Discovery highlights how ongoing microbiome research points to new opportunities that can lead to development of more effective cancer screening clinical laboratory tests
New research from the Fred Hutchinson Cancer Center in Seattle once again demonstrates that the human microbiome plays a sophisticated role in many biological processes. Microbiologists and anatomic pathologists who diagnose tissue/biopsies will find this study’s findings intriguing.
This breakthrough in colon cancer research came from the discovery that a “subspecies” of a common type of a bacteria that resides in the mouth and causes dental plaque also “shields tumor cells from cancer treatment,” according to NBC News.
The scientists inspected colorectal cancer (CRC) tumors and found that 50% of those examined featured a subspecies of Fusobacterium nucleatum (F. nucleatum or Fn) and that this anaerobic bacterium was “shielding tumor cells from cancer-fighting drugs,” NBC News noted. Many of these tumors were considered aggressive cases of cancer.
“The discovery, experts say, could pave the way for new treatments and possibly new methods of screening,” NBC News reported.
“Patients who have high levels of this bacteria in their colorectal tumors have a far worse prognosis,” Susan Bullman, PhD (above), who jointly supervised the Fred Hutch research team and who is now Associate Professor of Immunology at MD Anderson Cancer Center, told NBC News. “They don’t respond as well to chemotherapy, and they have an increased risk of recurrence,” she added. Microbiologists and clinical laboratories working with oncologists on cancer treatments will want to follow this research as it may lead to new methods for screening cancer patients. (Photo copyright: Fred Hutchinson Cancer Center.)
Developing Effective Treatments
Susan Bullman, PhD, Associate Professor of Immunology at MD Anderson Cancer Center, who along with her husband and fellow researcher Christopher D. Johnston, PhD, Assistant Professor at Fred Hutchinson Cancer Center, jointly supervised an international team of scientists that examined the genomes of 80 F. nucleatum strains from the mouths of cancer-free patients and 55 strains from tumors in patients with colorectal cancer, according to the National Institutes of Health (NIH). The NIH funded the research.
The researchers targeted a subspecies of F. nucleatum called F. nucleatum animalis (Fna) that “was more likely to be present in colorectal tumors. Further analyses revealed that there were two distinct types of Fna. Both were present in mouths, but only one type, called Fna C2, was associated with colorectal cancer” the NIH wrote in an article on its website titled, “Gum Disease-related Bacteria Tied to Colorectal Cancer.”
“Tumor-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumor niche,” the Fred Hutch researchers wrote in their Nature paper.
“We have pinpointed the exact bacterial lineage that is associated with colorectal cancer, and that knowledge is critical for developing effective preventive and treatment methods,” Johnston told the NIH.
How Bacteria Got from Mouth to Colon Not Fully Understood
Traditionally, F. nucleatum makes its home in the mouth in minute quantities. Thus, it is not fully understood how these bacteria travel from the mouth to the colon. However, the Fred Hutch researchers showed that Fna C2 could survive in acidic conditions, like those found in the gut, longer than the other types of Fna. This suggests that the bacteria may travel along a direct route through the digestive tract.
The study, which focused on participants over 50, comes at a time when colorectal cancer rates are trending upward. Rates are doubling for those under 55, jumping from 11% in 1995 to 20% in 2019. CRC is the second-leading cancer death and over 53,000 will succumb to the disease in 2024, according to NBC News.
Many of the newer diagnoses are in later stages with no clear reason why, and the Fred Hutch scientists are trying to understand how their findings tie into the increase of younger cases of colon cancer.
Bullman says it will be important to look at “whether there are elevated levels of this bacterium in young onset colorectal cancer, which is on the rise globally for unknown reasons,” she told NBC News.
Possibility of More Effective Cancer Screening
There is hope that scientists equipped with this knowledge can develop new and more effective screening and treatment options for colon cancer, as well as studying the microbiome’s impact on other diseases.
On the prevention side, researchers have seen that in mice the addition of Fna “appeared to cause precancerous polyps to form, one of the first warning signs of colorectal cancer, though Bullman added that this causation hasn’t yet been proven in humans.” NBC reported.
Future research may find that screening for Fna could determine if colorectal tumors will be aggressive, NIH reported.
“It’s possible that scientists could identify the subspecies while it’s still in the mouth and give a person antibiotics at that point, wiping it out before it could travel to the colon,” Bullman told NBC News. “Even if antibiotics can’t successfully eliminate the bacteria from the mouth, its presence there could serve as an indication that someone is at higher risk for aggressive colon cancer.”
There is also the thought of developing antibiotics to target a specific subtype of bacteria. Doing so would eliminate the need to be “wiping out both forms of the bacteria or all of the bacteria in the mouth. Further, it’s relevant to consider the possibility of harnessing the bacteria to do the cancer-fighting work,” NBC noted.
“The subtype has already proven that it can enter cancer cells quite easily, so it might be possible to genetically modify the bacteria to carry cancer-fighting drugs directly into the tumors,” Bullman told NBC News.
