Can Placenta Be a Model to Study Tumour Invasion? NTU's Dr Sivasubramaniam Explains at SciBar

First we look at the rationale for chemotherapy. Normal, healthy cells grow, have a controlled cell division, do their function and then die. Sometimes the cells turn into tumour initiators, then you get rapidly dividing cancer cells. These become spheroids, or stem-like cells, and this is when cancer symptoms usually occur.

If we can detect the cancer early enough, then we can target it with chemotherapy. The chemotherapy will only work in the rapidly dividing cells including these stem-like cells. However, there are some healthy cells in the body that also divide rapidly, such as hair follicular cells, intestinal mucosal cells, ovary oocytes, the testes and bone marrow cells. The chemotherapy would also kill these cells and this is what leads to side effects such as hair loss, ulcers, infertility and anaemia. Many deaths are actually caused by the chemotherapy rather than the cancer itself.

We do not have a model to examine the effects of chemotherapy on good, rapidly dividing cells. Could we use the placenta? The placenta is amazing – it allows gaseous, nutritional and excretal exchange, as well as foeto-maternal communication, for example food cravings. It performs the endocrine function and it is an immune barrier that stops the mother's immune system from attacking the "alien" cells from the father in the foetus.

The precursor to the placenta are the trophoblast cells. These rapidly divide and "invade" into the womb. Some researchers in China and Canada have managed to extract these cells following abortions and can now make them grow indefinitely. These cells have a number of similarities with cancerous cells:

• Proliferation
• Dissociation
• Invasion
• Capacity to evade host immunity
• Establishment of nutrient supply
• Vasculogenesis

However, there are still some differences. A tumour will invade while differentiating while trophoblast cells differentiate and then invade. With the cancer, it is an uncontrolled invasion while it is transient for the trophoblast cells. The trophoblast would be considered a "well behaved tumour" rather than a malignant one. Having said that, both do contain stem-like cells. So, can trophoblast cells be in vitro models to study the toxicology of chemotherapeutic drugs?

We can't collect these cells straight from the mother as that would be unethical. So, we go to the banks in China and Canada for cells. However, these cells have had to be transformed so that they can survive outside of the womb. The cell lines are very good at growing on a plate so they grow in 2D but we need them in 3D to be an accurate model for the human body. There are a few things we need to check to see if it is a good model:

• Do these trophoblast cell lines retain stem-like characteristics?
• We can check for the expression of certain markers.
• Can these cell lines grow in 3D culture while retaining stem-like characteristics?
• We can grow them in a 3D culture and the check for those same markers.
• Can these cell lines produce drug resistant phenotypes?
• We can treat them with a chemotherapeutic drug and see what happens.
• Can these phenotypes retain invasiveness?
• We can do an in vitro invasion analysis.

Then comes testing the hypothesis. Firstly, the parental cells are grown in normal 2D conditions, then they are treated with doxorubicin, one of the cheapest chemotherapeutic treatments. Then they are grown in normal 3D conditions and finally the spheroid cells are treated with doxorubicin. A qualitative confirmation is also done for stem-cell markers. The cells from Canada expressed stem-cell markers but those from China didn't show OCT4 in 2D. However, they did express it in 3D and for both cell lines the expressions of the stem-cell markers increased in 3D. Invasion also increased with the 3D spheroid cells.

In conclusion, the transformed trophoblast are capable of producing spheroids. Untreated spheroid bells have shown the highest invasive potentials. So, it may be possible to use these cell lines as non-tumour models with invasive capacities.

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