According to Cancer Research UK, approximately 14.1 million new cases of cancer were reported worldwide in 2012. Cancer is a global issue that needs to be tackled on several different levels.
Text: Nicklas Hägen
CANCER RESEARCH in Turku, Finland, is being carried out at all levels ranging from fundamental biological research to the pharmaceutical research taking place both at the universities and in the city’s pharmaceutical industry. Clinical research is also undertaken at Turku University Hospital. Åbo Akademi University and the University of Turku with their shared facility, the Turku Centre for Biotechnology, are major players in this field.
A little bit like unmasking the villain right at the start of a detective story, let us cut straight to the chase: Lea Sistonen, Professor of Cell and Molecular Biology at Åbo Akademi University, will we ever be able to cure cancer?
“We can do a lot to tackle it already. For example, leukaemia in children was usually fatal 20–30 years ago, but today there is often a cure for it. Against this background we may not be able to foresee how the situation will develop,” says Sistonen.
“However, my personal belief is that we won’t eradicate cancer. I think that in many cases it will become a condition that the patient will live with. And patients can have a good life, as is the case with a number of other chronic diseases. I therefore consider it hugely important to develop better medicines and there is a lot to do in this respect, but I don’t think we will get rid of cancer completely.”
Why not?
“Cancer is incredibly adaptable – we’ve already seen that. It adapts well to different conditions and obstacles we try to put in its way. But as I have said, the situation may be different in 20 years’ time.”
Many different diseases
Cancer research is continuously moving forward, but the major breakthrough that would solve the riddle of cancer once and for all has failed to materialise to date. For every new insight gained, it is notable that providing an answer as to why cancer develops and what processes lie behind it is an increasingly complex task.
Or “it” is actually the wrong word. We normally refer to cancer as one disease, but a more accurate description might be to call it a group of different diseases with certain common denominators.
Lymphoma and leukaemia are forms of blood cancer that differ in character from the forms of cancer which develop as stationary tumours, for example. But the differences between these, too, are huge, depending on where the cancer is located in the body.
In fact, the situation is even more confused. A specific form of cancer, such as breast cancer or prostate cancer, doesn’t appear to consist of a single cell type. So it isn’t just that there are many different types of breast cancer, for example, with some being hormone-related and some not, but the individual tumour consists of many different types of cells.
“I carried out cancer research as a postgraduate student in the 1980s. The belief then was that all cells in a certain type of cancer were the same – that there was one cell that became a cancer cell and then made copies,” says Sistonen.
“Now we think differently, that actually different types of cells are involved. When we try to kill cancer cells, it is possible to kill maybe 95% of the cells, but there may be a few cancer stem cells that are not caught, and it is these cells that spread. The common factor in all forms of cancer is that they are malignant and – if they cannot be cured – fatal diseases. But cancer cannot be considered one disease.”
The DNA sequence in our genes has its molecular building blocks, the nucleotides, organised in a certain order. When changes, so-called mutations, occur in this order, these can ultimately cause cancer.
“Mutations occur every day, so it is a miracle that we don’t all have cancer all the time. We have many smart systems in the body that keep it under control,” says Sistonen.
Each time a cell divides, there are two or three control points in the cell cycle that check whether all chromosomes are in the correct order and whether the cell is ready to divide. If any error exists, the division is aborted.
After cell division, too, there are control points in the cell that react if something has gone wrong and eliminate the processes. Apoptosis, programmed cell death, eliminates poor cells that should not exist in the body.
“However, a number of errors can occur, for example if the control points are not as they should be. A mutation may take place in a gene that should code for a protein that is supposed to be in the control point, causing the protein to be absent or incorrectly structured. The errors accumulate and can ultimately lead to cancer,” says Sistonen.
“We can demonstrate relatively simply how individual cells become cancer cells in the model system, so we know what happens or can happen. If the cancer exists in the form of tumours, it is relatively easy to cure by removing them, but the metastases are the problem and it is these that cause death. The cells in the tumour can vary considerably – they are not homogeneous, as we once thought and some people may still think even now. Individual cells escape and resort to various tricks to survive, even during treatment. Cancer cells are extremely cunning in the way they exploit the body’s mechanisms and ingenious in the way they spread.
Lea Sistonen. Photo: Nicklas Hägen.
Inherent stress
Sistonen is not a cancer researcher by definition. In her research she studies cell stress. How the cells react to changes in temperature, acidity levels or pressure, for example, are questions that are much more fundamental in nature than more specific questions about how cancer develops or is cured. And yet it has turned out to be the case that cell reactions to stress factors appear to be closely linked to cancer.
