Mouth bacterium may cause colon cancer to spread

Mouth bacterium may cause colon cancer to spread

A diverse array of bacteria live in the human mouth as part of a vital ecosystem known as the oral microbiome. The researchers have discovered that one of these common bacteria can leave the mouth and potentially cause existing cancer cells in other parts of the body to spread.

These bacteria are believed to predominantly travel through the blood to different sites in the body where they are associated with serious infections of the brain, liver, and heart; preterm birth in pregnant women; and are present in high levels in colon tumors. Poor oral hygiene could cause the bacteria to migrate to other parts of the body where cancers exist. Also, evidence exists for a link between severe gum disease and colorectal cancer.

"Our team's discovery shows that infection with these bacteria initiates cancer cell migration," said the senior author. "This is vital information because 90 percent of cancer-related deaths result from nonprimary tumors or sites that have metastasized to somewhere else in the body."

The findings were published as the cover story in Science Signaling, which is produced by the American Association for the Advancement of Science.

Since 2012, multiple studies have shown this bacterium, Fusobacterium nucleatum, directly invades colon tumors, but questions remained as to how this bacterium is contributing to cancer.

A 2017 study showed that when human colon tumors containing F. nucleatum are put into a mouse, cancer cells containing live bacteria will break off and reattach in the liver, providing the first evidence that F. nucleatum could be directly involved in causing the spread of cancer cells throughout the body.

To address the potential of F. nucleatum driving metastasis, the researchers asked the broad question: How do human cells respond when colon cancer cells are infected with F. nucleatum? Their findings provide a deeper understanding of the critical role bacteria can play in cancer.

The relatively benign nature of F. nucleatum initially intrigued the team of researchers. At first glance, Fusobacterium nucleatum appears quite unremarkable and lives in harmony with other bacteria under the gums in the oral microbiome. Despite its role as a common bacterium in the mouth, the correlations with colon cancer were too strong to ignore.

According to the team, there is no evidence that this bacterium is directly initiating cancer. Also, this bacterium does not appear to be releasing molecules that are causing the cancer cells to migrate.

Instead, F. nucleatum sticks to and even enters cancer cells using the protein Fap2, which docks with sugars overrepresented on the surface of cancer cells. This in turn causes cancer cells to release two proteins known as IL-8 and CXCL1, which are members of the cytokine protein family that play critical roles in immune system activation against infections.

Strikingly, the cytokine combination of IL-8 and CXCL1 was previously shown in multiple studies to induce the spread of cancer cells. However, the team believe this is the first example of a tumor-associated bacterium producing this distinct cytokine combination.

These cytokines released by an infected cell then can talk back to the same cell or those signals can be sent out to other cancer cells, immune cells, and various other cell types that surround a tumor. In essence, one infected cell could be affecting multiple neighboring cells, so there doesn't have to be a widespread infection within a tumor for it to be influencing a large surrounding area.

In addition to IL-8 and CXCL1 contributing to cellular migration or metastasis, they are also potent immune cell attractants, which can lead to inflammation; a hallmark of cancer. The attraction and subsequent infection of immune cells known as neutrophils and macrophages by F. nucleatum could in turn lead to additional pro-cancerous proteins being released, which the authors show in this work..

F. nucleatum, a common bacteria that can leave the mouth and potentially cause existing cancer cells in other parts of the body to spread, pictured inside of colon cancer cells.