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Virginia Tech researchers have discovered that a species of bacteria commonly found in the mouth can migrate around the body via the blood and trigger existing colorectal cancer cells (CRC) to spread, or metastasize. Studies have previously linked Fusobacterium nucleatum with colorectal tumors, increased tumor microenvironment inflammation, and poor patient prognosis. The new findings indicate that the bacterium may also directly and indirectly modulate immune and cancer cell signaling and migration.

“Our team’s discovery shows that infection with these bacteria initiates cancer cell migration,” said Daniel Slade, PhD, who is an assistant professor in the department of biochemistry in the College of Agriculture and Life Sciences, and an affiliated researcher in the Fralin Life Sciences Institute. “This is vital information because 90% of cancer-related deaths result from nonprimary tumors or sites that have metastasized to somewhere else in the body.”

Slade and colleagues reported their results in Science Signaling, in a paper titled, “Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration.”

Over recent years multiple studies have shown the bacterium, Fusobacterium nucleatum, directly invades colon tumors. “Fusobacterium nucleatum is implicated in accelerating CRC and is found within metastatic CRC cells in patient biopsies,” the authors wrote. These bacteria are believed to predominantly travel through the blood to different sites in the body where they are also associated with serious infections of the brain, liver, and heart, and preterm birth in pregnant women. 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.

Fusobacterium nucleatum (Green) inside of human colon cancer cells (Red, Blue). [Image courtesy of Daniel J. Slade]
However, questions remain as to how this bacterium is contributing to cancer, and studies have thrown up just as many questions as they have found answers for the mechanisms and proteins that the bacterium might use to potentiate disease. “An overarching question in the field is: How does F. nucleatum enter and reside in tumors after likely arriving via the bloodstream from its native oral cavity?” the scientists noted. “… a second theme of pathogenesis that remains understudied is: Are these bacteria capable of leaving the primary tumor on or within immune or cancerous cells to seed and accelerate metastatic cancer sites?” Finding answers to these questions will help to understand both host and bacterial mechanisms involved in such “microbe-accelerated cancers.”

A 2017 study showed that when human colon tumors containing F. nucleatum are put into a mouse, cancer cells containing live bacteria break off and reattach in the liver, providing initial evidence that F. nucleatum could be directly involved in causing the spread of cancer cells throughout the body. To address the potential for F. nucleatum to actually driving metastasis, the Virginia Tech researchers wanted to know how human cells respond when colon cancer cells are infected with F. nucleatum.

The relatively benign nature of F. nucleatum initially intrigued the Slade team. The bacterium appears quite unremarkable and lives along with other bacteria under the gums as part of the oral microbiome. Yet despite its role as a common bacterium in the mouth, the correlations with colon cancer couldn’t be ignored.

“Dan convinced me that this bacterium was a viable research direction as a bacterium that could directly influence the behavior of cancer cells,” said co-author Scott Verbridge, PhD, associate professor in the Virginia Tech department of biomedical engineering and mechanics in the College of Engineering, and principal investigator of the Laboratory of Integrative Tumor Ecology. “He had developed the ability to genetically modify this bacterium. He had some amazing technology to culture this bacterium with cancer cells that was beyond anything that we could do in my lab.”

According to Slade and his team, there was no evidence that the bacterium was directly initiating cancer, and it didn’t appear to be releasing molecules that would cause the cancer cells to migrate. Rather, the studies have shown that F. nucleatum can stick to and even enter 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 the cytokines IL-8 and CXCL1, which play critical roles in immune system activation against infections.

The two cytokines released by an infected cell can then talk back to the same cell, or signal 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.

Daniel Slade, PhD, left, and Scott Verbridge, PhD, right, research how poor oral hygiene could cause the bacteria to migrate to other parts of the body where cancers exist. [Virginia Tech]
Slade and his team believe this is the first example of a tumor-associated bacterium producing this distinct cytokine combination. Previous research had shown that the combination of IL-8 and CXCL1 induce the spread of cancer cells. “Multiple studies have characterized their role in influencing CRC invasiveness,” the authors stated.

In addition to their contribution to cellular migration or metastasis, IL-8 and CXCL1 are also potent immune cell attractants, which can lead to inflammation, another hallmark of cancer. A key contributor to the team in understanding the interactions of F. nucleatum with immune cells was Liwu Li, a professor in the department of biological sciences and an affiliated researcher in the Fralin Life Sciences Institute. The studies indicated that the attraction and subsequent infection of neutrophils and macrophages by F. nucleatum could in turn lead to additional procancerous proteins being released. “In our study presented here, the results indicate that direct binding and invasion of host cancer and immune cells by F. nucleatum induce the secretion of the proinflammatory and prometastatic cytokines interleukin-8 (IL-8) and C-X-C motif chemokine ligand 1 (CXCL1),” the investigators wrote. “CXCL1 and IL-8 both play roles in immune cell recruitment, particularly neutrophil recruitment and programming. Through paracrine signaling, F. nucleatum interactions with CRC cells could be releasing factors that create not only a metastatic environment but also one that provides protumor inflammation.”

Identifying prometastatic human proteins that are released by cancer cells upon bacterial infection has opened the door for future research. The long-term goal of Slade and colleagues is to progress cancer treatment, by addressing the role bacteria play in disease. The newly reported results provide new insights into how bacteria influence cancer. While this process was shown to occur with colorectal cancer cells, the team is exploring if the same process is influencing other types of cancer, including pancreatic cancer, breast cancer, and oral squamous cell carcinoma of the mouth.

The newly reported results also hint that blocking the release of cytokines could feasibly combat metastasis induced by bacteria. This is an attractive alternative to using antibiotics to kill F. nucleatum, as antibiotics might also clear beneficial bacteria. Also, the authors suggested, “… because the consensus belief is that F. nucleatum leaves the oral cavity and traverses the human body through the blood and potentially lymph, it could be advantageous to use a vaccine-based strategy whereby antibodies block and clear this bacterium before leaving the bloodstream, thereby preventing downstream tumor interactions … Hence, interfering with F. nucleatum interactions in the human body could be a targeted approach that provides an alternative to using nonspecific antibiotics.”

“We need to know if there are other important bacteria that could be working in synergy with F. nucleatum to drive cancer, Verbridge said. “We need to understand the physiological role of these bacteria as we can’t just go about clearing them from the body because we need them for some situations. Oftentimes, bacteria are needed for chemotherapy to be fully effective … I also think it’s interesting to ask if the bacteria are causing this cellular migration as a way to get around in the human body. There could be a selective advantage for any infectious agent, a virus or bacteria, that could get inside of a host cell and migrate.” This could be particularly important for F. nucleatum which is classified as a nonmotile bacterium, as it lacks the machinery, such as flagella, that drive movement.

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