Beating the Odds of Cancer: Not Just a Tall Tale

elephants_webWhen it comes to combating cancer does size matter? If every cell in the body has the propensity to become cancerous, it should naturally follow that larger animals that pack greater number of body cells and that those whose cells undergo greater number of cell divisions are more likely to develop cancer. By the same logic, organisms with longer lifespans must also have a greater chance of accumulating mutations leading to cancer. Surprisingly, the risk of developing cancer is only 5% in elephants and 18% in whales whereas it is as high as 30% in humans and rodents.  The apparent lack of correlation between body mass, longevity and cancer- known as Peto’s paradox- has flummoxed scientists for several decades.1

A recent study published in Journal of the American Medical Association  by  Abegglen and colleagues has unlocked the secret weapon held by the pachyderms in fighting cancer2. While the weapon itself might not be new to cancer biologists, the stash carried by these marvelous animals is the highest recorded for any living species so far. To understand this weapon let’s revisit the coping mechanisms developed by cells to prevent cancer. When mammalian cells are exposed to cancer inducing treatments, such as UV radiation for example, a gene encoding TP53, kicks into gear making copies of the tumor suppressing protein of the same name. TP53 acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way. It does so by either repairing any damage to the cells caused by the UV exposure or by killing off the cell by a self-destructing mechanism known as apoptosis which is akin to committing suicide.

Many mammals, including humans carry only two copies of this important gene; one copy or allele is inherited from each parent. If the TP53 gene is inactivated by mutations, the risk of developing cancer increases by several fold. A rare but lethal condition called Li-Fraumeni Syndrome marks patients who have only one working copy of TP53 with more than a 90 percent lifetime cancer risk from childhood into their adult years.  In a quest to investigate the unexplained resistance to cancer by elephants, the scientists combed through the elephant genome and stumbled upon 40 copies of genes that code for TP53. One pair was ancestral in origin, whereas the remainder appear to have diverged from the ancestral copy and were archived within the genome over the course of evolution as retrogenes. Continue reading “Beating the Odds of Cancer: Not Just a Tall Tale”

A “Spare Tire” for Proto-oncogene Promoters

A guanine tetrad (left) and G-quadruplex (right). Image courtesy of Wikimedia Commons.
A guanine tetrad (left) and G-quadruplex (right). Image courtesy of Wikimedia Commons.

Proto-oncogenes are genes that organisms rely on for normal growth and development but, when mutated or dysregulated, can cause cells to grow uncontrollably, resulting in cancer and metastasis. In some cases, a single DNA mutation is sufficient for cancer to develop. Why then, do so many proto-oncogene promoters contain strings of guanine residues, which are extremely vulnerable to DNA damage from factors such as oxidative stress and hyperinflammation, to control transcription levels? From an evolutionary viewpoint, this is a contradiction: DNA sequences that are the most vulnerable to damage and mutation are key to regulating one of the cell’s most dangerous classes of genes. This seems to be a recipe for genomic instability and disease. Fortunately, evolution has provided a very clever solution to this potential problem.

Continue reading “A “Spare Tire” for Proto-oncogene Promoters”