Spanish biochemist Mariano Barbacid, one of the pioneers in the discovery of oncogenes, has recently referred to current cancer drugs as “poisons,” which, in fact, they most certainly are. As any patient undergoing chemotherapy can attest to, the side effects of the treatments are devastating. In order to attack cancer, it is currently necessary to poison the whole body, trusting that it will be the most proliferative cells, (i.e., the tumour cells) that die first.
However, this should not be the case. The future of the fight against cancer involves designing more specific and harmless therapies for the body, and an intense line of current research indicates what they should be targeting: cancer stem cells, a small and select group of cells that act as a factory and food source for the tumour. Researchers think that by destroying this incubator the cancer would end, or at least it could be treated as a chronic disease with which the patient could coexist until old age.
In 1994, Canadian biologist John Edgar Dick, from the University of Toronto, discovered that when human leukaemia was transplanted to immunodeficient mice only a few cells from the blood sample were able to spread the cancer in the animals; specifically, he calculated that it was one in every quarter million. This observation by Dick was not strictly novel: in previous decades, other researchers had already noticed that only a minority of cells in a tumour were capable of reproducing cancer.
A stronghold of rebellious cells
But in Dick’s study there was something else, the realisation that these cells possess markers typical of blood stem cells. At a time when the field of stem cells was in full swing, the somewhat veiled reference to these cells in cancer did not attract much attention. But when Dick showed that his cells were also present in other types of leukaemia, that they renewed themselves indefinitely and that they generated a hierarchy of other cell types in the tumour, the eyes of the scientific community turned to his findings. The hypothesis of cancer stem cells had emerged: the idea that this disease is born, feeds and spreads from a stronghold of rebellious cells originally similar to those that serve to repopulate tissues.
In subsequent decades, Dick’s hypothesis has illuminated one of the most promising areas of research in the battle against cancer. However, it is still debated as to what extent these cancer stem cells are a signature characteristic of all the multiple types of malignant tumours. “The view of their relevance is complex,” says Dick to OpenMind. “The evidence is clear for many tumours such as brain, colon, acute myeloid leukaemia, skin and many others.” However, continues the researcher, in other cases such as liver cancer there is no conclusive evidence yet.
Progress in regenerative medicine research has revealed a thread that converges with Dick’s theory, showing that the great risk of renewing organs with stem cells from patients is the possibility that they act as seeds for a tumour. “When the cell has stemness properties it is bad, no matter how it gets there,” says Dick.
The theory of cancer stem cells has provided an argument to explain why chemotherapy is not always as effective as might be expected. These treatments mainly affect cells that divide more wildly, but this is not the case with cancer-initiating cells, which have a slower rhythm, similar to that of normal somatic stem cells. “People are beginning to find out why cancer stem cells resist therapy and trying to break that barrier,” says Dick. One way to achieve this, adds the researcher, is to find a way to activate these sleeping cells to sensitise them to drugs.
The high command of the tumour hierarchy
But at the same time, the fact that these cells are different from the rest opens up another avenue for treatment: understanding their peculiarities will allow researchers to design therapies that exploit the weak points of this high command of the tumour hierarchy. For example, one of the most immediate possibilities would be to direct the drugs to their target —by means of antibodies that recognise the specific molecular markers present on the surface of the cancer stem cells.
In recent years, various studies have revealed some peculiarities in the metabolism of these cells. For example, it has been noted that at least some of them are highly dependent on the elevated activity of the mitochondria (the cells’ energy centres). And that they can take advantage of certain environmental conditions of the tumour itself, such as high acidity and a lack of oxygen and nutrients. “Often cancer stem cells have unique ways of dealing with stress signalling, and so modulating that is also being done,” says Dick.
Another approach is to tackle the processes that give rise to cancer stem cells; the problem is that these processes are not yet known with certainty. In the case of epithelial tumours, a critical mechanism could be the epithelial-mesenchymal transition (EMT), by which epithelial cells lose their differentiation and become stem cells capable of migrating to other parts of the body and originating different cellular types. This phenomenon is key in the development of the embryo and the healing of wounds, but also in metastatic tumours. Some studies indicate that EMT also has the potential to convert normal tumour cells into cancer stem cells.
In this vein, a recent study has managed to use drugs to induce mammary tumour cells to enter EMT and then lose their character as stem cells to differentiate into harmless adipocytes (fat cells). It is still a preliminary investigation in mice, but it is a suggestive example that strongly supports the possibility of taming these rebellious cells. In the words of Dick, this amounts to being able to look inside the black box of cancer.