Why do some colorectal cancers not respond to chemotherapy? The answer may lie in the gut microbiota, where a bacterial toxin called colibactin 'trains' the cancer to resist treatment. This was discovered by a group of scientists from the Ifom (Firc Institute of Molecular Oncology) of Milan and the University of Turin, in a study published in 'Cell Reports Medicine', supported by the Airc Foundation and by the EU with a grant from ERC-European Research Council.
Chemotherapy is still a fundamental weapon against tumors today, especially intestinal ones, explain from Ifom and UniTo. Numerous drugs are available, some of which share the common mechanism of damaging the DNA of diseased cells, crumbling it piece by piece, until the tumor remains without 'instructions' and regresses. However, they are medicines which can also affect normal cells, with side effects that may preclude the continuation of treatment. Furthermore, not all intestinal cancers respond to the same drug from the beginning. Hence the need to optimize the therapeutic choice to maximize the benefit-risk ratio.
To do this, the researchers coordinated by Alberto Bardelli, Ifom scientific director and full professor at the University of Turin, have found a new strategy that involves a change of perspective. Instead of focusing only on the tumor to predict the possible response to chemo, they studied what is around the disease, i.e. the microbiota. It is “an incredible set of microorganisms that live in the intestine. If each one were a star, the microbiota would be 100 times the size of the Milky Way”, is the metaphor used by Bardelli. “The microbiota performs many important and positive functions for our body, but there are some bacteria that promote the development of cancer.” Not only that: treatments can also protect him, Italian researchers have now demonstrated.
“In particular – continues the Ifom scientific director – it is known that some species of Escherichia coli and other intestinal bacteria are capable of producing a specific toxin, colibactin, which has been found enriched in a fraction of colorectal tumors. This toxin is in capable of causing the transformation of normal intestinal cells into tumors by inducing mutations, alterations in the sequence of their DNA: the same target of chemotherapy drugs commonly used in clinic. We therefore asked ourselves if there could be a correlation, that is, if exposure to toxin could affect how tumors respond to treatment.”
“With the help of microbiologists from Professor David Lembo's group of the Department of Clinical and Biological Sciences of the University of Turin – explains Alberto Sogari, Airc researcher of the UniTo Oncology Department and first author of the study – we cultivated colorectal cancer cells in the laboratory and colibactin-producing bacteria, simulating what happens in the intestine. We used both cell lines and so-called organoids, innovative patient-derived models that recapitulate the three-dimensional structure of the tumors of origin, and we studied the functional impact of colibactin on cells with cutting-edge sequencing and bioinformatic analysis technologies.” In this way “we discovered that colibactin works as a sort of 'gym' for tumors: it trains tumor cells to withstand a constant load of DNA mutations, so when we start treatment with a chemotherapy drug that has a very similar mechanism used in the clinic, irinotecan, the tumor is already trained to tolerate the damage caused by chemotherapy and becomes resistant”.
The study opens new perspectives. The researchers have in fact observed that tumors 'trained' by colibactin can also respond to other chemotherapy approaches that act with a different mechanism. In other words, colibactin may represent a key biomarker for selecting the most effective therapeutic strategy. “Starting from our pre-clinical results – concludes Bardello – we began to analyze the presence of colibactin in clinical samples from patients at the Niguarda hospital in Milan, in collaboration with Professor Siena and Professor Sartore-Bianchi, to correlate the toxin to the clinical response to drugs. We have already obtained the first encouraging results which confirm the translational implications of our discovery.” The goal now is to validate this approach in the clinic, on larger numbers.
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