Uninhibited Helper
Just looking at the end suggests that the body is completely helpless against cancer - tumors have to overcome a quite impressive cellular defense bulwark before the worst can happen. And even then, it might still be worth lending a helping hand to the seemingly defeated organizer of the defense. The greatest enemy of cancer researchers is diversity: Too many things can go wrong in the human cell, too many things can be a trigger that ultimately causes the entire cell to degenerate malignantly. The dimensions of the problem are illustrated just by a brief look at the first estimate of the "metabolome" of a human body. Like the genes in the genome and the proteins in the proteome, all the molecules involved in the metabolic process are listed there – from the specially assembled sugar to the last lipid ingested with food [1]. In total, there are already 7,200 different substances on this vaguely complete list – the composition of which can vary dramatically if, for example, a single DNA base in the cells is not called A but C, and, hey presto, the amount of a certain substance ends up being around the factor 100 000 larger or smaller.
If you need to know exactly how the cell innards interact, for example to understand the fate that turns a liver cell into a liver tumor, you first have to get used to an unmanageable mass of potential suspects. And even in the case of success, he usually still knows nothing about why normal skin cells elsewhere degenerate into melanoma. For a brief moment it looked as if the entire variety of cancer might converge at one point in the metabolism of all cells. It was precisely there that people hoped to find a lever with which all types of cancer could be fought at the same time. The lever was dubbed p53 after its discovery in 1979: a gene that is deactivated in over half of all cancers, activating a metabolic mechanism that appears to be defective in some way in all cancers.
It quickly became clear that the gene, as a "tumor suppressor gene", is an unexpected universal emergency nail for the cell to prevent it from degenerating. With the p53 program, cells react to mutations in their DNA that occur, for example, under the influence of chemicals or hard radiation. If such damage activates the p53 gene, this ensures the construction of various signaling molecules that ultimately stop the cell cycle – i.e. the continuous cycle of cell work and cell division. If this pause for thought is not enough to repair the damage, p53 finally resorts to one of two possible drastic methods: either it initiates "senescence", the final stop in growth, which allows the cell to age inactively dividing until the end of its time - or it causes it right away for their quick suicide, apoptosis.
The p53 meaning is enormous: If any secondary mishap throws a spanner in the works, then the fate of cancer becomes much more likely. And so scientists have been working for decades to unmask possible misguided sand spreaders and render them harmless - also a game with many unknowns. Two working groups were now pursuing a different idea: Perhaps, according to researchers led by Scott Lowe from the Cold Spring Harbor Laboratory and a team led by Tyler Jacks from the Massachusetts Institute of Technology, it could instead be ensured that the p53 - way out is turned on again elsewhere?
The approach is not entirely new and has some pitfalls. As is well known, it is not enough to simply stimulate p53 production in tumor cells again: the protein that may then be produced again must be protected against degradation and stimulated to become active, among other things. In addition, the artificially stimulated p53 mechanism should only start its work in tumor cells, but not in he althy cells, for the survival of which it should normally remain silent.
The Lowe and Jacks teams therefore initially set about doing basic experiments to test the value of p53 activation and its potential danger for he althy cells. In both laboratories, mice were used as guinea pigs, which had been genetically modified in such a way that p53 was no longer produced, making the animals very susceptible to tumours. At the same time, the researchers made sure that the gene function could be switched on again at any time by supplying certain molecules from the outside.
The findings of both groups give hope: the condition of all mice with cancerous growths clearly improved when the tumor suppressor was suddenly switched on. In detail, for example, the liver cell tumors of mice in Lowe's laboratory stopped growing after p53 activation, as if they had entered typical senescence, and even began to shrink [2]; while Jack's rodents, which were increasingly suffering from blood cancer, suddenly began to switch off the degenerated cells via apoptosis under p53 guidance [3]. In addition, none of the investigators observed a concomitant adverse effect on he althy cells while the tumors were receiving the suppressor.
So far, so good - the hope that cancer can be fought by reactivating tumor suppressor genes is fueled by the results of Jack, Lowe and colleagues. It must be said, however, that both working groups had a decisive advantage over the tumor combatants on the medical practice front: In their model, the researchers knew at which point the p53 mechanism was interrupted, because after all, they had built in the predetermined breaking point themselves and then corrected it to be able to specifically close the development of tumors again.
Furthermore, painstaking, meticulous educational work in the cellular thicket remains essential to find out where which participants are torpedoing what in the p53 mechanism. In addition, p53 is only the most famous, but by no means the only tumor suppressor of the cell. Other researchers around Peiquing Sun, who were on the trail of the senescence-triggering activity of the not-so-famous p38, only publicize how complicated the overall picture "cancer" can be in individual cases. The researchers from the Scripps Research Institute discovered that in addition to the two well-known complicated signal chains that the cell can use to set p53 in motion with the help of various inhibitory and activating proteins, there is probably at least a third way. Without taking the details of this work into account: Sun and colleagues revealed another, previously unrecognized role of the already well-studied protein PRAK, which activates the suppressor p38, which has been known for a long time, at a previously unnoticed site [4].
The bottom line is that all current studies actually show new starting points for combating tumours. Of course, there can never be enough of these, regardless of whether they lead to the release of the brakes on the natural tumor defense system or the brakes on tumor triggers. For better or for worse, the fact that every possible fight strategy at the moment also increases the complexity of what is already an inscrutable process of cancer has to be accepted. With every newly discovered sophistication, the realism of our idea of cancer increases, so much optimistic realism must be.
