Researchers are studying how bacteria living in the tumor microenvironment and in our gut affect cancer progression and response to therapies

We now know that the healthy functioning of our bodies depends eavily on the integrity of our microbiota, the ecosystem of bacteria, viruses and fungi that populate virtually all of our organs and tissues, starting with the gut, where 70% of our microbiota resides. The fact that the microbiota plays a major role in the progression of cancer, as in so many other diseases, should thus come as no surprise. The number of microorganisms we harbor is greater than the number of our cells, and the DNA of these microorganisms is, collectively, 100 times greater than our own. Their metabolic activities are essential for many physiological functions, from digestion and absorption of nutrients in the gut to training and activation of the immune system.

In the case of cancer, the interaction between our cells and the microbiota is even more complex, as recounted in a recent scientific review published in Trends in Immunology and authored by Prof. Maria Rescigno, vice rector for research at Humanitas University and head of a frontier laboratory at Humanitas Research Hospital, where she is studying the microbiota and its effects on our health.

Indeed, studies tell us that the microbiota is capable of influencing both cancer cells and immune system cells, and that it can do that in two ways: remotely, by releasing molecules into the gut (the so-called postbiotics) that rapidly enter the bloodstream and influence disease progression; and proximally, by directly colonizing the tumor microenvironment and altering the functioning of cancer cells.

“The outcome is varied and complex. Depending on the type of tumor, the specific family of bacteria or fungi, and their location – in the gut or in the tumor microenvironment – these microorganisms may have an antitumor versus a protumoral activity,” explains Maria Rescigno. “But we are just at the beginning: we need to continue research on microbiota and cancer if we want to understand how to harness the former and hinder the latter, paving the way for new therapies.”

The role of the intratumoral microbiota in metastasis formation

Metastasis represent a step change in disease progression: diseased cells acquire the ability to migrate from the primary site, where they originated, and reach and colonize new organs. Before the 1800s, it was thought that cancer cells, once they are metastatic, migrate and proliferate in the first tissue they encounter. Today we know, on the contrary, that the site of metastasis formation depends on specific factors, including the type of tumor. Breast cancer, for example, tends to metastasize to the bone first; pancreatic cancer, to the liver. Recent studies, however, have found that the bacteria we harbor also play a role in the process.

For example, we know that some of these bacteria, if present in the tumor, are capable of accelerating the process of metastatization or changing their target organ. In the case of colorectal cancer, on the other hand, it is the microbiota residing in the intestine that influences the process of metastasis formation: due to the weakening of the intestinal barrier, some populations of bacteria enter the bloodstream and reach the liver, where they prepare the tissue to receive metastatic cells, creating a favorable niche for their arrival.

Fortunately, not all microbiota support disease progression: there are also bacteria or fungi that, if present in the tumor microenvironment, are capable of exerting a positive action, inhibiting cell proliferation and their migratory capacity.

The influence of the microbiota on the efficacy of therapies

The microbiota residing in tumor tissues, in addition to influencing disease progression, plays also a role in modulating the tumor’s response to therapies. Certain populations of bacteria, for example, have been shown to protect nearby tumor cells by absorbing chemotherapy drugs (such as gemcitabine) and transforming it into an inactive form that no longer poses a threat to the cancer. In a laboratory study, researchers tried to defuse this protective mechanism by combining the chemotherapy with an antibiotic, thus weaking the protective action of the bacteria. The result is better disease control, at least in a laboratory model.

Once again, however, we need to avoid generalizations: continued treatments with antibiotics are a known risk factor for several types of tumors, from breast to colon cancer, from prostate and bladder to lung cancer; and we know conversely that a healthy gut microbiota is associated with greater efficacy of immunotherapies. All of this evidence suggests the need for targeted approaches to the use of antibiotics, whose effect on the gut microbiota may prove detrimental to the immune system’s ability to respond to cancer.

“The more we study the microbiota and the mechanisms by which it influences tumor progression, the more we realize how much the organism as a whole – the healthy cells, the cancer cells and the microorganisms that inhabit us – behaves like a complex ecosystem,” says Prof. Rescigno. “Potential therapeutic targets lay at the interactions between the elements of the system: it is our goal to identify the meaningful interactions and turn them into opportunities to improve cancer therapies.”