In the fight against disease and mortality caused by cancer, it is crucial to suppress the ability of tumors to destroy the healthy tissue around them.
Now, a new study, conducted on tumors derived from human tumors, reveals a possible way to do just that.
The study reveals a competitive mechanism used by human tumor cells to kill their healthy neighbors and shows that, by combining substances that block this mechanism and chemotherapies, it is possible to eliminate tumors more effectively. These results could lead to the development of new cancer therapies.
One of the reasons cancer cells resist the body's natural defenses so well is that these cells are actually human.
As such, they have the innate machinery that, in addition to allowing them to elude the body's defenses and maintenance systems, even makes them capable of using these mechanisms to their advantage. Therefore, the fight against cancer necessarily involves being able to understand all the “tricks” of cancer cells.
Eduardo Moreno, principal investigator at the Champalimaud Center in Lisbon, has just taken an important step in this direction, by discovering a new trick that malignant cells use: a cell competition mechanism, which he himself called “fitness fingerprints” (FF) – which loosely translates to something like “cellular fitness barcode”.
“We first identified this cellular barcode in 2010 in the fruit fly, Drosophila melanogaster. And now, in this new study published in the journal Nature, we were able to show that this cell competition mechanism also exists in humans and that its blockage interrupts the growth of human cancer cells”, says Moreno.
bad neighborhood
Moreno and his team found that in the body, cells are constantly assessing the good health – or fitness – of their neighbors using certain markers that all cells have on their surface.
“We found that there are actually two types of markers: the 'Win' (win), which indicate that the cell carrying these markers is young and healthy, and the 'Lose' (lose), which indicate that the cell is old and healthy. damaged,” explains Moreno. "When a cell is less fit than its neighbors, which means it has fewer Win markers or more Lose markers, those neighbors will eliminate it and thus ensure the health and integrity of the tissue as a whole."
According to Moreno, his team showed that the process is important for the normal development of the body, for tissue regeneration following trauma and for preventing premature aging. But it has also shown that it can be diverted from its normal goal and benefit tumor growth.
“Cancer cells use FF to disguise themselves as super-fit cells, which have a relatively much higher number of Win markers [than their healthy neighbors]. This makes the normal cells around the cancer cells look less healthy than the cancer cells in comparison. In this way, cancer cells are able to trick their healthy neighbors and lead them to death, thereby destroying normal tissue and creating space for tumor expansion.”
When FF were identified by Moreno's group in the fruit fly, it was not known whether this cell competition mechanism would also exist in humans, since different species can use different strategies to detect unwanted cells. In fact, Moreno himself thought that this mechanism would not be common among different species.
“FF can be very helpful, but they also significantly increase the risk of cancer as they make tumors more aggressive. Such a risk-benefit ratio may be acceptable in animals that live for a short time, such as the fruit fly, but in longer-lived animals, such as humans, it could represent too high a risk”, he stresses. However, after a series of experiments with human cancer cells, scientists have found that we humans, after all, also possess this double-edged mechanism.
Cellular fitness and cancer
To determine whether human cells express fitness barcodes and whether these are involved in cancer, two lab scientists, Rajan Gogna and Esha Madan, performed a series of experiments.
They started by identifying the gene that encodes these barcodes in the human genome. Once the gene was identified, they showed that it actually encodes four different types of FF: two types of Win and two types of Lose.
Next, to determine whether these FF had an impact on cancer growth, the team analyzed the expression of the four types of FF in different tissue types: (malignant) breast and colon cancer, benign breast and colon tumors , tissue adjacent to tumors and normal tissue (no tumor).
The analysis revealed several striking results. Notably that, in normal tissue, Win's expression was globally quite rare and Lose's even lower. And, on the other hand, that Win expression increased significantly in all tumors, but its levels were higher in malignant tumors than in benign ones.
More worryingly, the tumors appeared to be turning the fitness level in the surrounding tissue to their advantage: “Lose expression was substantially higher in tissues adjacent to tumors than in normal tissues. In addition, Lose levels were higher in tissues adjacent to malignant tumors than around benign tumors,” explains Gogna.
"In fact, further statistical analysis of the results showed that, from the expression levels of Win in the tumor and Lose in neighboring tissue, it is possible to correctly predict cancer malignancy in 86,3% of cases."
On the way to potential therapies
The team's results strongly suggest that high expression of Win markers in the tumor, coupled with high expression of Lose in tissues around the tumor, is a prerequisite for tumor growth. Therefore, scientists decided to test the effect of blocking this mechanism. To do this, they implanted human tumors into mice and canceled the expression of FF in those animals.
The results were promising: “we found that this manipulation significantly reduced the volume of tumors, that is, it reduced the destructive power of the tumor against the host tissue. However, this approach alone does not eliminate the cancer cells, but only slows down their progression,” explains Madan.
Next, to test the full therapeutic potential of this approach, the scientists decided to combine blocking the expression of FF and chemotherapy. This dual strategy worked very well: “we managed to further reduce, and in some cases completely eliminate the tumor!” says Gogna.
According to Moreno, this is another example of basic research, driven by curiosity, which ends up having important implications for human health.
“When we started to study cell competition in the fruit fly, we were trying to answer a fundamental question in biology: how do tissues manage to eliminate cells that, although they are viable, are not in optimal conditions? From there to potential cancer therapies, making the leap seems almost impossible, but that's how research works. It starts with the curiosity to understand how things work and, from there, the path sometimes leads us to the development of potential new therapies.”
Moreno's team now plans to further study the mechanism of cell competition, while continuing to collaborate with clinicians in the development of future cancer drugs. “These results are very encouraging, but they are still preliminary and it will take us a few years to be able to use them to help cancer patients”, he concludes.
Author Champalimaud Center
Science in the Regional Press – Ciência Viva
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