Lab rats... or lab lizards?
Bridget Murphy investigates how reproduction in reptiles may help us better understand the evolutionary history of cancer as well as identify new targets for treatment.
It all starts with a single cell, a cell genetically different from the rest in the body. This cell doesn’t have an identity yet and has the potential to develop into any cell type in the body. The single cell divides, repeatedly and rapidly, to form a growing clump of cells. The body’s immune system does not recognise or attempt to destroy the alien cells, which are very effective at “hiding” themselves from the host’s immune system. With the body powerless to halt their rapid growth, the cells continue to grow, unchecked, and begin to tap into the blood supply of the host. The invading cells have now secured the oxygen and nutrients they need to continue to invade and parasitise the body…
This foreboding description sounds like the birth of a cancerous tumour, spreading uncontrollably through the body. But actually, it also perfectly describes the first stages of embryogenesis, when a fertilised egg divides to form a ball of cells that implants into the wall of the uterus at the beginning of its development.
The similarities between a growing cancer and a developing embryo have long been recognised. In fact, the commonalities are so striking that some scientists think that embryos and cancers share an evolutionary connection. To understand this concept, we need to delve hundreds of millions of years back into our evolutionary past, to a time when the ancestors of modern-day mammals laid eggs instead of giving birth to live young.
Embryos and cancerous tumours grow in similar ways. Photo: Nadav Pezaro
Scientists think that our egg-laying ancient ancestors might have been less susceptible to cancer than modern humans because they laid eggs (Medical Hypotheses, vol 66, p 888). This is because as the ability to give birth to live young evolved in our ancestors, a series of gene systems also evolved. Among other things, these gene systems helped to prevent immune rejection of an embryo during pregnancy. They also allowed embryos to produce blood vessels in their placenta, helping to shuttle oxygen and nutrients between the mother and her baby.
Giving birth to live young instead of laying eggs has definite advantages for an animal, but, unfortunately, evolutionary advantages come with side effects. Scientists think that these same gene systems that developed during the evolution of live birth are also the systems that result in cancer cells being so successful at growing and spreading throughout the body. In other words, live-bearing animals (including humans) can’t have their cake and eat it too.
It is sobering to think that cancer, a disease that always seems to be one step ahead of the treatments we develop, may be woven inextricably into our evolutionary history. But researchers hope that this evolutionary connection will allow them to better understand cancer’s arsenal and will help identify new ‘chinks in the armour’ that they can exploit to treat the disease.
But how do you study evolution once it’s already happened? Live birth evolved in the ancestors of rats and mice, the animals usually used in research, about 103 million years ago (Science, vol 294, p 2348). Surprisingly, it’s probably not mammals that will provide the answers about what happens during the evolution of live birth, but lizards and snakes.
More than 20% of snakes and lizards give birth to live young, and live birth has evolved more than one hundred times in the reptile family tree. In fact, scientists have recently discovered an Australian lizard that is right in the middle of this evolutionary process.
The lizard in question is three-toed skink (Saiphos equalis). Living most of its life underground, the three-toed skink is approximately 10 cm long and has tiny legs, each with three toes, helping it slither snake-like through narrow tunnels in the soil. It has a bullet-shaped head, allowing easy burrowing, and its small eyes are ultra-sensitive to light.
The three toed skink (Saiphos equalis) gives birth to live young. Photo: Nadav Pezaro
Scientists think that the three-toed skink is at an “intermediate stage” of the evolutionary process (Journal of Morphology, DOI: 10.1002/jmor.10877). Its egg-laying relatives lay eggs with a thick shell that make take months to hatch, while its live-bearing relatives give birth to fully-developed babies surrounded by a placenta instead of an eggshell. The three-toed skink is somewhere in the middle, laying eggs with very thin translucent eggshells that can hatch in less than 24 hours.
Just as transitional forms in the fossil record can help retrace steps in the evolutionary process, the three-toed skink could tell us more about what happens during the evolution of live birth. New research suggests that this lizard may also harbour secrets about the important evolutionary connection between embryos and cancer.
A rare gene, called VEGF 111, was found expressed in the placenta of the three-toed skink, where it promotes the growth of blood vessels (Journal of Experimental Zoology, vol 314B, p 148). The only other place that medical scientists had seen this gene before was in precancerous human cells grown in the laboratory (Journal of Cell Biology, vol 179, p 1261). It seems that VEGF 111 is a gene that is important for placental growth and maybe also for the evolution of live birth in the three-toed skink, but it is possibly also involved in the transformation of healthy human cells to cancerous ones.
VEGF 111 may be another example of a genetic system that first evolved to allow embryos to grow successfully in utero, but has since been hijacked by cancer cells to improve their own growth. It is information like this that can identify the ‘chinks in the armour’ that cancer researchers are looking for, providing potential targets for future drugs and therapies. The new lab rats in cancer research may, in fact, be lab lizards, if scientists continue to investigate the disease from this novel perspective.
