cells protect their telomeres, and different cancer cells use one or the other.

1. Transcriptional activation of a gene called TERT.

Located on the short arm of chromosome 5, the Telomerase Reverse Transcriptase gene, or TERT, provides the template for the cell to produce a catalytic subunit of telomerase. The telomerase complex has many functions including the addition of the sequence TTAGGG repeatedly to the telomeres thereby extending their length and protecting them through successive cycles of cell division.

In the healthy state, TERT is activated in stem cells, preventing them from entering premature senescence. In differentiated cells, TERT expression is repressed.

However, TERT expression is activated in 90% of cancer cells. In many of them, TERT enables the abnormal lengthening of telomeres allowing the cells to survive unlimited cell divisions.

Scientists have observed that using drugs or gene therapy to inhibit the abnormal activation of TERT can be useful for killing cancer cells when this approach is used in combination with radiation therapy. In mice studies, the use of a TERT inhibitor called NU-1 in combination with radiation therapy was helpful in killing cancer cells.

2. Activation of alternative lengthening of telomeres (ALT)

About 10-15% of cancer cells achieve longer telomeres by activating a DNA repair mechanism called alternative lengthening of telomeres (ALT). A wide variety of cancer cells with ALT hallmarks such as heterogeneous telomere length and ALT-associated promyelocytic leukemia nuclear bodies (APBs) fall into the ALT category. Since this mechanism is known to affect a minority of cancers, it was not studied extensively until about a decade ago.

However, the mechanism is active in highly aggressive cancers such as in 49-86% of osteosarcomas which are the most common primary bone cancer in children and young adults. The ALT mechanism is being actively studied by scientists, hoping to discover some therapeutic targets in ALT cancers.

According to some new studies, yeast cells with similar ALT mechanisms may not be immortal as previously thought but just have very long lifespans compared with other cells. After a number of cell divisions, the cells reached replicative senescence. If this is true for human ALT-associated cancer cells, drugs targeting senescent cells may help achieve a breakthrough in treating ALT-associated cancers.