Cholesterol, Enemy of the Immune System Against Breast Cancer - Professor Sérgio Dias
The idea of studying the effects of bad cholesterol in oncological diseases has been explored for several decades, but it was Sérgio Dias and his team of the Institute of Molecular Medicine (iMM) João Lobo Antunes that discovered that high levels of cholesterol decrease the immune system's ability to fight breast cancer cells.
Sérgio Dias: We have studied, for a number of years, the importance of lipids (fats) in cancers. My group has been interested in this for more than 6 years, and within systemic lipids, which can be measured in circulation, cholesterol has always been of great interest. Why? Because cholesterol, even in other oncological situations, ends up having different functions: it creates inflammation. Everybody is able to associate high levels of cholesterol with cardiovascular disease, heart attacks, strokes, but this relationship between inflammation and cancer is a relatively old idea in the field of oncological research. A few years ago, we started by showing that the cholesterol molecule - which is complex, and has the protein part, the lipid part - when interacting with breast cancer cells, when breast cancer cells are exposed to high levels of cholesterol, they absorb cholesterol, and use it as a source of energy to divide more. Thus, breast tumours, exposed to high cholesterol, eventually proliferate more, progressing more quickly.
And this is where the paths of the laboratories ran by Sérgio Dias and Bruno Silva Santos, also a researcher and Vice-Director of the iMM, reach a crossroads. While Bruno Silva Santos' laboratory states that T lymphocytes, multiplied many times by themselves (around 1 billion) and with chemical and biological compounds, reinforced the immune system against cancer, Sérgio Dias and his Lab say that cholesterol can mitigate the effectiveness of the lymphocytes.
Sérgio Dias: In this more recent study, what we have come to demonstrate is that the pro-inflammatory effect of cholesterol, that is, the effect of facilitating inflammation, also exerts effects on the immune system. So, what are we revealing? A student that we have in common, Neidy Rodrigues, whose Ph.D. I am supervising, while Bruno is acting as joint supervisor, was studying the effect that high levels of cholesterol would have on a subtype of lymphocytes that has an anti-tumoural effect, in our specific case, in breast cancer. What we have confirmed is that these lymphocytes, when exposed to high levels of cholesterol, stop functioning normally, that is, they cannot exert their anti-tumoural effect. Their ability to recognise tumour cells and, subsequently, to trigger a response by releasing factors that kill these tumour cells, is severely diminished. The message we seek to convey in our paper is that, if there is an attempt to develop immunotherapeutic strategies, that is, immunotherapy against cancers, such as breast cancer, in the presence of high levels of cholesterol, if the host has high levels of cholesterol, these anti-tumour responses may be diminished.
And what are high levels of cholesterol?
Sérgio Dias: I would say that we are always talking about figures above 200 mg/dL. There are people who have, via family genetics, hypercholesterolemia, and these people have cholesterol levels, on the same scale, of 600/700mg/dl. We perform lab tests on mice and if we provoked this type of hyperlipemia in them then they would have serious cardiovascular problems because there would be a severe inflammation of the vessels.
Are the lymphocytes we're talking about only the T cells, studied by Bruno Silva Santos?
Sérgio Dias: For a few years, he studied a subtype of the T lymphocyte, gamma delta T cells. In our paper, we actually addressed the possibility of the effect of cholesterol on other cell populations of the immune system not being the same. We have only specifically studied this subtype of lymphocyte. Because it is in his group's interest and because of the idea of immunotherapy that he developed, based on the production, isolation and optimisation of these cells, so they can later be transferred to people. In animal models of breast cancer, these cells work exactly in that way, i.e. if we transfer gamma delta T cells, lymphocytes activated for animals with cancer, these cells are going to severely diminish the growth of the cancer, they're going to destroy tumours.
Why did you initially focus on breast cancer?
For two reasons, firstly because we wanted to try to understand the effect of fat, of lipids, on hormone-dependent tumours. As there is a very well-known biochemical relationship between the production of hormones and lipids, where lipid levels are important in guaranteeing an adequate hormonal production. Then, from the epidemiological point of view, older studies tried to establish a relationship, namely in women, between high levels of lipids and a greater risk of developing breast cancer. My group carried out a study, that started when I was still at the IPO, in which a group of more than 300 women diagnosed with breast cancer (excluding cases of familial hypercholesterolemia), those who had lipid levels above the normal threshold, had clinically more aggressive tumours, with the presence of metastases, with an increased proliferation of cells. Thus, the conclusion we present in the paper as a result of the study concerned the relationship between high levels of lipids (cholesterol) and more clinically aggressive breast tumours.
Sérgio Dias is a biologist. He graduated in the Faculty of Sciences of the University of Lisbon, got his Ph.D. at Cancer Research UK and completed his Post-Doctoral studies at the University of Cornell, in the USA. After 8 years abroad, he returned to Portugal, where he created a research group at the IPO Lisbon. He stayed there for almost 12 years, and then he decided to move to the iMM, after a challenge issued by João Lobo Antunes who wanted to focus strongly on the field of Oncology. Currently, apart from being a Group Leader, he is also teaching Oncobiology at the Faculty of Medicine of the University of Lisbon.
In his DNA, he has the right formula to bring together courage, and the spirit of entrepreneurship and change. He decided to work with the country's strongest research institute and address cancer, which is seen at the iMM as a systemic disease, where "the hosts and the way they deal with their cancer" are integrated.
He has been carrying out his work at the iMM and speaks about Science with his feet firmly on the ground that he treads, but without losing the magic of scientific curiosity.
His feet are firmly on the ground because he knows that in order for research to continue, researchers need cyclical subsidies that are only awarded if they apply for them. He also knows that financing can be national, or foreign, from public or private institutions. And it may or may not be granted. And even in the best of scenarios, with funding, he knows that tenders may not open every year, so the wait is long and must be well managed from the financial point of view. Even so, despite all of the strangulation that the economy and the country have been suffering, the State is still largely financing the wages and grants of the people who work with him.
In an paper recently published by Cornell University, where he completed his Post-Doctoral studies, they speak about a study that weighs talent versus luck, measuring whether the path points more towards to the success or to the failure of the many scientists who need funding to continue their research. Of the various methods studied, they conclude that funding should not be elitist, promoting only those who are already well known by the community.
Will Science be mostly a path for visionaries, or for people who were merely lucky when it came to choosing the project they are working on? And if the current scenario is less promising, why do they follow that path if they have no idea where they're going?
When asked how he finds the right motivation to continue researching diseases like cancer, which insist on not giving respite, he answers immediately. "Oh, that's easy, we are a group of people that share values and characteristics that stimulate us and help us to move forward: curiosity is the pleasure of studying, thinking about experiments and reaching conclusions."