Journal Club: Cancer Biology

Contributor
Graduate Division

Presentation: “Multiple Roads to Cancer Immortality”

Presenter: Brad Stohr, MD, PhD

Paper: Hu J., et al. Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell. 2012 Feb 17;148(4):651-63.

In a nutshell:

Cancer is largely a game of chance.  Cells become cancerous when they acquire certain mutations, and the probability of acquiring these mutations rises with the number of cell divisions, which increases with age.  This is why cancer is more prevalent among older people.

Our cells, however, have developed a number of ways to deal with the mutations that arise from our mistake-prone DNA replication machinery. They have multiple DNA repair mechanisms, for instance, and they have telomeres to protect the ends of chromosomes.

This is where our replication machinery blunders the most, each time failing to copy a small portion of our genetic material at the ends.  Our telomeres shorten over time as a result, sacrificing themselves for the more important genes.  When telomeres become too short, our aged cells reach a point called crisis, and they either die or become senescent, which is suggested to be a permanently non-dividing state.

Telomerase is an enzyme that adds a bit of DNA sequence back onto the ends of telomeres to keep them from shortening too quickly.  Telomerase is more active in stem cells and rapidly or regularly dividing adult cells, such as those in the gut or immune system.  Increasing telomerase activity in adult cells can also potentially lead to cancer, as it can allow the cells to escape senescence indefinitely and become immortal.

In this paper, the authors found that reactivating telomerase indeed promoted tumorigenesis.   Mice with short telomeres and reactivated telomerase had more tumors and tumors that were more aggressive. (Specifically, if telomerase was reactivated in tumors, it could promote increased malignancy.)

The authors then maintained telomerase loss over several generations, which they described as genetic extinction of telomerase. This initially inhibited tumor growth, reinforcing the idea that telomerase can promote the development of cancer. But alas, cancer cells are pretty smart and manage to evade just about anything given enough time.

So eventually, over subsequent generations of mice, the authors saw a re-emergence of tumor growth.  They determined that these cancer cells without telomerase had developed another survival mechanism, called alternative lengthening of telomeres (ALT), which is similar to normal DNA repair mechanisms.  More importantly for us, ALT appears to be a mechanism used by some human cancers, hinting at another possible therapeutic approach.