Cancer: The mystery of the microbes that live in tumors – 07/07/2023 – Science

Our bodies are also habitats for other forms of life.

The gut, mouth, nose and skin are home to diverse communities of microbes that can be good or bad for our health.

In recent years, scientists have found evidence of the existence of microbes in an even more surprising place: tumors.

It is common to think of tumors as simply cellular changes that have overgrown. But they are actually communities of many different cell types, which partly explains the difficulty of eliminating them without damaging healthy tissue.

Tumors, however, also harbor a collection of cells from other forms of life: bacteria and fungi. Some thrive in the environment around the tumor, while others live inside the cancer cells themselves.

Until recently, it was not clear what role microbes played in tumors. Now scientists are starting to unravel whether these microorganisms are accomplices helping cancer cells to develop or just bystanders trapped in the tumor.

The answers to this question could help in the development of new approaches to treat and prevent cancer.

Bacteria that protect tumors

In a 2017 study, Ravid Straussman, a cancer biologist at the Weizmann Institute of Science in Israel, and his team proved that some bacteria that live inside tumors in the pancreas can protect them from common chemotherapy drugs.

They discovered that a particular class of bacteria, known as Gammaproteobacteria, could stop the effect of gemcitabine, a drug used to treat several types of cancer, including those found in the bladder, breast and pancreas. That is, it helps tumors become resistant to the drug.

When the team injected the bacteria into mice with colon cancer, the tumors also became resistant to the drug. But when the researchers gave the mice an antibiotic along with the chemotherapy drug, the resistance disappeared.

In addition to these findings, research published in 2019 by a team at Tohoku University, Japan, retrospectively analyzed patients with advanced tumors treated with chemotherapy alone and others who received antibiotics in addition to chemotherapy, in an attempt to prevent or treat an existing infection.

They found that patients given antibiotics responded better to treatment.

Although the study did not look at the number of bacteria present in the cancerous tissue of these patients, the researchers speculated that the antibiotics may have killed the tumor-associated bacteria and interfered with the treatment of the cancer.

Current studies may offer important clues about what happens inside tumours.

Straussman and his team now hope to advance their research by conducting a clinical trial involving patients with pancreatic cancer who have failed even with first-line treatments.

They will give patients an antibiotic that works against the Gammaproteobacteriaalong with gemcitabine, to see if the antibiotic improves your results.

Bacteria that make cancer worse

The bacterium may also play other roles in cancer patients, in addition to protecting tumors from drug treatment.

In 2020, Straussman’s team analyzed more than 1,500 human tumors in seven different types of cancer: breast, lung, ovary, pancreas, melanoma, bone and brain. They found that all types of tumors were invaded by bacteria, which lived inside the cancer cells and in some of the immune system cells.

Different types of tumors had different communities of bacteria. “Each of these bacteria has adapted to the unique tumor microenvironment they live in,” says Straussman.

“In lung cancer, we showed how people who smoke have more bacteria that can break down nicotine, which is a metabolite related to smoke.”

In bone tumors, we see bacteria that metabolize hydroxyproline, which is an enriched metabolite in bone tumors.”

In many cases, it remains unclear whether the bacteria helps the patient keep cancer cells in check.

Bacteria found in some types of breast cancer, for example, can detoxify arsenate, a type of carcinogen known to increase the risk of breast cancer.

Others can produce a chemical called mycothiol, which helps reduce levels of reactive oxygen molecules that can damage DNA.

However, there is growing evidence that, in some cases, the bacteria that live in tumors can make the cancer worse.

“There is more and more work showing how they can be part of carcinogenesis”, says Straussman.

The bacteria can also alter the immune system’s ability to attack and destroy cancer cells, he adds. “We are really scratching the surface.”

Straussman says much more needs to be done to study the effects that bacteria inside tumors have on the course of the disease.

some clues

There are some clues. A 2022 study by scientists in China suggests that some bacteria in breast tumors may make it easier for cancer cells to spread to other parts of the body.

The researchers found bacteria that live inside breast tumor cells circulating in the blood of mice. These cells slough off from the primary tumor and can travel to other parts of the body, metastasize and grow.

However, as tumor cells circulate through the bloodstream, they are subjected to stress that causes some of them to rupture.

