Australasian Science Magazine

The same protein found in pre-cancerous skin cells helps blood vessels to grow in the placenta of the three-toed skink (Saiphos equalis). Photo: Nadav Pezaro

By Bridget Murphy

A gene found in a pregnant lizard may provide important information about the origins and treatment of cancer in humans.

Cancer cells always seem to be one step ahead of medical researchers. Tumours grow and spread by piggy-backing on the molecular systems in our body that evolved to keep us healthy. This is part of why cancers are so difficult to treat – because drugs often hurt healthy cells as well as the cancerous ones.

Recent research shows that cancer cells are using the same genes that first evolved to allow pregnancy in animals. For example, embryos and cancer cells both use the same genetic systems to avoid immune rejection.

During pregnancy, the embryo must come into contact with its mother’s uterus. Since the embryo is genetically different from its mother, this situation is not unlike what happens during organ transplants, where the patient needs to take immunosuppressant drugs to prevent their body rejecting the donated organ. The mother’s immune system should identify the embryo as foreign and attack it, but this obviously doesn’t happen too often because healthy babies are born all the time.

So how do embryos avoid immunological rejection? In part, this process involves “switching off” some of the immune genes on the surface of the embryo’s cells that identify it as foreign, effectively allowing the embryo to hide from the maternal immune system and avoid rejection.

Cancer cells are the body’s own cells, but they have undergone mutations that make them genetically different from the rest of the body. In a clever display of evolutionary resourcefulness, cancer cells use the same mechanism as embryos to hide from the body’s immune system, switching off the immune genes that identify the cells as foreign.

This is just one of the many disturbing similarities between embryonic development and tumour growth. Years of experiments using rats, mice and some primates have uncovered many more examples.

An Unconventional Lab Rat
New evidence from an unexpected discovery in a native Australian lizard may be able to tell us more about how our normal cells change into cancerous ones. Living most of its life underground, the three-toed skink (Saiphos equalis) is an animal perfectly adapted to its habitat. Evolution has reduced the legs of this lizard to little stumps, each with three toes, allowing the lizard to slither, snake-like, through the soil. Its bullet-shaped head allows it to burrow easily, and its small eyes are ultra-sensitive to light.

The three-toed skink is also viviparous, which means females give birth to live young (viviparity) instead of laying eggs (oviparity). This lizard’s reproductive strategy may seem just as curious as the rest of its behaviour, but it is by no means unique in this respect.

Most of us associate live birth only with mammals, but reptiles are actually better “lab rats” for studying the evolutionary history of this type of reproduction. About 20% of snakes and lizards are viviparous, and they are the result of more than 100 separate evolutionary transformations on the reptile family tree.

In contrast, all mammals (except for monotremes, the echidna and the platypus) are viviparous, but live birth in mammals is the result of an evolutionary change that happened just once in a common ancestor of all the present-day mammal species.

The Evolution of Live Birth
Researchers are now studying all the separate evolutionary events of reptiles and mammals to discover what they have in common, and whether viviparity may have evolved in reptiles and mammals in similar ways.

Evolutionary biologists think that viviparity in reptiles may have evolved in response to cold or fluctuating climates. The majority of viviparous species seem to be concentrated in higher latitudes and in high altitude regions where temperatures are lower and more variable. In low or fluctuating temperatures, eggs laid by oviparous females are subject to sub-optimal and potentially lethal temperatures.

The theory suggests that females that are able to hold embryos inside their uterus until embryonic development is complete are able to keep their body temperature, and the temperature of the embryo, within a safe range by basking in the sun or hiding under warm rocks. This is still just a theory, because while we know what the present-day climate conditions are, we can’t be sure what the climate was like when these evolutionary changes actually happened.

For a successful pregnancy, a viviparous mother needs to be able to transfer oxygen, food and water to her developing baby. In both mammals and reptiles, these resources are transferred via the placenta, where the uterus and the embryo come into contact with each other to allow the transfer of oxygen and nutrients to the baby.

Reptilian placentas have intrigued zoologists for more than 150 years, ever since an Italian scholar described the structural relationship between the uterus and embryo in a pregnant lizard. Placentas in mammals and reptiles have evolved independently, but both have evolved from the same basic components, and recent comparisons of the two are revealing surprising similarities in their structure and function.

Both mammalian and reptilian placentas are full of blood vessels, which speed up the transfer of materials between the mother and foetus. As the embryo develops and its needs for oxygen and nutrients increase, more blood vessels multiply from existing ones in the placenta.

A number of genes control the growth of blood vessels in the mammalian placenta, but some of the most potent are vascular endothelial growth factors (VEGF). This family of genes makes blood vessels grow by causing the cells in the blood vessel wall to divide and multiply.

A Serendipitous Discovery
As part of my PhD, I wanted to find out whether viviparous lizards use the same genes as mammals to promote blood vessel growth in their placenta during pregnancy. I started looking for VEGFs in the placenta of some viviparous lizards found in NSW: the eastern water skink (Eulamprus quoyii), the southern grass skink (Pseudemoia entrecasteauxii) and the three-toed skink.

All three lizards contained two common types of VEGF in their placenta – the same types that are present in the placenta of mammals. This indicated that both mammals and viviparous lizards are using VEGFs to promote blood vessel growth in their placentas.

But an additional third type of VEGF turned up in the placenta of the three-toed skink, a type not associated with the mammalian placenta. In fact, the only other place that medical scientists had seen this type of VEGF before was in precancerous human cells grown in the laboratory.

This third type, called VEGF111, is a gene with a split personality. It looks as if this gene is really important for placental growth in the three-toed skink, but it also may be involved in the initial transformation of healthy human cells to cancerous ones. VEGF111 may be another example of a genetic system that first evolved to allow the embryos of viviparous animals to grow successfully in utero, but has since been hijacked by cancer cells to improve their own growth.

In the future, researchers will be able to use the three-toed skink to find out more about how VEGF111 works. If we can figure out how to disable this gene in a lizard, this strategy may form the basis of next-generation cancer treatments, or even cancer prevention.

This research highlights that rats and mice aren’t always the answer to questions in medical science. Other animals, including lizards, provide such fantastic opportunities for medical research but are so often overlooked because they aren’t as easy to keep and breed as rats and mice.

I hope to keep studying our amazing Australian reptiles to find out more about how live birth evolved and what this might mean for cancer and other human diseases.