The Mystery Of The Microbes That Live Inside Tumors

The gut, mouth, nose, and skin are home to diverse communities of microbes that can be good or bad for our health. However, in recent years scientists have found microbes in a more surprising place: tumors .

It is common to think of tumors as simply masses of the patient's cells that malfunction and grow out of control. In fact, they are communities of many different cell types, which partly explains the difficulty in attacking them without damaging healthy tissue.

But tumors also harbor a collection of cells from other life forms: bacteria and fungi. Some thrive in the environment around the tumor, while others live within the cancer cells themselves. However, until recently it was not clearly understood what role microbes play in tumors.

Now, scientists are beginning to unravel whether these microorganisms are complicit in helping cancer cells develop or just bystanders trapped in the tumor. The answers could provide new approaches to treating and prevent cancer.

In a 2017 study, Ravid Straussman, a cancer biologist at the Weizmann Institute of Science in Rehovot, Israel, and his team showed that some bacteria that live inside pancreatic cancer can protect tumors by inactivating a chemotherapy drug. common. They discovered that a particular class of bacteria, known as Gammaproteobacteria, could break down gemcitabine, a drug used to treat various types of cancer, including those found in the bladder, breast, and pancreas. This helps the 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 in Japan retrospectively analyzed patients with advanced tumors who were treated with a chemotherapy drug and those who received an antibiotic in addition to chemotherapy, in an attempt to prevent or treat an existing infection. They also found that patients who received an antibiotic responded better to the 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 might have killed the tumor-associated bacteria and might have interfered with cancer treatment.

Straussman and his team now hope to build on these studies with a clinical trial involving pancreatic cancer patients who have failed their first-line treatment. They will give patients an antibiotic that works against Gammaproteobacteria, along with gemcitabine, to see if the antibiotic improves their results.

The bacteria could also play other roles in cancer besides protecting tumors from drug treatment. In 2020, Straussman's team analyzed more than 1,500 human tumors across 7 different types of cancer; namely, breast, lung, ovarian, pancreatic, melanoma, bone, and brain. They found that all types of tumors were invaded by bacteria, which lived inside cancer cells and some of the immune cells.

“Each of these bacteria has adapted to the unique tumor microenvironment in which they live”, says Straussman.“In lung cancer, we showed how people who smoke have more bacteria that can break down nicotine, which is a smoke-related metabolite. In bone tumors, we see bacteria that metabolize hydroxyproline, which is an enriched metabolite in bone tumors”.

In many cases, it is not yet clear whether the bacteria help the patient keep the cancer cells in check. Bacteria found in some types of breast cancer, for example, can detoxify arsenate, a type of carcinogen known to increase breast cancer risk. Others can produce a chemical called mycothiol, which helps reduce levels of reactive oxygen molecules that can damage DNA.

However, there is increasing evidence that, in some cases, the bacteria that live in tumors can make cancer worse.“There are more and more papers 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; in this regard, he adds“we are really scratching the surface”. Actually, Straussman says much more needs to be done to study the effects that bacteria inside tumors have on the course of disease.

A 2022 study by scientists in China suggests that some bacteria in breast tumors could make it easier for cancer cells to spread to other parts of the body. The researchers found bacteria living inside the breast tumor cells circulating in the blood of the mice. These cells break away 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.

The 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 rearrange the internal cellular 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 their ability to metastasize, even though the primary breast cancer continued to grow.“There is increasing evidence that specific microbes in the gut, skin and other mucosal organs, as well as in tumors, can either promote tumor growth and progression or alternatively antagonize it”, says Douglas Hanahan, M.D. from the Swiss Institute for Experimental Cancer Research in Lausanne, Switzerland.“The scenario is very complicated. Although there are clues, there is no definitive clarity on who does what”.

Other studies looked at an oral bacterium called Fusobacterium nucleatum, which is associated with gum disease but may also be linked to various types of cancer. It appears that these bacteria can migrate from the mouth to colorectal cancer cells through the bloodstream. Each bacterium carries specific particles on its surface that bind to the surface of cancer cells, allowing it to colonize them.

Once established, the bacteria can accelerate the growth and spread of tumors by 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. In addition, Fusobacterium nucleatum DNA 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 bacterium was introduced into mice with breast cancer, it accelerated the progression and spread of the disease. Giving the mice antibiotics prevented that process.

It may seem tempting to include antibiotics in cancer therapies, but it is not as simple as that. Many of the microbes in our bodies are benign or even beneficial, so a course of antibiotics could cause more harm than good, Hanahan says. 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 troublesome Fusobacterium nucleatum. However, certain strains of Escherichia coli, common bacteria found in the intestine, inactivate the drug.

At least 33 different types of cancer have been found to have colonies of bacteria associated with them, thanks to techniques developed at the University of California San Diego that search 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 tumor-associated bacteria in a patient's blood.

The team behind this study joined forces with Ravid Straussman to do research in 2022 that revealed 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 fungi, and those with fewer bacteria have less fungus”, Straussman says.“We can only assume at this point that some tumors are more restrictive for the presence of microbes, while some are more permissive”, he notes. As with bacteria, some of these fungi appear to be manipulating the immune system in favor of the tumor itself.

For example, the fungus Malassezia globosa has been found to accelerate the development of a form of pancreatic cancer. The same fungi have also been found in breast cancer patients who tend to have shorter overall survival, according to work by Straussman and colleagues at the University of California, San Diego.

Other research found that some fungi present in pancreatic tumors hijack parts of the immune system to promote tumor growth. A 2022 study also showed that stomach tumors rich in Candida fungi show increased expression of tumor genes that promote inflammation and that colon tumors rich in Candida DNA are more likely to be metastatic.“This could be because increased numbers of Candida may be associated with loss of the intestinal epithelial barrier [the cells that line the intestine]”, says Iliyan Iliev, a Cornell University microbiologist whose team conducted the research.

Despite the rapid pace of these findings, 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 in our fight against cancer?

In the coming years, targeting tumor microbes may become as important as going after the cancer cells themselves, leading to earlier diagnoses and even new treatments. However, that work is just beginning...

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