Chinese researchers found that the microbes inside these mobile tumor cells appear to protect them from some of the stress they experience. In doing so, they help reorganize the cell’s internal support structures, known as the cytoskeleton, to make cells more robust.

When the scientists removed these bacteria from tumors in mice, the lesions appeared to lose the ability to metastasize, although the primary breast cancer continued to grow.

“There is growing evidence that specific microbes in the gut, skin and other mucosal organs, as well as in tumors, can promote tumor growth and progression or, alternatively, antagonize it,” says Douglas Hanahan, MD at the Swiss Experimental Institute for Cancer in Lausanne, Switzerland.

“But it’s very complicated. While there are clues, there’s no definitive clarity on who does what.”

bacteria that migrate

Other studies looked at an oral bacteria called Fusobacterium nucleatumwhich is associated with gum disease, but may also be linked to several types of cancer.

Apparently, these bacteria can migrate from the mouth to colorectal cancer cells through the bloodstream.

Each bacteria carries specific particles on its surface that attach to the surface of cancer cells, allowing it to colonize them.

Once established, the bacteria can accelerate the growth and spread of tumors, hampering the immune system’s ability to kill cancer cells.

The bacterium also deploys a molecular arsenal that makes cancer cells more resistant to chemotherapy.

Furthermore, the DNA of Fusobacterium nucleatum was found in human breast cancer samples. This suggests that it also affects tumors in other parts of the body.

In one study, when the bacteria was introduced into mice with breast cancer, it accelerated the progression and spread of the disease. Giving the mice antibiotics prevented this process.

The risk of antibiotics

It may seem tempting to include antibiotics in cancer therapies, but it’s not that simple.

Many of the microbes in our bodies are benign or even beneficial, so a course of antibiotics could do more harm than good, says Hanahan.

Instead, researchers must try to unravel the full complexity of the tumor-associated microbiome. Entire communities of microbes can be found within tumors, supporting each other in unexpected ways.

One such example revolves around the main drug used to treat patients with colorectal cancer, 5-fluorouracil (5-FU), which appears to inhibit the growth of the nuisance. Fusobacterium nucleatum.

However, certain strains of Escherichia colicommon bacteria found in the gut, inactivate the drug.

It was discovered that at least 33 different types of cancer have colonies of bacteria associated with them, thanks to techniques developed at the University of California at San Diego (USA), which look for their DNA.

The researchers believe the techniques could also be used to develop new ways to diagnose cancer by looking for the DNA of different bacteria associated with tumors in a patient’s blood.

The presence of fungi

The team behind this study joined forces with Ravid Straussman to do research in 2022 that revealed that another type of microbe, fungi, also lives in tumors.

They found fungi in 35 types of cancer, many of which harbor different combinations of species.

“We found that tumors that have more bacteria also have more fungus, and those with less bacteria have less fungus,” says Straussman.

“We can only assume at this point that some tumors are more restrictive for the presence of microbes, while others are more permissive,” he says.

Like bacteria, some of these fungi appear to be manipulating the immune system in favor of the tumor.

It was found that the fungus malassezia globosa accelerates the development of a form of pancreatic cancer. The same fungi have also been found in breast cancer patients who tend to have a shorter overall survival, according to work by Straussman and colleagues at the University of California San Diego.

Other research has found that some fungi present in pancreatic tumors hijack parts of the immune system to promote tumor growth.

A 2022 study also showed that fungal-rich stomach tumors candida show increased expression of tumor genes that promote inflammation and that colon tumors rich in DNA from candidate are more likely to be metastatic.

“This may be because the increase in the number of candidate may be associated with loss of the intestinal epithelial barrier [as células que revestem o intestino]”, says Iliyan Iliev, a microbiologist at Cornell University, in the USA, whose team conducted the research.

Despite the rapid pace of these discoveries, many questions remain about the relationship between tumors and the microbes that live in them.

Do microbes play a role in tumor development in the first place? Or are they simply opportunistic residents who have adapted to protect their cancerous home when they find it? Can this community of microbes be harnessed to help us treat cancer?

In the coming years, studying tumor microbes could become as important as going after the cancer cells themselves, leading to earlier diagnoses and even new treatments.

However, this work is just beginning.

Read the original version of this report (in English) on the BBC Future website.