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When evolutionary biologist Günter Wagner was still a child in Vienna, he watched a documentary on the Lipizzaner horses used in his city’s famous horse-riding academy. As he later learned, these horses were prone to developing skin cancers similar to those found in humans. Unlike their human counterparts, the Lipizzaner horses rarely died from their cancers, instead living long lives with chronic yet nonfatal disease. Wagner was fascinated by this breed’s remarkable resistance to malignant cancers, and nearly fifty years later, these performance horses would build the basis for his research comparing cancer to pregnancy.
Leading a team of scientists funded by an National Institutes of Health center grant, Wagner and systems biologist Andre Levchenko sought to identify the relationship between the method of embryo implantation within a species and the relative vulnerability of that species to malignant cancers. In placental mammals, embryos adheres to the uterine walls in two major ways. For some species, such as dogs and humans, the placenta embeds itself deep within the uterus. For others, such as cows and horses, the placenta remains on the surface of the uterus and is prevented from moving deeper in the maternal tissue. Clinical data on various mammals revealed a similar split when it comes to cancer. While dogs and humans are more likely to have their cancers spread throughout the body, cows and horses have a lower likelihood of initial invasion and thus malignancy. From their preliminary research, the team hypothesized that hoofed animals may have developed through evolution a method to both resist invasive embryo implantation and limit the spread of cancer. “I started to make the connection to this old memory about… Lipizzaner horses,” Wagner said, “and I thought, maybe there’s a connection between the ability of mothers to keep the placenta out and the ability of the [species] to minimize the invasion of cancer cells.”
The team acquired samples of human and cow stroma, a type of supportive tissue prevalent in the skin and the uteri of both species. The scientists isolated the stromal tissues in a culture with trophoblasts, the part of the embryo that develops into the placenta, and melanoma cells, both known for their invasive properties. Using the technique pioneered by the Levchenko group, they found that, on average, bovine tissue was more resistant invasion by the trophoblasts as well as cancerous cells, compared to human tissue. To further test the innate properties of the cow stroma, they sequenced the RNA of the bovine and human tissue samples. The team noticed that the cow cells showed a lower expression of genes regulating the interactions between stroma and cancer cells, allowing cows to better resist the spread of cancer. When the same genes were turned off in another sample of human stroma, the tissue was also able to resist melanoma invasion. This led the team to believe the cow stroma evolved a mechanism to better defend themselves against invasive cells.
Wagner and Levchenko aspire to change the public perception of cancer and how to treat it. “I think there’s sort of a split in the thinking about cancers,” Wagner said. “The mainstream way that people think about the cancer is that you want to target the cancer and… eliminate it or to kill it, which, by its very nature, also breeds resistance.” As of now, chemotherapy remains one of the most popular treatment options for cancer. However, cancer cells may become resistant to chemotherapy due to their rapid rate of mutation, which means that patients thought to be in remission could eventually return to a state of illness. The research led by Wagner and Levchenko offers an alternative to treating cancer, focusing more on managing cancer cells rather than eradicating them. “In a way, this strategy is similar to the recent revolutionary successes of immunotherapy, also relying on immune cells in the organism,” Levchenko said, “In this case the stromal cells can perhaps generate the key to anti-cancer defense, as seen in other species.” As Wagner puts it, “It’s a little bit less straightforward than just ‘Let’s kill them all.’ But I think [ours] might be the more intelligent strategy in the long run.” The research team is already one step closer to developing better cancer management plans.
Source:
Kshitiz, Afzal, J., Maziarz, J. D., Hamidzadeh, A., Liang, C., Erkenbrack, E. M., … Wagner, G. P. (2019). Evolution of placental invasion and cancer metastasis are causally linked. Nature Ecology & Evolution, 3(12), 1743–1753. doi: 10.1038/s41559-019-1046-4