“We try to understand how the cells function normally and to see how the processes are changed in different disease conditions. We use cell stress as a model system. This means that we investigate what happens in the genetic make-up and genes in connection with acute and chronic stress. Which processes are activated and which are toned down?”
Different stress factors influence our bodies constantly. The cells cannot know if the changes are temporary or permanent, and immediately trigger a stress defence mechanism, often by ceasing all activity and just waiting.
“The stress defence reactions are really old in evolutionary terms, some of the oldest functions we have in our cells,” says Sistonen.
“Even if the normal reaction to stress is that everything freezes and energy metabolism is minimised, there are certain genes that are active. Our job is to understand which genes are active when others are quiet and why this is.”
It has been observed that cancer cells handle stress situations better than the body’s healthy cells. Genes that are normally quiet or moderately active can be hyperactive in cancer cells. The cancer cells are de facto dependent on stress; they have inherent stress factors that keep them alive.
“When stress occurs, certain genes are activated that produce proteins, which protect the cells’ other proteins. These are chaperones, which have the job of ensuring that the cell’s normal functions are protected when the conditions are abnormal. The intention is that these protective functions should be active for a brief period and that everything should return to normal when the stress has passed,” says Sistonen.
“The cancer cells can exploit these functions also when the external stress is absent. They use this protection to make themselves stronger.”
Cell stress and how it affects the quantity of protective proteins can be used as a clarification model for many other diseases also, for example Parkinson’s Disease and Alzheimer’s, even if the clinical picture is completely different. But as we have already indicated above, cancer is a very broad disease, and while Sistonen refuses to assert that it could underlie all forms of cancer, she won’t rule it out entirely either.
Cancer takes away the lives of those who develop it by knocking out the body’s own functions. Paradoxically, it can be described as an extremely vigorous form of life.
“In lower organisms the stress reaction system exists in a similar form. These mechanisms have made the existence of life possible. Cancer is a very primitive life form, and its cells have one function only, which is to divide,” says Sistonen.
“All forms of cancer can overcome many types of functions and obstacles. They are able to do this because they eliminate all sophisticated functions. Their mission is simply to survive and multiply, and in this they remind us of the foetal stage, in which growth is all and more mass needs to be gained.”
Start out from a system that can be controlled
Lea Sistonen is engaged in what is called fundamental research. This means that she seeks knowledge without the primary objective of applying it in a certain way, for example by developing a new drug.
“We work at the cell and molecular level in model systems that can be controlled. We can investigate phenomena that may have significance for medicine, since they can only be discovered in a controlled system. If we go directly to complex biological systems such as the human being, we have no idea what we should be looking at,” adds Sistonen.
“We must study grubs and flies and yeast cells and mice, simpler systems, and get to the roots of individual phenomena, because it is too complex to try and go directly to man.”
Bruce A. Beutler and Jules A. Hoffmann were awarded the Nobel Prize in Physiology or Medicine in 2011 for increasing our understanding of the immune system by studying fruit flies.
“We have a group in Turku also trying to understand the immunity of fruit flies. It’s not that anyone’s worried about whether fruit flies are sick or not, but what is interesting is that they have an immune response to certain bacteria and viruses,” says Sistonen.
“Fruit flies are suitable for studying when attempting to understand genes, because they have fewer genes and they are mapped better than our own are. Without this knowledge we can’t move on to the complex system.”
From linear biology to systems
Research has now reached a point at which individual components of simplified systems have been investigated. A reasonable understanding has been gained of how the signals follow one another when the cell receives a stimulus, for example a growth factor or a heavy metal, and reacts to it.
The next major challenge is to combine what we know to form a picture of larger entities, but a problem with such system biology, as it is termed, is that the quantities of data involved are simply huge.
“Will a cell become active and divide when it receives a stimulus? Will it wait, forward the signal to another cell or perhaps die? We have taken a linear approach to this issue. Something external appears that passes through the membrane into the cell and is received by a signal molecule,” says Sistonen.
“But in reality a host of factors are involved, which are integrated into each other’s processes, come together and influence one another. All organs and all tissues consist of different types of cells. The cells are not isolated, but interact with one another.”
Sistonen says that cancer research needs to be linked better to metabolism.
“Cancer cells interact continuously with their environment, and they are not indifferent to it. They can ‘infect’ or influence their environment, just as the environment feeds the cancer cells and must therefore also be observed. They influence the metastasis properties; the tumours aren’t going anywhere without individual cells,” says Sistonen.
“Without the knowledge we already have we would not be able to investigate this. That is why interdisciplinary research is so important. We need people who can handle computers, because so much data is being generated and we can produce simulations and images in resolutions that we could only dream of a few years ago. So we need IT and technicians, but we also need doctors and people who do what we do.”