Further studies and research are needed. However, the Fred Hutch researchers’ findings highlight the sophistication of the human microbiome and hint at the potential role it can play in the diagnosis of cancer by clinical laboratories and pathology groups, along with better cancer treatments in the future.
If the link between certain types of gut bacteria and improved effectiveness of certain cancer treatments can be leveraged, then medical laboratories could soon have another diagnostic tool to use in supporting physicians with cancer care
The goal of both studies was to determine whether there was a link between gut bacteria and the efficacy of cancer drugs known as PD-1 inhibitors. These drugs are used for several types of cancer, including:
Melanoma;
Lung;
Bladder; and,
Stomach cancers.
They function by freeing up the immune system to attack cancer cells.
Greater Bacterial Diversity in Gut Brings Improved Response to PD-1 Inhibitors
One of the studies, “Gut Microbiome Modulates Response to Anti–PD-1 Immunotherapy in Melanoma Patients,” found that a microbiome populated with “good” bacteria can elevate the potency of certain drug treatments. The researchers discovered that the gut bacteria in patients who responded well to PD-1 inhibitors differed from that found in patients who did not respond to the treatment.
For this study, researchers at the MD Anderson Cancer Center at the University of Texas collected oral, gut, and fecal microbiome samples and tumor biopsies from 112 patients with advanced melanoma. Clinical laboratorians took the samples before and after PD-1 treatments. They divided the patients into two groups—responders and non-responders—and profiled each microbiome using genetic sequencing.
“What we found was impressive: There were major differences both in the diversity and composition of the gut microbiome in responders versus non-responders,” Jennifer Wargo, MD, MMSc, leader of the study, told STAT. “Those who did well had greater bacterial diversity in their gut, whereas those whose tumors didn’t much shrink had fewer varieties of microbes present.”
Melanoma patients who experienced success with PD-1 therapy had a more diverse microbiome and higher concentrations of bacteria known as Ruminococcus and Faecalibacterium. Patients involved in the study who did not respond well to PD-1 therapy had the presence of another bacterium called Bacteroidales.
Jennifer Wargo, MD (above center) with her team at the MD Anderson laboratories. The researchers cautioned that clinical trials are needed before a definitive conclusion can be reached on whether altering gut bacteria can improve the effectiveness of PD-1 therapy. “If you’re changing the microbiome, depending on how you do it, it may not help you—and it might harm you,” Wargo emphasized in STAT. “Don’t try this at home.” (Photo copyright: MD Anderson.)
Antibiotics Can Reduce Effectiveness of PD-1Therapy
Researchers for this study, led by Laurence Zitvogel, MD, PhD, of the Gustave Roussy Cancer Campus in Villejuif, France, examined 249 patients who were given a PD-1 inhibitor for lung, kidney, or urinary tract cancers. A little over one fourth of these patients had recently taken antibiotics, which can strip the gut of essential bacteria necessary to treat infections.
The team found that patients who had ingested an antibiotic relapsed faster and did not live as long as patients who had not taken an antibiotic before receiving PD-1 therapy. When they analyzed variances between patients who responded well to treatment versus patients who did not, they detected the presence of Akkermansia muciniphila, a mucin-degrading bacterium, in the responders.
Personalized Treatment Based on Each Patient’s Gut Microbiome
The culmination of this type of research raises questions about how cancer medications may interact with microbiomes.
“Should we be profiling the gut microbiome in cancer patients going into immunotherapy?” asked Wargo in the STAT article. “And, should we also be limiting, or closely monitoring, the antibiotic use in these patients?
“This is all very context-specific, and multiple different factors need to be considered on how best to change the microbiome,” she continued. “When it comes to optimizing cancer therapy, treatments will have to be heavily personalized, based on what a patient’s gut microbiome looks like already.”
Diagnostic tests that could determine whether a certain drug will be beneficial for a patient would perform a critical role in healthcare decision-making. Since cancer drug treatments can cost tens of thousands of dollars or more, it would be advantageous to know which therapies would be optimal for individual patients. The hope is that in the future, clinicians, working with anatomic pathologists and clinical laboratories, will have the tools needed to ascertain if patient’s microbiomes will best work with a particular drug and if they would likely encounter any side effects.
IBM’s Watson continues to seek a role as a cognitive computing tool of choice for physicians and pathologists in need of evidence-based clinical patient data
Remember IBM’s Watson? It’s been five years since Watson beat human contestants on Jeopardy. Since then, IBM has hoped Watson could be used in healthcare. To that end, some oncologists are exploring the use of Watson in cancer care. This could have implications for anatomic pathologists if oncologists developed a way to use Watson in the diagnosing cancers and identifying appropriate therapies for those cancers.
In 2011, IBM’s Watson supercomputer defeated human contestants for a charity prize during the television show Jeopardy. Just days later, Dark Daily reported on IBM’s goal for Watson to play a major role in helping physicians diagnose and treat disease. Since then, IBM has been exploring ways to commercialize Watson’s cognitive computing platform through partnerships with some of the healthcare industry’s biggest brands. (more…)
